This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Matthaei, S. Articles by Häring, H.-U. Search for Related Content PubMed PubMed Citation Articles by Matthaei, S. Articles by Häring, H.-U.

Pathophysiology and Pharmacological Treatment of Insulin Resistance¹

Department of Internal Medicine IV (Endocrinology, Metabolism, Angiology, Pathobiochemistry and Clinical Chemistry), University of Tübingen, D-72076 Tübingen, Germany

	Abstract

Top Abstract I. Introduction II. Pathophysiology and... III. Pharmacological Treatment IV. Perspectives V. Summary and Conclusion References

 
Diabetes mellitus type 2 is a world-wide growing health problem affecting more than 150 million people at the beginning of the new millennium. It is believed that this number will double in the next 25 yr. The pathophysiological hallmarks of type 2 diabetes mellitus consist of insulin resistance, pancreatic ß-cell dysfunction, and increased endogenous glucose production. To reduce the marked increase of cardiovascular mortality of type 2 diabetic subjects, optimal treatment aims at normalization of body weight, glycemia, blood pressure, and lipidemia. This review focuses on the pathophysiology and molecular pathogenesis of insulin resistance and on the capability of antihyperglycemic pharmacological agents to treat insulin resistance, i.e., -glucosidase inhibitors, biguanides, thiazolidinediones, sulfonylureas, and insulin. Finally, a rational treatment approach is proposed based on the dynamic pathophysiological abnormalities of this highly heterogeneous and progressive disease.

I. Introduction

II. Pathophysiology and Pathogenesis of Insulin Resistance

A. Introduction

B. Multiple sites of insulin resistance: muscle, liver, and adipose tissue

C. Pathogenesis of insulin resistance

D. Inactivity-related insulin resistance

E. Molecular events in obesity-related insulin resistance

III. Pharmacological Treatment

A. -Glucosidase Inhibitors

B. Biguanides

C. Thiazolidinediones

D. Insulinotropic agents

E. Insulin

IV. Perspectives

A. Agents to enhance insulin action

B. Agents to increase insulin secretion

C. Agents to inhibit fatty acid oxidation

V. Summary and Conclusion

	I. Introduction

Top Abstract I. Introduction II. Pathophysiology and... III. Pharmacological Treatment IV. Perspectives V. Summary and Conclusion References

 
DIABETES mellitus type 2 represents the final stage of a chronic and progressive syndrome representing a heterogeneous disorder caused by various combinations of insulin resistance and decreased pancreatic ß-cell function caused by both genetic and acquired abnormalities (1, 2, 3, 4, 5, 6, 7). Currently, type 2 diabetes mellitus is diagnosed when the underlying metabolic abnormalities consisting of insulin resistance and decreased ß-cell function cause elevation of plasma glucose above 126 mg/dl (7 mmol/liter) in the fasting state and/or above 200 mg/dl (11.1 mmol/liter) 120 min after a 75-g glucose load (8). However, the fact that many newly diagnosed type 2 diabetic subjects already suffer from so called "late complications of diabetes" at the time of diagnosis (9) indicates that the diagnosis may have been delayed and, in addition, that the prediabetic condition is harmful to human health and requires increased awareness by physicians and the general public. Thus, type 2 diabetes mellitus represents only the "tip of the iceberg" (Fig. 1) of long existing metabolic disturbances with deleterious effects on the vascular system, tissues, and organs. Consequently, urgent efforts are required to avoid the growing number of patients with this form of a "silently killing" metabolic disease.

View larger version (77K): [in this window] [in a new window]   Figure 1. Diabetes mellitus type 2: the tip of the iceberg. This simplified schematic presentation illustrates the evolution of type 2 diabetes mellitus. Diabetes mellitus type 2 represents the end stage of long lasting metabolic disturbances caused by insulin resistance associated with hyperinsulinemia, obesity, dyslipoproteinemia, arterial hypertension, and consequently premature atherosclerosis. Since this detrimental metabolic milieu is present for many years before plasma glucose levels (as our diagnostic indicator) are elevated, it is not surprising that type 2 diabetic patients have already micro- and/or macrovascular complications at the time of the initial diagnosis. Subjects in stage I have normal glucose tolerance due to the ability of their ß-cells to compensate for the insulin-resistant state. At this stage elevated triglyceride levels and reduced HDL levels as well as an increased waist to hip ratio may indicate insulin resistance and should lead to therapeutic action. In stage II, glucose tolerance after an oral glucose load (75 g) is impaired due to developing insulin-secretory deficiency. To avoid progression to clinically overt type 2 diabetes (stage III), these IGT subjects must receive treatment options to reduce insulin resistance, such as dietary advice and increase of physical activity. The stage model of the pathophysiology of type 2 diabetes has been adapted from Beck-Nielsen and Groop (9 ).

After an introduction into the pathophysiology and molecular pathogenesis of insulin resistance, this review will focus on the mechanism of insulin action and the capability of the available antihyperglycemic pharmacological agents to treat insulin resistance. In the conclusion a rational treatment approach, based on the dynamic pathophysiological abnormalities of the disease, is proposed. The importance of optimal treatment of other abnormalities often associated with type 2 diabetes, i.e., obesity, hypertension, dyslipidemia, disturbances in the fibrinolytic system, becomes evident when the pathophysiology of the type 2 diabetic syndrome is examined closely (see Fig. 1). These essential aspects in the medical care of type 2 diabetic patients have been recently reviewed (14, 15, 16, 17, 18, 19, 20) and thus will not be covered in this review.

	II. Pathophysiology and Pathogenesis of Insulin Resistance

Top Abstract I. Introduction II. Pathophysiology and... III. Pharmacological Treatment IV. Perspectives V. Summary and Conclusion References

 
A. Introduction
Clinically overt type 2 diabetes is characterized by ß-cell dysfunction and insulin resistance in all major target tissues, such as skeletal muscle, liver, kidney, and adipose tissue. Various studies have been performed in genetically predisposed individuals to elucidate whether insulin resistance or ß-cell dysfunction represents the primary defect in the pathogenesis of type 2 diabetes (reviewed in Ref. 1). These studies provided evidence that both insulin resistance and ß-cell dysfunction are prevalent in offspring of type 2 diabetic subjects. Although ß-cell dysfunction and insulin resistance are well accepted as pathogenetic factors of type 2 diabetes, there is still controversy whether these defects have a primary genetic origin or occur secondarily due to other factors. This debate has been recently summarized in the reviews by Gerich (1) and Ferrannini (4). There is also an ongoing discussion on which target tissue is mainly affected by insulin resistance (reviewed in Refs. 2, 21). Therefore, the contribution of the different target tissues to insulin resistance will be discussed in the following section.

B. Multiple sites of insulin resistance: muscle, liver, and adipose tissue
The term "insulin resistance" in humans is frequently used synonymously with impaired insulin-stimulated glucose disposal (3, 22, 23) as measured with the hyperinsulinemic-euglycemic clamp technique (24). Consequently, basic research in the area of insulin resistance as a fundamental component of the pathogenesis of type 2 diabetes has focused on tissues responsible for insulin-mediated glucose uptake, namely muscle and, to a minor degree, adipose tissue (5). However, it is well known that not only muscle glucose uptake but also adipose tissue lipolysis and suppression of glucose production are regulated by insulin.

1. The euglycemic-hyperinsulinemic clamp for the assessment of insulin resistance in vivo. It is unquestioned that in conditions commonly associated with the term "insulin resistance," such as obesity or type 2 diabetes, peripheral glucose disposal, as measured by a hyperinsulinemic-euglycemic clamp, is lower for the level of hyperinsulinemia achieved compared with healthy subjects. However, it is important to point out that, in people with type 2 diabetes, glucose uptake by skeletal muscle, both in the fasting state and postprandially, although inefficient for prevailing insulin levels, is not reduced in an absolute sense (25, 26, 27). In an attempt to identify "insulin resistance genes" underlying the disease (9, 28, 29), the hyperinsulinemic-euglycemic clamp has also been used to determine insulin resistance in healthy subjects with a first-degree family history of type 2 diabetes, who are of normal weight and whose glucose tolerance is normal. The classical hyperinsulinemic-euglycemic clamp, however, generates insulin levels above those these subjects usually experience and may therefore fail to reveal potential abnormalities of processes regulated by lower insulin concentrations. The manner in which insulin sensitivity is determined during the hyperinsulinemic-euglycemic clamp (using MCR, i.e., glucose infusion rate divided by plasma glucose at steady state) is based upon the assumption [unless appropriate tracer techniques are used (30)] that endogenous glucose production [largely attributable to liver, less so to kidney (31)] is completely shut off by the insulin infusion. This implies, however, that suppression of glucose production is regulated by much lower insulin concentrations than stimulation of glucose uptake. This should make the liver (and kidney) a target for insulin resistance whose effects on glucose homeostasis would be at least as important as those of muscle insulin resistance. In fact, excessive basal glucose production in the presence of fasting hyperinsulinemia is a key feature of type 2 diabetes (32, 33, 34, 35). Moreover, defective suppression of endogenous glucose production by normal or elevated insulin levels has been observed in type 2 diabetes (36, 37). Both observations demonstrate that insulin resistance of glucose production is involved in the pathogenesis of type 2 diabetes.

2. Potential role of adipose tissue for insulin resistance. In addition to muscle and liver, adipose tissue is the third metabolically relevant site of insulin action. While insulin-stimulated glucose disposal in adipose tissue is of little quantitative importance compared with that in muscle, regulation of lipolysis with subsequent release of glycerol and FFA into the circulation by insulin has major implications for glucose homeostasis. It is widely accepted that increased availability and utilization of FFA contribute to the development of skeletal muscle insulin resistance (38, 39, 40). Moreover, FFA have been shown to increase endogenous glucose production both by stimulating key enzymes and by providing energy for gluconeogenesis (41). Finally, the glycerol released during triglyceride hydrolysis serves as a gluconeogenic substrate (42). Consequently, resistance to the antilipolytic action of insulin in adipose tissue resulting in excessive release of FFA and glycerol would have deleterious effects on glucose homeostasis.

3. Glucose uptake vs. glucose production: comparison of EC₅₀s. Only one study has examined the entire insulin dose response characteristics for stimulation of glucose uptake and suppression of glucose production in normal and type 2 diabetic subjects (43). This study showed a significant right shift of the dose-response curve for glucose uptake with an EC₅₀ for glucose uptake (58 µU/ml) more than double that for glucose production (26 µU/ml). In another study also using the stepwise hyperinsulinemic-euglycemic clamp, a plateau for glucose uptake was not reached at the highest insulin concentration. Thus, dose response characteristics could only be approximated but appeared to range in the same order (44). These findings clearly demonstrate that with low physiological increments in plasma insulin, the liver is the primary determinant of whole body glucose homeostasis. In patients with type 2 diabetes the dose-response curves for both glucose uptake and glucose production were markedly shifted to the right (43, 44). The EC₅₀ values for glucose uptake (EC₅₀, 118 µU/ml) and glucose production (EC₅₀, 66 µU/ml) in the patients with type 2 diabetes, however, were increased similarly (2-fold) compared with normal subjects. Similarly, in obesity a parallel right shift of the dose-response curve for both glucose disposal and production was found (45). Thus, the relative impairment in the sensitivity of glucose uptake and suppression of glucose production was not different, which suggests that both processes are equally resistant to insulin in type 2 diabetes. At plasma insulin concentrations below 50 µU/ml, however, impaired suppression of glucose production appears to contribute quantitatively more than defective glucose uptake to the abnormal glucose homeostasis of type 2 diabetes.

4. Lipolysis is most sensitive to insulin. More data on whole body lipolysis as determined by isotopic measurements of glycerol appearance in plasma are available from stepwise hyperinsulinemic-euglycemic clamps. The insulin EC₅₀ values for suppression of lipolysis in normal subjects ranged between 7 and 16 µU/ml (44, 46, 47, 48, 49), placing the dose-response curve of adipose tissue distinctly left of those for glucose production and glucose uptake. From these studies it becomes evident, that lipolysis is the process most sensitive to the action of insulin with a greater than 90% effect well within the physiological insulin range. In obese subjects and patients with type 2 diabetes the EC₅₀ values are increased 2- to 3-fold (44, 47, 49), indicating that adipose tissue lipolysis is at least as resistant to the action of insulin as muscle and liver. Since failure to adequately turn off lipolysis directly affects liver (and kidney) and muscle metabolism while the reverse does not hold true, it is tempting to speculate that adipose tissue might even be a primary site for the defect leading to insulin resistance elsewhere and, ultimately, to type 2 diabetes.

To summarize, lipolysis is the most insulin-sensitive process followed by glucose production and, far behind, glucose uptake with EC₅₀ values in the physiological range only for insulin-induced inhibition of lipolysis and glucose production, but not for insulin-stimulated glucose uptake. In full-blown diabetes mellitus, insulin sensitivity in muscle, liver (and kidney), and adipose tissue is compromised to a similar degree. While several studies unanimously showed defective insulin action on glucose uptake and lipolysis in prediabetic states [obesity, impaired glucose tolerance (IGT)], data for suppression of glucose production are somewhat divergent. During an oral glucose tolerance test, suppression of endogenous glucose production was significantly diminished in IGT (50), whereas during a hyperinsulinemic-euglycemic clamp, suppression was comparable between IGT and normal glucose-tolerant (NGT) (51).

C. Pathogenesis of insulin resistance
Insulin resistance, as determined by the euglycemichyperinsulinemic clamp technique, reflects defective insulin action predominantly in skeletal muscle and liver. The major causes of skeletal muscle insulin resistance in the prediabetic state may be grouped into genetic background-related and as obesity- and physical inactivity-related (Fig. 2). Despite intensive research efforts, there is, so far, no clear understanding of the factors that define the genetic accessibility of insulin resistance. One approach to analysis of the genetic background is to define candidate genes based on the present knowledge of the insulin-signaling chain. We have recently reviewed the present knowledge of the insulin-signaling chain (52). Abnormalities in insulin signaling that may induce insulin resistance in type 2 diabetes will be discussed in the following section.

View larger version (21K): [in this window] [in a new window]   Figure 2. Pathogenesis of skeletal muscle insulin resistance. Schematic presentation of factors involved in the pathogenesis of skeletal muscle insulin resistance in prediabetes and type 2 diabetes.

View larger version (108K): [in this window] [in a new window]   Figure 3. Molecular mechanism of insulin-stimulated transport. The insulin-dependent glucose transporter 4 (GLUT4) is translocated by a phosphatidylinositol 3-kinase (PI 3K)-dependent pathway including PKB/AKT and PKC stimulation downstream of PI3K [Reproduced with permission from H. U. Häring: Exp Clin Endocrinol Diabetes 107[Suppl 2]:S17—S23, 1999 (7 ).] PI3,4,5P, Phosphatidylinositol 3,4,5-phosphate; PDK, phosphatidylinositol (3 4 5 )-phosphate-dependent kinase; IRS, insulin receptor substrate.

b. PI 3-kinase and protein kinase B (PKB).
At the molecular level, insulin causes activation of the insulin receptor and phosphorylation of IRS proteins on tyrosine residues. Phosphorylation of IRS proteins creates binding sites for PI 3kinase and enables activation of PI 3-kinase. The activated PI 3-kinase converts PI 4- or PI 4,5-phosphate into PI 3,4- and PI 3,4,5-phosphate (PIP₃). PIP₃ can bind PKB/AKT (for cellular homolog of the transforming oncogene v-akt) and phosphatidylinositol-3,4,5-phosphate-dependent kinase-1 (PDK-1) by their PH (pleckstrin homologous) domains (72). Colocalization of PKB/AKT and PDK-1 at the plasma membrane region enables phosphorylation of PKB/AKT on threonine₃₀₈ by PDK-1. PKB/AKT regulates several protein kinase cascades involved in insulin signal transduction to glucose uptake, to glycolysis, to glycogen synthesis as well as to protein synthesis (73). In addition to phosphorylation of PKB/AKT, there is evidence that PDK-1 is also able to phosphorylate protein kinase C (PKC) isoforms (74, 75). Insulin-dependent activation of the atypical PKC isoform has been demonstrated recently (76). Recent evidence suggests that PDK-1 mediates insulin-dependent activation of atypical PKC through phosphorylation on threonine₄₁₀ in the activation loop (74, 75). In addition, insulin-dependent stimulation of atypical PKC has been shown to mediate insulin effects on protein synthesis (76). Moreover, there is evidence that the atypical PKC isoforms and are involved in coupling of the insulin signal to the glucose transport system (77, 78). This demonstrates that insulin-stimulated glucose transport can be mediated via different signaling cascades. This signaling diversity potentially opens compensatory mechanisms if gene mutations were to occur, for example, in PKB/AKT or atypical PKCs.

Expression level and possible gene mutations of PI 3kinase and PKB in insulin-resistant and diabetic patients have been investigated by a small number of studies. Decreased activation of PKB in skeletal muscle of type 2 diabetic patients in spite of normal protein levels has been described (79). However, these results are controversial since another recently published study described normal PKB/AKT activation in skeletal muscle of type 2 diabetic patients (80). In skeletal muscle of lean and obese type 2 diabetic patients, decreased IRS-1 phosphorylation and PI 3-kinase activity as well as a 50–60% reduction in the protein expression level of IRS-1 and PI 3-kinase have been shown (81, 82). Thus, decreased expression and phosphorylation level of early insulin signaling elements (i.e., IRS, PI 3-kinase, and PKB) have been demonstrated in insulin target tissues of type 2 diabetic patients. This may contribute to insulin resistance in type 2 diabetic patients. However, it does not necessarily mean that this represents a genetic defect since it is not clear to what extent metabolic disturbances are able to induce the above mentioned signaling defects.

2. Possible genes for insulin resistance and obesity. Substantial evidence that type 2 diabetes is an inherited disease was demonstrated by twin studies, familial clustering of type 2 diabetes, and the high prevalence of this disease in some ethnic groups. Efforts to identify potential type 2 diabetes and insulin resistance genes have been undertaken by screening of different candidate genes and genome scans.

a. Candidate gene studies for insulin resistance and type 2 diabetes.
1. Insulin receptor. In the candidate gene approach, several genes have been screened for their potential role in the development of insulin resistance. A wide spectrum of insulin effects is mediated by the insulin receptor and its substrates IRS-1 and IRS-2 as well as the PI 3-kinase (reviewed in Ref. 5). Therefore, these genes have been tested for their potential role in the pathogenesis of insulin resistance. It is now well established that mutations of both insulin receptor alleles occur in very rare cases and cause severe syndromes of insulin resistance (e.g., leprechaunism, and Rabson-Mendenhall syndrome), which, in most patients, result in death during the first year (reviewed in Refs. 83, 84). Other insulin receptor mutations affecting only one allele are compatible with life and cause severe insulin resistance syndromes (called "type A insulin resistance") often without developing hyperglycemia during young adulthood. Since these early reports have clearly demonstrated that insulin receptor mutations could induce insulin resistance, patients with common type 2 diabetes were also screened for the presence of insulin receptor gene mutations. Thus far, several insulin receptor mutations (Lys1068Glu, Arg1152Gln, and Val985 Met) have been identified in about 1–5% of patients with common type 2 diabetes (85, 86, 87). Only one population-based study in the Netherlands could demonstrate a Val985 Met mutation of the insulin receptor at a relatively high rate of 5.6% (87), which was not found in other population groups (85). Functional characterization of the described insulin receptor mutations in type 2 diabetes revealed only mild degrees of insulin-signaling defects. However, overt diabetes may develop in combination with other genetic defects. In summary, insulin receptor mutations were not commonly found in random type 2 diabetes, and only a small number of individuals may have mutations that could contribute to insulin resistance, probably in concert with other genetic defects which are not yet identified.

2. IRS-1 and -2. Mutations of IRS-1 and IRS-2 have also been described in humans. However, these mutations were found with the same frequency in nondiabetic compared with diabetic individuals (12% for Gly972Arg mutation in the IRS-1 gene and 33% for Gly1057Asp in the IRS-2 gene) (88, 89). Cell culture studies indicated that the mutation in codon 972 of IRS-1 impairs insulin-stimulated signaling (90). Whether this mutation is correlated with insulin resistance in vivo seems contradictory at present (88, 91, 92). It appears, however, that Gly972Arg is associated with a slightly lower insulin secretion rate (88, 91, 93), which has recently been confirmed by in vitro studies (94) and which might also contribute to the development of type 2 diabetes. In addition to IRS-1, an amino acid polymorphism of the IRS-2 gene causing replacement of glycine to aspartate at position 1,057 was found at a high frequency of 33% in an unselected Scandinavian population. This amino acid exchange, however, was not associated with type 2 diabetes (89). Furthermore, genome screening of the IRS-2 locus has been performed in families with early-onset autosomal dominant type 2 diabetes (95). The results of this study did not suggest that the IRS-2 gene represents a major pathogenetic factor in this highly selected group. In summary, mutations of the IRS-1 and IRS-2 genes seem to occur at a relatively high rate of 12–33% in nonobese healthy, as well as type 2 diabetic, human subjects (88, 89). Although some data suggest impaired insulin action by these mutations, the high prevalence in healthy subjects does not support a major role in the development of type 2 diabetes in humans.

3. PI 3-kinase. Gene mutations in the PI 3-kinase gene have also been studied. Screening for mutations in the PI 3-kinase gene could be complicated by the existence of several isoforms of the PI 3-kinase regulatory and catalytic subunit (reviewed in Ref. 96). In human skeletal muscle more than four different regulatory subunit variants are expressed and differently regulated by insulin (97). It has been shown that a splice variant of approximately 50 kDa of the p85 regulatory subunit of PI 3-kinase is highly sensitive upon insulin stimulation in human skeletal muscle (97). Although PI 3kinase activation seems crucial for insulin-dependent glucose uptake, mice lacking the p85 subunit of PI 3-kinase are surprisingly more insulin sensitive and mildly hypoglycemic (98). This has been explained by a switch from p85 to the p50 subunit expression and activation which led to increased generation of phosphatidylinositol 3,4,5-phosphate (98). These results demonstrate that interpretation of potential mutations in the regulatory subunit of PI 3-kinase is difficult without the knowledge of total PI 3-kinase activity and the functional status and expression level of other regulatory isoform subunits. Screening for PI 3-kinase mutations in human subjects has revealed a mutation at codon 326 replacing methionine by isoleucine in the regulatory subunit. This mutation was found in a Scandinavian insulin-resistant population at a frequency of approximately 30% in its heterozygous form and 2% in its homozygous form. The homozygous mutation was found to be associated with a significant reduction of insulin sensitivity (99). However, this could not be found in Japanese type 2 diabetic patients (100). Moreover, in Pima Indians, this mutation was not associated with insulin resistance but rather with an increased acute insulin response after a glucose challenge test (101). It has been suggested by these investigators that the Met326Iso mutation might even protect homozygous carriers in the female Pima population against the development of type 2 diabetes. This may also agree with the data from p85 knockout mice, which are characterized by increased insulin sensitivity and hypoglycemia instead of developing diabetes (98).

4. Other candidate genes. In addition to these early insulin-signaling elements, mutations of the liver glucokinase promoter, of GLUT4, glycogen synthase, and the protein phosphatase-1, among others, have also been identified, but these mutations were not associated with insulin resistance or type 2 diabetes apart from a very few cases (reviewed in Ref. 102).

Although a large number of genes remain to be screened for their potential role in insulin resistance, it can be concluded from present studies that heterozygous mutations in insulin signaling molecules are often found with a high frequency in human subjects. In most cases these mutations are not sufficient to cause insulin resistance or type 2 diabetes. However, if these mutations are in rare cases homozygous or occur together with mutations of other insulin-signaling proteins or obesity, this combination of different disturbances might ultimately lead to insulin resistance and type 2 diabetes. This would also be in agreement with the postulated polygenic pathogenesis of type 2 diabetes.

b. Genome scans for susceptibility genes for insulin resistance and type 2 diabetes.
While the candidate gene approach serves to identify mutations of known genes, the method of genome scanning in family cohorts or sib pairs could reveal previously undetected type 2 diabetes genes (103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119). This method has identified new diabetes loci on different chromosomes, which are listed in Table 1 103–115). The chromosomal loci are partially located in the vicinity of known genes such as the hepatic nuclear factor 1 (HNF 1), the sulfonylurea receptor, the apolipoprotein A-2, and others. To date, most of the genome scan studies suggested that there are different chromosomal linkage regions for type 2 diabetes confirming the role of diabetes susceptibility genes. However, these gene loci are often restricted to a special trait and ethnic group, which means that they are probably not a major gene locus for the large group of common type 2 diabetic patients. A more general impact for common type 2 diabetes has recently been discussed for a gene locus on chromosome 20 near the hepatic nuclear factor 1 gene, but more studies are needed to identify this gene and to evaluate its potential role for the development of diabetes.

E. Molecular events in obesity-related insulin resistance
The negative impact of increased body fat mass on insulin sensitivity can be clearly shown for the vast majority of individuals. Furthermore, the insulin-sensitizing effect of weight reduction and physical training is well documented (reviewed in Refs. 10, 11).

1. The role of FFA in obesity-related insulin resistance. Among the signaling molecules that are derived from adipocytes, FFA have been implicated in the pathogenesis of insulin resistance (40, 126). FFA are generated via lipolysis mainly in fat cells. In insulin resistant and obese subjects increased FFA release into plasma can occur. Obesity-related insulin resistance leads to reduced antilipolytic effect of insulin (123). Another mechanism by which obesity could contribute to increased FFA production is overactivity of the sympathetic nervous system, which has been demonstrated in obese human subjects and type 2 diabetic patients (127, 128, 129). FFA are taken up by liver and skeletal muscle cells. They counteract the effects of insulin by increasing hepatic gluconeogenesis and by inhibiting glucose uptake and oxidation in skeletal muscle (130, 131, 132). This fatty acid-induced insulin resistance in liver and skeletal muscle has been suggested to be a result of increased acetyl-CoA production and inhibition of glucose oxidation by FFA (130, 133). The concept of a glucose-fatty acid cycle, which was originally described by Randle et al. (130), has now been called into question by Wolfe (134). While Randle et al. suggested that increased availability of FFA and fatty acid oxidation regulates glucose oxidation, Wolfe has developed a vice versa concept in which the rate of glycolysis rather than the availability of fatty acids regulates fatty acid oxidation. Evidence that glucose oxidation could directly regulate fatty acid oxidation by inhibition of fatty acid transport to the mitochondria was provided by this group recently (134). Nevertheless, increased fatty acids can regulate this process by reducing intracellular glucose availability through inhibition of glucose uptake. Therefore, the initiating effect of fatty acids to induce insulin resistance could be inhibition of glucose uptake, which would be followed by a decrease of intracellular glucose availability and glucose oxidation. This would consequently lead to increased fatty acid oxidation according to the concept of Wolfe.

2. The role of leptin in obesity-related insulin resistance. Leptin has gained much attention recently in the study of the underlying mechanisms of insulin resistance in obesity. In 1994, it was identified as an adipocyte-derived hormone in by Friedman and colleagues (135). Leptin reduces body weight via specific receptors in hypothalamic areas regulating energy expenditure and satiety (136, 137, 138). Secretion of leptin from fat cells is strongly dependent on body fat mass (reviewed in Ref. 138). Leptin deficiency and receptor defects in rodents cause marked obesity as well as hyperinsulinemia and hyperglycemia (139). Thus, many studies have focused on the effects of leptin on insulin resistance and insulin secretion. Both inhibition and stimulation of insulin action have been shown by leptin in different cell systems (140, 141, 142, 143). In addition, several groups have shown inhibitory effects of leptin on insulin secretion in isolated cell lines and perfused pancreatic islets (128), while others have found that leptin stimulates insulin secretion (144, 145, 146, 147, 148, 149, 150). Therefore, the conclusion that leptin causes a defect in the insulin-signaling chain or that it is capable of improving ß-cell dysfunction in human subjects cannot yet be made on the basis of these studies.

In human subjects congenital leptin deficiency or mutations of the leptin receptor occur in extremely rare cases. These mutations have been associated with severe obesity but not with diabetes (151, 152, 153). However, it must be considered that these few cases reported recently were of young age, and it remains to be seen whether IGT or diabetes may still develop with advancing age.

3. The role of tumor necrosis factor- (TNF) in obesity-related insulin resistance. A great number of studies have been performed in the last years to elucidate the role of TNF for obesity-related insulin resistance. Spiegelman and co-workers recently proposed that TNF may contribute to insulin resistance in obese subjects (reviewed in Ref. 154). Several studies have shown that TNF is able to impair insulin signaling through serine kinase and tyrosine phosphatasedependent modulation of the insulin-signaling chain (155, 156, 157). However, these studies have been performed in isolated cell systems, and to date there is no evidence that these mechanisms are relevant in type 2 diabetic patients. While the data from isolated cell systems and animal models provide a plausible molecular basis for TNF-induced insulin resistance, clinical results from different insulin-resistant populations so far do not support a major role of TNF on insulin resistance in humans (158, 159). However, one study has shown increased adipose tissue expression of TNF in obese premenopausal women when compared with control subjects (506).

4. The peroxisome proliferator-activated receptor- (PPAR): potential role for insulin resistance and ß-cell function. Thiazolidinediones are pharmacological compounds that reduce insulin resistance both in prediabetic as well as diabetic individuals (see also Section III.C.). Thiazolidinediones are ligands of the PPAR2 (160). PPAR2 is predominantly expressed in adipocytes, intestine, and macrophages (161). There is some evidence that a low level expression might also occur in muscle cells. The PPAR receptor is a transcription factor that controls the expression of numerous genes. It is assumed that the effect of thiazolidinediones on insulin sensitivity is mediated through altered expression of PPAR2-dependent genes (reviewed in Refs. 162, 163). Recently, the Pro12Ala and two other polymorphisms were described in the PPAR2 receptor (164). It appears that the Pro12Ala polymorphism in its heterozygous form occurs in approximately 30% of humans. Auwerx and colleagues (165) have shown that this polymorphism appears to be functionally relevant, leading to a reduced transcriptional activity and improved insulin sensitivity (165). In our studies, an obese subgroup with a body mass index (BMI) >35 kg/m² carrying this polymorphism in the heterozygous form appears to be less insulin resistant compared with individuals without this PPAR2 mutation (166). Although the total number of subjects studied is still very low, it might be speculated that this polymorphism protects against the negative influences of obesity on insulin sensitivity. Interestingly, we also found differences in insulin secretion measured during an oral glucose tolerance test. Individuals carrying the polymorphism showed lower insulin secretion at 60 and 120 min. The lower secretion might be interpreted as a consequence of the increased insulin sensitivity of these individuals. Alternatively, it might be speculated that the PPAR2 polymorphism directly interferes with ß-cell function. In agreement with this, direct effects of PPAR agonists on ß-cells have been demonstrated. Studies on isolated pancreatic islets and on a hamster ß-cell line have shown that thiazolidinediones could enhance glucose- and glibenclamide-induced insulin release (167). Although the underlying mechanism for this direct effect on ß-cells is not completely clear, it has been suggested that thiazolidinediones stimulate insulin release by increase of glucose uptake in the ß-cell (167). In animal studies, treatment with thiazolidinediones resulted in improvement of pancreatic islet cell integrity and hyperplasia (168, 169). Moreover, it has been demonstrated that PPAR activation reduces triglyceride content in islets of Zucker diabetic fatty rats, leading to a significant increase in insulin secretion (170). However, in humans only preliminary data are available concerning a direct effect of PPAR agonists on pancreatic islets. One study demonstrated that troglitazone treatment in humans could increase glucose-stimulated insulin secretion (171). Thus, in addition to the insulin-sensitizing effects, PPAR agonists may directly improve ß-cell dysfunction in humans. However, clearly more studies are needed to investigate direct effects of PPAR agonists on pancreatic ß-cells in humans.

	III. Pharmacological Treatment

Top Abstract I. Introduction II. Pathophysiology and... III. Pharmacological Treatment IV. Perspectives V. Summary and Conclusion References

 
In the following section the available antihyperglycemic agents known to ameliorate insulin resistance will be discussed. One major mechanism of action to increase insulin sensitivity, which all antihyperglycemic agents have in common, is reducing the deleterious effects of chronic hyperglycemia on insulin action and insulin secretion. This concept of "glucose toxicity" plays a pivotal role in glucose homeostasis, and excellent reviews have been published during the last decade (172, 173, 174) . In addition to the effect on insulin sensitivity by reducing glucose toxicity, the evidence of a primary effect of the respective agents on insulin action will be reviewed.

A. -Glucosidase inhibitors
1. Mechanism of action. These agents delay digestion of complex carbohydrates and disaccharides (starch, dextrin, sucrose) to absorbable monosaccharides by reversibly inhibiting -glucosidases within the intestinal brush border (glucoamylase, sucrase, maltase, and isomaltase). This leads to a reduction of glucose absorption and, subsequently, the rise of postprandial hyperglycemia is attenuated. The currently available -glucosidase inhibitors are acarbose, miglitol, and voglibose. Extensive and excellent reviews about their pharmacology have been published (175, 176, 177, 178, 179, 180, 181, 182, 183).

2. Effect of -glucosidase inhibitors on hyperglycemia in patients with type 2 diabetes mellitus. The effect of monotherapy with -glucosidase inhibitors (usually 100 mg three times daily) on postprandial hyperglycemia is well documented in numerous randomized placebo-controlled studies, and the decrease of postprandial glycemia averages about 3 mmol/liter (184, 185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203). The effect of -glucosidase inhibitors on fasting plasma glucose levels is less pronounced and averages -1.3 mmol/liter. The overall effect of -glucosidase inhibitors on glycemia of diet-pretreated subjects with type 2 diabetes, as determined by HbA1c-measurements, averages 0.9% (range, 0.6–1.4), as recently reviewed by Lebovitz (204).

Addition of acarbose to type 2 diabetic subjects pretreated with insulin, metformin, or sulfonylureas causes a reduction of HbA1c levels between 0.5 and 0.8%. This beneficial effect seems to last for at least 3 yr as has been recently shown in the UKPDS study. During the last 3 yr of this long-term trial, 379 patients were additionally treated with acarbose in a placebo-controlled design. This resulted in a mean reduction of the HbA1c by 0.5% in the group of patients who still took acarbose after 3 yr. This significant effect was sustained over the 3-yr time period (205). However, at 3 yr a significant lower proportion of patients were taking acarbose compared with placebo (39 vs. 58%), the main reasons for noncompliance being flatulence and diarrhea. Intention to treat analysis showed that all patients allocated to acarbose, compared with placebo, had 0.2% significantly lower HbA1c at 3 yr (205).

3. Effect of -glucosidase-inhibitors on insulin sensitivity. Eight randomized placebo-controlled studies have been published examining the effect of -glucosidase inhibitors on insulin sensitivity in patients with IGT or type 2 diabetes mellitus (Table 2). In subjects with IGT, Chiasson et al. (206) demonstrated that acarbose (100 mg three times daily) for 4 months caused a 21% decrease in steady-state plasma glucose (SSPG) during an insulin suppression test using somatostatin, glucose, and insulin infusions. Similar results were obtained by Laube et al. (207), who reported that 12 weeks of acarbose treatment (100 mg three times daily) increased steady-state glucose infusion rate (SSGIR) by 45%. In addition, Shinozaki et al. (208) treated subjects with IGT with a different glucosidase inhibitor, voglibose (0.2 mg three times daily), for 12 weeks, and showed that SSPG levels decreased significantly after voglibose treatment. Thus, these data suggest that -glucosidase inhibitors improve insulin sensitivity in subjects with IGT and hyperinsulinemia possibly secondary to an amelioration of glucose-induced insulin resistance by reducing hyperglycemia in the postprandial period. In contrast to studies in subjects with IGT, studies examining the effect of -glucosidase inhibitors on insulin sensitivity in patients with type 2 diabetes showed no amelioration of insulin resistance despite decreased postprandial glycemia (209, 210, 211, 212, 213). Thus, these data are in support of the notion that -glucosidase inhibitors improve insulin sensitivity in subjects with IGT but have no effect on insulin sensitivity in subjects with overt type 2 diabetes.

View this table: [in this window] [in a new window]   Table 2. Effect of -glucosidase inhibitors on insulin sensitivity

4. -Glucosidase inhibitors in type 2 diabetes prevention studies.

In addition, two other multicenter studies are investigating the effect of diet, increased physical activity or metformin [Diabetes Prevention Program (DPP)] and diet, increased physical activity and sulfonylurea [Fasting Hyperglycemia Study (216)] to prevent type 2 diabetes mellitus. The results of these long-term studies will be available between 2002 and 2004.

5. Adverse effects of -glucosidase inhibitors. -Glucosidase inhibitors have not been associated with life-threatening adverse effects, possibly due to the low systemic absorption.

a. Gastrointestinal adverse effects.
The major adverse effects associated with acarbose therapy are gastrointestinal complaints, including flatulence and abdominal discomfort, resulting from malabsorption and consequently increased fermentation of carbohydrates. Depending on the acarbose dosage used (300–900 mg/day), the frequency of gastrointestinal effects was as high as 56–76% (placebo, 32–37%) in earlier studies (217). When the new recommendations for use of -glucosidase inhibitors were considered in the study protocols (low acarbose starting dose of 50 mg/day, slow increase of dosage over weeks, maximum dose 100 mg three times daily), the incidence of gastrointestinal adverse effects were reported to be as low as 7.5% (203). Furthermore, it has been shown that the incidence of gastrointestinal side effects decreased during long-term treatment (218).

b. Systemic effects.
The systemic availability of nonmetabolized acarbose is reported to be 0.5–1.7% (217, 219, 220). Due to the low systemic absorption of acarbose, systemic effects are rare. However, liver transaminase elevations [defined as treatment-induced increases of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) > 1.8-fold the upper limit of the normal range] were documented in 3.8% of acarbose recipients (placebo 0.9%) in the early studies carried out in the United States, using high acarbose daily dosage (900 mg/day) (221). Animal studies on ethanolinduced hepatotoxicity revealed that high-dose acarbose treatment augmented ethanol-induced hepatotoxicity (222). However, in all major acarbose trials using 100 mg three times daily as the maximum dose, hepatic transaminase elevations were extremely rare (203, 223) and in the five cases published, transaminase levels were reversible upon withdrawal of the drug (224, 225, 226, 227). Furthermore, a recent study from Japan demonstrated that acarbose treatment in patients with chronic liver disease and diabetes mellitus was effective and caused no significant alterations in hepatic transaminase levels after 8 weeks of treatment (228). Recently, it has been reported that acarbose induced a generalized erythema multiforme in a middle-aged Japanese type 2 diabetic patient (229).

6. Guidelines for the clinical use of -glucosidase inhibitors.
a. Selection of the most appropriate patients.
Postprandial hyperglycemia represents a major metabolic disturbance of carbohydrate metabolism in IGT and early phase type 2 diabetic subjects. Since -glucosidase inhibitors decrease postprandial glycemia these patients are suitable candidates for treatment with -glucosidase inhibitors, provided that the individual therapeutic goal was not achieved by dietary advice and increased physical activity. In type 2 diabetic patients suffering predominantly from fasting hyperglycemia, glucosidase inhibitors are less effective but may be used in combination with other antihyperglycemic agents, such as metformin, sulfonylureas, or insulin. The results of the UKPDS have shown that combination therapy using these drugs is effective and safe over at least 3 yr. In patients remaining on their allocated therapy, the HbA1c-difference at 3 yr was 0.5% lower in the acarbose study group compared with placebo (205).

B. Biguanides
1. Introduction. There is now a large body of data documenting the clinical efficacy of metformin in the treatment of type 2 diabetes (230), and most of its clinical, pharmacological, and basic cellular aspects have been addressed in several excellent reviews published during the past 20 yr (231, 232, 233, 234, 235, 236, 237, 238). Recently, the UKPDS showed that metformin is particularly effective in overweight type 2 diabetic subjects, a condition usually characterized by insulin resistance (239). Moreover, in essentially all clinical studies the improvement of hyperglycemia with metformin occurred in the presence of unaltered or reduced plasma insulin concentrations (e.g., Refs. 240, 241). Taken collectively, these findings indicate the potential of metformin as an insulin-sensitizing or insulin-mimetic drug, which is the focus of the following.

Despite almost 40 yr of research, the precise cellular mechanism of metformin action is still not entirely understood. Several cellular mechanisms have been described but a single unifying site of action, such as a receptor, an enzyme, or a transcription factor, has yet to be identified. Nevertheless, it is generally undisputed that metformin has no effect on the pancreatic ß-cell in stimulating insulin secretion (234). Mild increases in glucose-stimulated insulin secretion after metformin treatment (242) are thought to be the result of reduced glucose toxicity on the ß-cell secondary to improved glycemic control (243).

2. Mechanisms of action in humans.
a. Glucose production.
Accelerated endogenous glucose production is thought to be a key factor in the development of fasting hyperglycemia in type 2 diabetes (244, 245). In patients with type 2 diabetes, metformin has been shown to inhibit endogenous glucose production in most studies (246, 247, 248, 249, 250, 251, 252). This could be accounted for largely by inhibition of gluconeogenesis (247), although an additional inhibitory effect of metformin on glycogen breakdown is likely (247, 248). The observation in many studies that, in the basal postabsorptive state, overall glucose disposal (metabolic plasma clearance rate of glucose) did not change while endogenous glucose production decreased (246, 247, 248, 251, 252, 253) suggests that the improvement in glycemic control is largely attributable to the effect of metformin on glucose production.

b. Peripheral glucose metabolism.
Many (246, 249, 251, 252, 254, 255, 256), but not all, studies (248, 250, 253, 257) using the hyperinsulinemic-euglycemic clamp technique have shown a metformin-induced increase in insulin-stimulated glucose disposal in patients with type 2 diabetes. Since muscle represents a major site of insulin-mediated glucose uptake (244, 258), metformin must, either directly or via indirect mechanisms, have an insulin-like or insulin-sensitizing effect on this tissue. In humans, the increase in insulin-stimulated glucose disposal is mostly accounted for by nonoxidative pathways (252, 255, 259). Nonoxidative glucose metabolism includes storage as glycogen, conversion to lactate, and incorporation into triglycerides. While no effect on lactate production is observed (247, 248), implications on net triglyceride synthesis cannot be drawn. Nevertheless, it appears reasonable to propose that in human muscle glucose transport and, possibly as a consequence, glycogen synthesis are the major targets of metformin action in the insulin-stimulated state. However, in the basal state, metformin had no effect on glucose clearance or whole-body glucose oxidation, although the proportion of glucose turnover undergoing oxidation was increased (247). Moreover, forearm glucose uptake in the postabsorptive state was not significantly altered (247).

c. Metabolic effects independent of improved glycemia.
The interpretation of the above experiments is limited by the fact that treatment with metformin was always accompanied by improvement in glycemic control and sometimes also by reduction of body weight. It cannot be excluded, therefore, that the effects on endogenous glucose production and glucose disposal, at least in part, were secondary to reduced glucose toxicity (243) and/or weight loss (260) rather than metformin per se. Only four studies have examined the metabolic actions of metformin in the absence of any changes in glycemic control or body weight.

In one study, 1 g of metformin was administered acutely to patients with type 2 diabetes; after 12 h no effect on insulin-stimulated glucose disposal was seen while the excessive endogenous glucose production in the basal state was significantly reduced (253). This suggests that in patients with type 2 diabetes, improvement in insulin-stimulated glucose disposal is predominantly due to alleviation of glucose toxicity while endogenous glucose production is immediately affected by metformin. In another study, lean, normal glucose-tolerant, insulin-resistant first-degree relatives of patients with type 2 diabetes acutely received 1 g of metformin and the opposite effect was observed (259). In subjects with IGT, 6-week metformin treatment improved basal (HOMA) but not insulin-stimulated glucose disposal or glucose oxidation (261). In this study both fasting glucose and insulin decreased significantly. In android obese subjects with IGT, increased insulin sensitivity (using an iv glucose tolerance) was observed after only 2 days of metformin treatment (1,700 mg/day) (262). In obese women with the polycystic ovary syndrome (PCOS) 6 months treatment with metformin also significantly improved insulin-stimulated glucose disposal (263, 264). In another study in obese women with PCOS, the decrease in serum insulin levels was associated with an increased ovulatory response to clomiphene (265). Glucose production was not assessed in the latter study. These apparent discrepancies could be explained by differences in the type of insulin resistance. In the highly selected group of lean, first-degree relatives and women with PCOS, mechanisms may contribute to insulin resistance that are different than those in garden-variety type 2 diabetes in which insulin resistance is predominantly the result of obesity and longstanding hyperglycemia. Moreover, the reduction in endogenous glucose production after metformin treatment may only be seen in subjects in whom it was increased to begin with, such as patients with type 2 diabetes. The latter is supported by observations showing that metformin alone does not cause hypoglycemia or lower blood glucose in nondiabetic subjects (266, 267). The effect of metformin on endogenous glucose production in nondiabetic humans has not yet been studied.

Additional evidence for improved insulin action comes from studies combining insulin therapy and metformin. It was shown that requirements of exogenous insulin are reduced (by 30%) by addition of metformin in obese patients with type 2 diabetes (268, 269, 270) and in some patients with type 1 diabetes in whom glycemic control was unaltered (271, 272, 273).

d. Other mechanisms of action.
It has been suggested that part of the antihyperglycemic effect of metformin is due to decreased release of FFA from adipose tissue and/or decreased lipid oxidation (253, 274). However, reduced FFA levels after metformin treatment have been shown in some (251, 257, 274) but not all studies (247, 248, 259). Moreover, in vitro studies have shown that metformin does not enhance the antilipolytic action of insulin on adipose tissue (275). Only two studies have examined FFA turnover using isotope techniques and found either no difference (247) or a 17% reduction (255) after metformin treatment. In the latter study, the effect was seen in the basal state but not in the insulin-stimulated state in which FFA flux was largely suppressed. Thus, the metformin effect on peripheral glucose uptake may, at least in part, be mediated by suppression of FFA and lipid oxidation. In contrast, a causal relationship with endogenous glucose production is unlikely, since distinctly greater reductions in circulating FFA levels with acipimox failed to lower glucose production (276, 277).

Evidence for other proposed mechanisms of metformin action is less convincing. Increased intestinal utilization of glucose has been suggested by animal studies (278, 279, 280). More recently, in vivo treatment with metformin increased gene expression of the energy-dependent sodium-glucose cotransporter (SGLT1) in rat intestine (281). However, such a mechanism has not been confirmed in humans (250).

e. Weight loss.
Unlike other pharmacological therapies for type 2 diabetes (sulfonylureas, insulin), metformin treatment is not associated with weight gain. Clinical studies have consistently shown either a small but significant decrease in body weight (240, 251) or a significantly smaller increase in body weight compared with other forms of treatment (268). One study has shown that weight loss during metformin treatment was largely accounted for by loss of adipose tissue (247). This was explained by differential effects of metformin on adipose tissue and muscle. While metformin improves insulin sensitivity in muscle, it does not affect the antilipolytic action of insulin on adipose tissue (282). The overall effect of metformin on body weight is attributed to a reduction in caloric intake (268, 283) rather than an increase in energy expenditure (247, 253, 284). Since reduction in body weight per se reduces insulin resistance, this may also represent a mechanism by which metformin improves insulin resistance.

To summarize, the partly divergent observations from the numerous metabolic studies regarding metformin’s effect on muscle and liver (Table 3, A and B) may reflect different mechanisms of metformin action in the basal vs. the insulin-stimulated state. In the basal, postabsorptive state, the improvement of fasting hyperglycemia is mostly due to a decrease of the accelerated endogenous glucose production. This results from inhibition of both gluconeogenesis and glycogen breakdown. Direct or indirect effects on regulatory enzymes are likely to be involved. No data are available for suppression of glucose production during experimental hyperinsulinemia. However, the fact that reduction in basal glucose production occurs in the presence of lower or unaltered insulin levels suggests that glucose production in liver and kidney (285, 286) is more sensitive to the restrictive action of insulin after treatment with metformin.

3. Clinical efficacy of metformin in patients with type 2 diabetes mellitus.
a. Glycemic control.
The glucose-lowering effect of metformin, monotherapy or in combination, has been extensively reviewed (231, 232, 233). In a recent meta-analysis (230), all randomized, controlled clinical trials comparing metformin with placebo (239, 240, 252, 289, 290, 291, 292, 293, 294) and sulfonylurea (239, 240, 295, 296, 297, 298, 299, 300, 301) were evaluated. The weighted mean difference between metformin and placebo after treatment (median treatment duration, 4.5 months) for fasting blood glucose was -2.0 mM and for HbA1c -0.9%. Body weight was not significantly changed after treatment. Sulfonylureas and metformin lowered blood glucose (-2.0 and -1.8 mM, respectively) and HbA1c (-1.1 and -1.3%, respectively) equally (median treatment duration, 6 months). However, whereas after sulfonylurea treatment body weight increased by 2.9 kg, there was a decrease of 1.2 kg after metformin. In a retrospective study of 9,875 patients with type 2 diabetes mellitus who attended a large health maintenance organization, metformin treatment improved the mean HbA1c by 1.41% over a 20-month period (302). Among obese patients treated by intensive blood glucose control within the UKPDS, metformin showed a significantly greater effect than chlorpropamide, glibenclamide, or insulin for any diabetes-related endpoint, all-cause mortality, and stroke (239). In summary, metformin is as effective as sulfonylureas in improving glycemic control but, especially in overweight/obese patients, advantageous with respect to body weight, diabetes-related endpoints, and frequency of hypoglycemia.

b. Lipid profile and cardiovascular system.
In addition to improving glycemic control, metformin has been shown to reduce serum lipid levels. Metformin treatment results in a moderate (10–20%) reduction in circulating triglyceride levels, particularly in patients with marked hypertriglyceridemia and hyperglycemia (247, 257, 303), but also in nondiabetic subjects (304, 305). This has been attributed to a reduction in hepatic very low density lipoprotein (VLDL) synthesis (257, 292, 306). Small (5–10%) decreases in total circulating cholesterol have also been reported (286, 289, 290, 291) that were essentially attributed to reductions in low density lipoprotein (LDL) levels (307, 308, 309) since high-density lipoprotein (HDL) cholesterol levels were either increased (304) or unchanged (309).

In addition to the improvement of the lipid profile, metformin appears to have potentially beneficial hemostaseological effects. Fibrinolysis is increased (305, 307, 308) and the fibrinolysis inhibitor plasminogen-activator inhibitor 1 (PAI1) is decreased (292, 305, 310). Moreover, a decrease in platelet aggregability and density has been demonstrated (296, 311). These additional effects of metformin, which have been extensively reviewed elsewhere (231, 232), may explain the advantage of metformin over sulfonylurea or insulin treatment with respect to macrovascular endpoints shown in the UKPDS (239).

c. Combination therapies: metformin plus sulfonylureas and metformin plus insulin.
Metformin is also used in combination with other antihyperglycemic agents. Because of its unique mechanisms of action, a synergistic effect on glycemic control has been observed in combination with sulfonylureas (e.g., Refs. 240, 312, 313), troglitazone (Ref. 314 and see next chapter), and insulin where a dose-sparing effect was consistently demonstrated (268, 269, 270, 314, 315, 316). Interestingly, in patients in whom sulfonylurea therapy has failed to satisfactory glycemic control, the combination of bedtime NPH-insulin with metformin was advantageous compared with other combinations (316). In contrast to insulin alone, insulin plus sulfonylurea, and sulfonylurea alone, when bedtime NPH-insulin was combined with metformin, a decrease in HBA1c was achieved without significant weight gain (315, 316).

4. Adverse effects. While mild gastrointestinal disturbances are the most common side effects, lactic acidosis, although rare, is the most serious side effect of metformin treatment (317). In 9,875 patients one case of probable lactic acidosis was observed in 20 treatment months (302). The incidence of lactic acidosis is 10 to 20 times lower than with phenformin. This is explained by the necessity to hydroxylate phenformin before renal excretion, a step that is genetically defective in 10% of whites (318, 319). Metformin, in contrast, is excreted unmetabolized. In addition, in contrast to phenformin (320), metformin neither increases peripheral lactate production nor decreases lactate oxidation (247, 248), making lactate accumulation unlikely. One study investigating individual cases of metformin-associated lactic acidosis showed that in these patients metformin should never have been started or should have been discontinued with the onset of acute illness (321). Thus, strict adherence to the exclusion criteria of metformin treatment (renal and hepatic disease, cardiac or respiratory insufficiency, severe infection, alcohol abuse, history of lactic acidosis, pregnancy, use of intravenous radiographic contrast; reviewed in Refs. 213, 216) should minimize the risk of metformin-induced lactic acidosis.

5. Guidelines for the clinical use of metformin. As recently reviewed (231) metformin or sulfonylurea therapy can be initiated when patients with NIDDM continue to have hyperglycemia despite diet and exercise. Metformin appears to be the drug of choice to start pharmacological treatment in insulin-resistant and overweight/obese diabetic subjects (239, 322). However, since the antihyperglycemic effects of metformin are similar in lean and obese subjects, it can also be recommended as first-line treatment in the absence of obesity. Addition of metformin to sulfonylureas in patients with secondary sulfonylurea failure appears reasonable in view of their synergistic mechanisms of action and has been shown to improve glycemic control. Furthermore, especially in overweight/obese patients, the addition of metformin to insulin is advantageous compared with insulin alone (507). Finally, metformin is not recommended for patients with type 1 diabetes, or in insulin-resistant states in the absence of overt type 2 diabetes. However, metformin is currently under investigation as an agent to prevent type 2 diabetes in subjects with IGT as one of the three arms (vs. diet and intensive life-style modification) of the Diabetes Prevention Program (322), but it is not yet approved for use in subjects with IGT.

C. Thiazolidinediones
1. Introduction. The thiazolidinediones are a new class of hypoglycemic agents that were originally developed in the early 1980s in Japan as antioxidants (323). Soon after the synthesis of the first thiazolidinedione, ciglitazone, the blood glucose-lowering potential of these compounds was observed in animals, with particularly pronounced effects in animals with genetic insulin resistance such as the KK, db/db, and ob/ob mice, and fa/fa rats (324, 325, 326). The observation that glycemia improved in the absence of increasing insulin and the lack of effect in insulin-deficient animals (327) led to the conclusion that thiazolidinediones improved insulin resistance and resulted in the nickname "insulin sensitizers." However, due to an unacceptable side effect profile, ciglitazone and, later, englitazone never proceeded to human studies. Troglitazone became the first thiazolidinedione available for clinical use and was released in 1997 in the United States and Japan followed by rosiglitazone and pioglitazone (both marketed in 1999 in the United States). In Europe, except for the United Kingdom, where it was available for a few months, troglitazone has not been approved and, due to an untoward risk-benefit ratio (hepatotoxic side effects), was withdrawn from the US market by the Food and Drug Administration (FDA) in March 2000. Thus, at the present time rosiglitazone and pioglitazone are the two members of the thiazolidinedione class available for clinical use in some countries including the United States, Japan, and Europe. Since the majority of clinical data originate from studies using troglitazone, however, this substance will be included in this review.

2. Mechanism of action. The cellular mechanism of action of the thiazolidinediones is not precisely understood. However, the body of evidence indicating that a subtype of the PPAR is the principal receptor mediating the antidiabetic activity of the thiazolidinediones is substantial and has recently been reviewed (328, 329). Expression levels of the nuclear receptor PPAR are highest in adipocytes, intestinal cells, and macrophages but very low in most other tissues including muscle. PPAR activated by specific agonists, including thiazolidinediones, heterodimerizes with the retinoid X receptor to bind to specific DNA repeats, resulting in transcription of thiazolidinedione-responsive genes. In various cell models (preadipocytes, fibroblasts, myoblasts), thiazolidinedione treatment resulted in expression of a number of adipocyte-specific genes (lipoprotein lipase, fatty-acid binding protein, GLUT4, acyl-CoA synthetase, etc.) so that PPAR activation and/or overexpression has essentially been associated with adipose-cell differentiation and adipogenesis (330, 331, 332). Therefore, the clinical observations that treatment with thiazolidinediones improves insulin-stimulated (i.e., muscle) glucose uptake and endogenous (i.e., essentially hepatic) glucose production while PPAR is mainly expressed in fat cells makes it difficult to link cellular and metabolic mechanisms of action. In addition, considering the well known connection between obesity and insulin resistance, it seems paradoxical that an agent that promotes adipogenesis should improve insulin sensitivity.

A number of hypothetical schemas to reconcile these apparent quandaries and explain the overall mode of action of thiazolidinediones have been put forward. First, the minute quantities of PPAR expressed in muscle may be sufficient or alternatively might be induced during treatment with thiazolidinediones, leading to a direct PPAR-mediated response. This is supported by the recent observation in a lipoatrophic mouse model in which thiazolidinedione treatment improved insulin sensitivity in the absence or near absence of adipose tissue (333). Prevention of hyperglycemia-mediated inhibition of the insulin receptor tyrosine kinase, as demonstrated in rat-1 fibroblasts, represents a potential mechanism (334). Second, the effect of thiazolidinediones may also be mediated by FFA, which have been shown to interfere with muscle glucose metabolism and contribute to the impaired insulin-stimulated glucose disposal (335, 336). Since thiazolidinediones have been shown to selectively stimulate lipogenic activities in fat cells, a thiazolidinedione/PPAR-mediated "fatty-acid-steal phenomenon" has been proposed leaving less FFAs available for muscle (328). Third, thiazolidinediones have been shown to reduce expression levels in fat cells of both TNF (337) and leptin (338, 339), both of which have been implicated in obesity-related insulin resistance. Although the definite role of the cytokine TNF for human insulin resistance remains to be determined, TNF has been shown to interfere with proximal insulin signaling events of (Ref. 340 and Section II.E.3.). In addition, leptin has been shown to impair insulin signaling in isolated rat adipocytes (341). Since thiazolidinediones have been shown to reduce expression levels of both TNF (337) and leptin (338, 339) in fat cells, they could contribute to alleviating obesity-related insulin resistance. Which of these mechanisms plays the most important role in vivo is unclear at present, but since they are not mutually exclusive all of them may be involved.

Parenthetically, a mechanism of action independent of PPAR was recently demonstrated for inhibition of cholesterol synthesis by troglitazone in various models of liver, muscle, and fat cells (342).

3. Clinical efficacy of thiazolidinediones in patients with type 2 diabetes mellitus.
a. Glycemic control.
Controlled clinical trials assessing the efficacy of rosiglitazone and pioglitazone as single therapeutic agent in patients with type 2 diabetes showed an average decrease of fasting plasma glucose levels by about 45 mg/dl and of HbA1c by about 1.0% (343, 344, 345, 346). Taking into account differences in study design (pretreatment glycemic control, duration, dose), rosiglitazone and pioglitazone appear to be similarly efficacious (Table 4). To date no study has directly compared the clinical efficacy of two or more thiazolidinediones. The effect on glycemic control was dose dependent and leveled off with daily doses greater than 8 mg for rosiglitazone and exceeding 30 mg for pioglitazone (347). The effect of troglitazone on glycemic control was slightly less pronounced, resulting in a decrease in fasting glucose and HbA1c of approximately 35 mg/dl and 0.7% (347, 348, 349). It thus appears that improvement in glycemic control using a single agent is slightly less with thiazolidinediones than with sulfonylureas or metformin.

c. Combination therapy with sulfonylurea, insulin, and metformin.
While thiazolidinedione monotherapy turned out to be disappointing compared with sulfonylureas or metformin, combinations with other forms of pharmacological treatment appeared to be more promising. In a carefully designed study, addition of various doses of troglitazone (200–600 mg) to the sulfonylurea compound Glynase in patients with secondary sulfonylurea failure has been shown to reduce fasting plasma glucose by 79 mg/dl and HbA1c by 2.65% (absolute numbers) below sulfonylurea alone in the highest dosage group. An additive effect with sulfonylureas was also reported for pioglitazone (353). In keeping with the concept that thiazolidinediones enhance insulin action are reports showing a marked reduction in exogenous insulin requirements in insulin-treated obese patients. Troglitazone reduced HbA1c by 1.3% below placebo while insulin dosage was reduced by 30% (354). Similarly, addition of pioglitazone in insulin-pretreated patients with type 2 diabetes resulted in an improvement of glycemic control vs. insulin only (355). The combination of all three available thiazolidinediones with metformin also showed significant additive effects (346, 356, 357). One study suggested that troglitazone improved peripheral insulin sensitivity while metformin preferentially acted on the liver in an insulin-mimetic or insulin-sensitizing way (356). It is somewhat unexpected in this study, however, that metformin had no effect on glucose production when added to troglitazone.

4. Effect of thiazolidinediones on insulin sensitivity.
a. Animal studies.
Initial studies of chronic administration of troglitazone showed an improvement of insulin sensitivity and hyperinsulinemia in rats (325). Using the hyperinsulinemic clamp technique, an increase in insulin-stimulated glucose disposal was demonstrated in obese rats (358). In contrast to the effects of prolonged troglitazone administration several studies in animals have demonstrated that troglitazone also has acute effects that are both insulin like and insulin sensitizing (359). In addition to improving insulin-stimulated glucose uptake, which is essentially attributed to muscle, thiazolidinediones were shown to enhance insulin’s action on glucose production, which occurs predominantly in the liver. In rats, troglitazone increased the sensitivity to the suppressive effects of insulin on endogenous glucose production, i.e., mainly on hepatic glucose output (327, 359). In diabetic mice and starved rats, troglitazone suppressed gluconeogenesis, possibly by inhibition of long-chain fatty acid oxidation (325, 360, 361, 362). Thus, animal studies provide ample evidence that thiazolidinediones sensitize both muscle and liver tissues to the hypoglycemic action of insulin.

b. Human studies.
A series of more mechanistically designed studies, employing oral glucose and meal tolerance tests, hyperinsulinemic clamps, and isotopic glucose turnover determinations, were performed to elucidate the metabolic mode of action of the thiazolidinediones (at the time troglitazone), in humans with and without type 2 diabetes (Table 5). No such data are available for rosiglitazone or pioglitazone at the present time.

5. Adverse effects of thiazolidinediones. Adverse events of both rosiglitazone and pioglitazone occurring with greater frequency than in the placebo group are edema and fluid retention (368, 369). The most commonly reported side effect with rosiglitazone is upper respiratory tract infection (343). Pioglitazone has been associated with significant, as yet unexplained, elevations of creatine kinase (Takeda, Japan; Actos package insert).

In the early studies troglitazone was generally well tolerated and in the United States, in 2,510 patients enrolled in clinical trials, reversible increases in liver enzymes more than 3 times the upper limit of normal occurred in 1.9% of troglitazone-treated patients vs. 0.6% of placebo-treated patients. At this time, 20 patients had treatment discontinued because of liver function abnormalities (370). However, prescription on a larger scale has led to 43 known cases to date (9/99) of severe liver damage associated with troglitazone resulting in 28 deaths (371, 372, 373). It is currently unclear to what extent the liver damage in those patients resulted from the drug vs. other factors and whether the hepatotoxicity was substance specific, i.e., PPAR-mediated vs. idiosyncratic. Recently, two cases of hepatocellular injuries were reported in patients taking rosiglitazone (374, 375). However, the causal relationship is open to question. In large cohorts, transaminases were not found to be significantly higher with rosiglitazone compared with placebo (376). On the basis of the available data, there is currently no evidence for hepatotoxicity with pioglitazone.

The adipogenic potential of thiazolidinediones in preadipocytes in vitro and in therapeutic doses in animals in vivo (377) has been of some concern. However, clinical use in patients has not revealed weight gain beyond that seen with other agents such as sulfonylurea or insulin (378). To explain this discrepancy, it has been suggested that preadipocytes in adult humans could be relatively resistant to the adipogenic effect of thiazolidinediones or, alternatively, that increased adipogenesis per se need not necessarily cause obesity (329).

Nevertheless, the concern regarding the potential of these agents to promote differentiation has been rekindled by the observation that PPAR-activation causes fatty transformation of bone marrow stromal cells, which is considered to be a serious condition (379). Furthermore, PPARs were recently shown to be involved in differentiation and uptake of oxidized LDL by macrophages/monocytes, suggesting that endogenous PPAR ligands are important regulators of gene expression during atherogenesis (380, 381, 382). Moreover, in mice, PPAR-agonists were shown to promote carcinomatous growth in colon epithelium (383, 384) while human colonic cancer cells transplanted into mice showed a significant growth retardation after treatment with thiazolidinediones (385). However, at present, lack of data makes it impossible to determine the clinical relevance in humans for any of these regulatory mechanisms.

In rodents exposed to more than 10 times the dose of troglitazone used in humans cardiac enlargement was observed (unpublished data cited in Ref. 349). In contrast, in patients with type 2 diabetes treated with troglitazone for 2 yr no increase in left ventricular mass was reported (349) and in controlled clinical trials no increase in cardiac events was observed in troglitazone-treated patients.

6. Guidelines for the clinical use of thiazolidinediones. The only approved indication of both rosiglitazone and pioglitazone at the present time is type 2 diabetes mellitus especially in patients where insulin resistance rather than insulin deficiency is the leading pathogenic mechanism. In Europe the approval of rosiglitazone at present is limited to combination therapy with metformin or sulfonylureas. The recommended dosage is 4–8 mg for rosiglitazone and 15–30 mg for pioglitazone to be taken with meals.

Because of the liver toxicity associated with troglitazone, the American FDA recommends the monitoring of liver function for patients taking rosiglitazone or pioglitazone. Liver enzymes should be measured at the start of therapy, every 2 months during the first year, and periodically thereafter.

There is insufficient data regarding use in pregnant or breast-feeding women as well as in children. Therefore, these drugs should not be used in any of these populations. Regarding development of colon cancer, no human data are available. However, it seems prudent not to prescribe thiazolidinediones in the setting of familial adenomatosis polyposis coli (386).

D. Insulinotropic agents
1. Introduction. The hypoglycemic potency of sulfonamides was discovered twice. In 1942 the French physician Jambon recognized severe hypoglycemia in patients treated with sulfonamides for typhoid fever, but the potential implications for the treatment of type 2 diabetes mellitus were disregarded possibly due to World War II and the associated low incidence of type 2 diabetes mellitus caused by widespread malnutrition. In 1955 Franke and Fuchs (393) tested a newly developed sulfonamide (carbutamide) on themselves and experienced tremor and sweating, which they correctly interpreted as a hypoglycemic reaction. Between 1955 and 1966 sulfonylureas of the first generation were in clinical use (tolbutamide, chlorpropamide, tolazamide, and acetohexamide). In 1966 the sulfonylurea derivatives of the second generation were introduced into clinical practice, i.e., Glyburide (in Europe, glibenclamide), glipizide, and gliclazide. In 1996 the first member of the third generation of sulfonylureas, glimepiride, was approved.

The pharmacology (394, 395, 396, 397, 398), the molecular mechanism of action (399, 400, 401, 402, 403, 404, 405, 406, 407, 408, 409, 410, 411, 412, 413, 414, 415), and the clinical efficacy of sulfonylureas (416, 417, 418, 419) have been extensively described. The principal mode of the antihyperglycemic action of sulfonylureas is based on its ability to stimulate insulin secretion in the pancreatic ß-cell. Whether or not sulfonylureas possess additional extrapancreatic effects to increase peripheral insulin action and in vivo insulin sensitivity is far less clear. Since there is a lot of evidence from in vitro studies that sulfonylureas have an effect on cellular insulin action [e.g., increase of insulin-stimulated glucose transport and lipogenesis (420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433)], the current evidence of the effect of sulfonylureas on in vivo insulin action will be briefly summarized.

2. Effect of sulfonylurea on in vivo insulin sensitivity. Although the first evidence for an extrapancreatic effect of sulfonylureas was the demonstration of potentiated insulin action in pancreatectomized dogs (434, 435), the discussion about the effect of sulfonylureas on in vivo insulin sensitivity will be focused on studies in human subjects utilizing the glucose clamp technique.

a. Effect of sulfonylurea on endogenous glucose production.
A total of six studies examining the effect of various sulfonylureas on endogenous glucose production in type 2 diabetic subjects have been published (417, 436) and are summarized in Table 6. All of them found a mild reduction of endogenous glucose output due to sulfonylurea treatment, averaging 18% (range, 7–27%). Thus, from this set of data it is tempting to conclude that sulfonylurea treatment potentiates insulininduced suppression of endogenous glucose production. However, looking at the effect of sulfonylurea treatment on fasting plasma insulin levels before and after the treatment period in the different studies, it becomes evident that posttreatment fasting plasma insulin levels were increased by an average of 20% (range, 0–38%). Thus, these data suggest that at least the vast majority of the effect of sulfonylureas to reduce endogenous glucose production is mediated by increased plasma insulin levels induced by the insulinotropic action of sulfonylureas. Whether or not there is any additional intrinsic activity of sulfonylurea compounds on endogenous glucose production remains to be proven by specifically designed clamp studies maintaining constant insulin levels under which the effect of sulfonylureas per se can be examined. However, until those studies are available, the conclusion that sulfonylureas per se reduce endogenous glucose production is not justified on the basis of the results of the studies published. Furthermore, in a study examining the effect of glyburide on endogenous glucose production in type 1 diabetic subjects, Simonson et al. (437) reported that treatment with this sulfonylurea compound did not influence endogenous glucose production. These results suggest that there is neither a direct effect of sulfonylureas on endogenous glucose production nor is there a synergistic action of the drug together with insulin to decrease endogenous glucose production. In addition, Lisato et al. (438) demonstrated no effect of gliclazide on endogenous glucose production in type 2 diabetic subjects under clamp conditions designed to inhibit endogenous insulin secretion by continuous infusion of somatostatin and simultaneously maintain constant plasma insulin and glucagon levels by infusion of the hormones.

Glimepiride is a recently introduced sulfonylurea that has some interesting pharmacokinetic and pharmacodynamic properties (449, 450). The molecular mechanism of action (451, 452, 453, 454, 455) as well as the clinical efficacy of glimepiride (456, 457, 458, 459, 460, 461, 462, 463) have been recently described. One advantage of this drug is that, due to its pharmacokinetic properties, it can be taken once daily. Furthermore, this compound is of special interest in the treatment of insulin resistance, since its antihyperglycemic potency is of similar magnitude compared with sulfonylureas of the second generation, i.e., glibenclamide, although the insulinotropic action of glimepiride is less pronounced than that of glibenclamide, as has been demonstrated in animal models of insulin resistance (454). These data indicate that glimepiride may have an intrinsic extrapancreatic activity. However, until human clamp data using intravenous formulations of glimepiride are available, the clinical relevance of these findings remains speculative.

In addition, it has been suggested that glimepiride has less cardiovascular activity compared with conventional sulfonylureas, which may be advantageous in the light of possible adverse effects of sulfonylureas on the cardiovascular system (464). However, these preliminary results must be proven in large-scale randomized controlled clinical trials.

The efficacy of glimepiride has been shown in numerous controlled clinical trials, demonstrating that glimepiride decreased HbA1c by 1.2–1.9% in patients with type 2 diabetes mellitus not sufficiently controlled by diet and exercise. Furthermore, like the other sulfonylureas, glimepiride can be used in combination with other antidiabetic agents, i.e., acarbose, metformin, and insulin.

3. Adverse effects. Safety aspects of sulfonylureas have been recently reviewed (465, 466). Adverse reactions of sulfonylureas are infrequent, occurring in about 4% of the patients taking first-generation sulfonylureas and slightly less in patients on second-generation agents (467). Rare adverse events include allergic reactions, gastrointestinal intolerance, cholestatic jaundice due to hepatotoxicity, severe dermatitis, hemolytic anemia, and effects on bone marrow, i.e., thrombocytopenia and agranulocytosis. However, the most common adverse effect of sulfonylureas is hypoglycemia. In the UKPDS, the rates for any hypoglycemic episode per year were 11.0% for chlorpropamide, 17.7% for glibenclamide, 36.5% for insulin, and 1.2% for diet-treated patients (468). Comparing glimepiride with placebo, US trials have shown that hypoglycemia occurred at a cumulative incidence of 13.9 vs. 2% (469). Furthermore, in a comparative study, hypoglycemia occurred in 10% of 289 patients receiving glimepiride and 16.3% of 288 patients receiving glibenclamide, suggesting that the hypoglycemic potency of glibenclamide may be more pronounced than that of glimepiride (470). Furthermore, in vitro studies suggest that glimepiride has less severe effects on cardiovascular parameters (464, 471). However, the clinical significance of these findings remains to be examined in a large-scale randomized controlled study.

It is noteworthy that a study by Campbell (472) demonstrated that the relative mortality risk of sulfonylureainduced hypoglycemia is similar compared with the mortality risk of biguanide-induced lactic acidosis. Thus, to prevent severe hypoglycemic reactions, the use of sulfonylureas should be well indicated, and clinical situations in which regular carbohydrate intake is potentially not warranted should be recognized early.

4. Guidelines for the clinical use of sulfonylureas. Sulfonylureas should be used in type 2 diabetic patients when nonpharmacological treatment modalities and the use of noninsulinotropic antidiabetic agents (acarbose, metformin, thiazolidinediones) are insufficient to reach the individual therapeutic goal. When sulfonylureas are used as a first-line drug in the hyperinsulinemic phase of type 2 diabetes, further weight gain and perpetuation of the vicious circle would result: insulin resistance >> hyperinsulinemia >> hyperphagia >> further weight gain >> worsening of insulin resistance, etc. Thus, insulinotropic agents are not first-line drugs in these overweight/obese type 2 diabetic patients, as has been recently demonstrated by the UKPDS (239). However, sulfonylureas represent first-line drugs in nonobese type 2 diabetic patients whose main pathophysiological problem is impaired insulin secretion. Due to the above mentioned characteristics (i.e., once daily medication, potential extrapancreatic effect, less cardiovascular adverse effects in vitro, lower hypoglycemic potency) the use of glimepiride may be advantageous over sulfonylureas of the first and second generation; however, more data from controlled randomized trials are needed to verify these preliminary results.

E. Insulin
Several studies have shown that insulin therapy improves peripheral insulin sensitivity and decreases endogenous glucose production in subjects with type 1 (473, 474) as well as type 2 diabetes, which are summarized in Table 8. Even short-term intensive insulin therapy for 2–3 weeks using large amounts of insulin per day to attain normoglycemia ameliorates both peripheral insulin resistance as well as endogenous glucose production quite substantially (475, 476). Interestingly, these beneficial effects were maintained after withdrawal of insulin therapy for at least 2 weeks (477). Furthermore, the study by Garvey et al. (476) suggests that second-phase insulin secretion is enhanced by about 6-fold after restoration of normoglycemia using continuous subcutaneous insulin infusion, while first-phase insulin secretion was not significantly affected. These results indicate that short-term restoration of normoglycemia is able to reduce the detrimental effects of glucose toxicity on both peripheral glucose disposal and hepatic glucose production, as well as insulin-secretory capacity. In addition, the study by Henry et al. (478) is in support of the notion that these beneficial effects of intensive insulin therapy aiming at normoglycemia last at least 6 months, although the effect on the peripheral glucose disposal rate (GDR) was less pronounced compared with the short-term studies (475, 476) [GDR + 17% vs. GDR + 74%], while the effects on endogenous glucose production were similar. One important message of the study by Henry et al. is their finding that the improvements in glucose homeostasis were accompanied by inducing peripheral hyperinsulinemia (average insulin dose, 100 U/day) causing marked weight gain in their type 2 diabetic subjects (+ 8.7 kg during 6 months) (478). It would be of great clinical importance to determine whether the degree of body weight gain could be decreased by using a different insulin therapeutic regimen than that used by Henry et al. (478). Taking into account the predominant defect in insulin secretion of type 2 diabetes mellitus—defective first-phase insulin secretion, while second phase insulin secretion is often even increased in these still overweight/obese patients—the portion of approximately 75% NPH-insulin in the total daily insulin dose is certainly not based on the underlying pathophysiology. In most insulin-requiring but still overweight/obese type 2 diabetic subjects, basal insulin requirements during daytime are negligible to zero. Thus, it is tempting to speculate, and should be examined in controlled studies, whether restoration of normoglycemia by using meal-adapted fast acting insulin preparations during daytime (and, if required, NPH-insulin at bedtime) is able to attain normoglycemia using less units of insulin/day and, thereby preventing excessive weight gain and its known deleterious effects on human health.

	IV. Perspectives

Top Abstract I. Introduction II. Pathophysiology and... III. Pharmacological Treatment IV. Perspectives V. Summary and Conclusion References

A. Agents to enhance insulin action
The trace metal vanadium, a phosphotyrosine phosphatase inhibitor, has been shown to have antihyperglycemic potency in animal models of diabetes (484, 485) as well as in type 2 diabetic patients (486, 487, 488). These studies have shown that vanadium compounds decrease endogenous glucose production, increase peripheral glucose disposal, and reduce lipolysis. However, the antihyperglycemic efficacy of vanadyl sulfate measured by reduced fasting glucose (-2 mmol/liter) and HbA1c (-0.5%) after taking 150 mg/day for 6 weeks was relatively mild in 12 type 2 diabetic subjects. It remains to be seen whether the antihyperglycemic efficacy can be improved by increasing intestinal absorption using modified vanadium compounds, such as bis-(maltolato)oxovanadium (489).

Another example of a compound that enhances insulin signaling by activating insulin receptor tyrosine kinase activity has recently been described by Moller and colleagues (490). By using a screening approach, this group has identified a nonpeptidyl fungal metabolite that selectively activates the insulin receptor tyrosine kinase. Moreover, these authors showed that oral administration of this small molecule to db/db and ob/ob mouse models of diabetes caused amelioration of hyperglycemia and hyperinsulinemia. However, numerous studies especially focusing on the possible mitogenicity of this compound must be performed before the potential clinical value can be assessed.

Prospectively, the engineering of drugs enhancing insulin action will be greatly stimulated and facilitated as soon as the molecular mechanism of insulin-stimulated glucose transport has been completely resolved.

B. Agents to increase insulin secretion
Glucagon-like peptide 1 (GLP-1) acts as an incretin to increase meal-stimulated insulin secretion by binding to GLP-1 receptors in the ß-cell membrane. Studies by Nauck et al. (491) and others have demonstrated that subcutaneous administration of GLP-1 in type 2 diabetic subjects lowered plasma glucose by increasing insulin secretion and decreasing glucagon secretion. However, due to its short plasma half-life of less than 5 min and the need for parenteral administration, more stable nonpeptidyl GLP-1 receptor agonists are being developed for oral administration.

Recently, BTS 67582, a morpholinoguanidine substance with insulinotropic activity, was tested in type 2 diabetic patients (492). BTS 67582 stimulates insulin secretion by closing K⁺- ATP channels in ß-cell membranes. The binding site of BTS 67582 is different compared with glibenclamide. Interestingly, BTS 67582 was still active in animals that were no longer responsive to glibenclamide (493). Whether or not BTS 67582 has extrapancreatic effects due to its guanidine moiety has not been examined in clamp studies, although in vitro evidence mitigates against this tempting speculation (494).

C. Agents to inhibit fatty acid oxidation
Inhibitors of carnitine palmitoyltransferase 1 (CPT-1), which is the rate-limiting enzyme for transfer of long-chain fatty acyl-CoA into the mitochondria, like etomoxir, have been shown to have antihyperglycemic activity in type 2 diabetic patients, predominantly due to inhibiting hepatic gluconeogenesis and decreasing plasma triglyceride concentrations (495). Furthermore, in the spontaneously hypertensive rat model, acute etomoxir treatment improved glucose tolerance and blood pressure significantly, suggesting an increased insulin sensitivity (496). However, Hubinger et al. (497) failed to demonstrate any effect of etomoxir treatment (100 mg/day) for 3 days in a placebo-controlled, randomized, double-blind study of 12 type 2 diabetic subjects. Prospectively, the slow reversibility of the antigluconeogenic effect of CPT-1 inhibitors and the resulting interrupted defense against hypoglycemia may limit the clinical usefulness of these compounds (498). Thus, based on the currently available data, agents to inhibit fatty acid oxidation do not have a marked antihyperglycemic potency.

	V. Summary and Conclusion

Top Abstract I. Introduction II. Pathophysiology and... III. Pharmacological Treatment IV. Perspectives V. Summary and Conclusion References

 
Peripheral insulin resistance, ß-cell dysfunction, and increased endogenous glucose production are the major pathophysiologically abnormalities in type 2 diabetes mellitus. The oral antihyperglycemic agents known to ameliorate one or more of these processes, which are discussed in this review, are shown in Fig. 4. Agents that may eventually supplement our therapeutic potential are included.

View larger version (114K): [in this window] [in a new window]   Figure 4. Antihyperglycemic agents. Summary of hyperglycemic agents currently available and potential new therapeutic targets and substances.

View larger version (82K): [in this window] [in a new window]   Figure 5. Starling’s curve of the pancreas and rational treatment of type 2 diabetes mellitus. Starling’s curve of the pancreas as originally described by DeFronzo et al. (245 ), indicating the relationship of mean plasma insulin levels during an oral glucose tolerance test (OGTT) and fasting plasma glucose levels of subjects with normal glucose tolerance, IGT, and type 2 diabetes. The depicted therapeutic options should be selected according to the pathophysiological stage of the individual patient. SU, Sulfonylureas.

If the individual HbA1c-treatment goal has not been reached after 3 months and the patient is still overweight/obese (BMI > 25 kg/m²), antihyperglycemic agents should be selected, which do not cause appreciable weight gain by increasing the preexisting hyperinsulinemia, i.e., -glucosidase inhibitors, metformin, or thiazolidinediones. Selecting these agents during this stage of the disease utilizes the endogenous hyperinsulinemia to improve insulin action and does not impede the goal of weight reduction by further increasing hyperinsulinemia/insulin resistance due to insulinotropic agents. If necessary during the course of the disease, combinations of these noninsulinotropic compounds can be selected, which have been proven to be efficacious (356, 499, 500).

If combinations of these noninsulinotropic agents are no longer effective during the progression of the disease, insulinotropic agents such as sulfonylureas or meglitinides should be started. If, at this point, obesity is still present, combination therapy with noninsulinotropic agents is indicated.

If oral insulinotropic agents are not sufficient to reach the HbA1c-goal, insulin therapy must be initiated. The study by Yki-Järvinen et al. (316) examining different treatment protocols for type 2 diabetic subjects suffering from secondary sulfonylurea failure has indicated that bedtime NPH-insulin combined with metformin during daytime is superior to other combinations of metformin, sulfonylurea, and insulin protocols to obtain the highest reduction in HbA1c and the lowest gain in body weight. Thus, this treatment option should be used preferentially when type 2 diabetic patients enter this stage of the disease. With advancing disease duration associated with progressive deterioration of ß-cell function, insulin substitution also during daytime is often required to achieve near-normoglycemia. In this respect, the introduction of fast-acting insulin analogs such as insulin lispro (1996) and insulin aspart (1999) has made it possible to optimize our treatment of the insulin-requiring and often still overweight/obese type 2 diabetic patient with as minimal as possible exogenous, meal-adapted insulin during daytime. Since in the vast majority of overweight/obese insulinrequiring type 2 diabetic patients, endogenous insulin secretion is still sufficient to maintain basal insulinemia, generally there is no need for basal insulin supplementation during the day. Moreover, unnecessary daytime basal insulin supplementation may cause weight gain and increased frequency of hypoglycemia. Thus, although data from large-scale randomized controlled clinical trials are currently not available, the pathophysiological guided daytime insulin therapy of the insulin-requiring and still overweight/obese type 2 diabetic patient should strive to substitute the deficient meal-related insulin-secretory response by using fast-acting insulin analogs. Unfortunately, however, until now most of these diabetic patients still get either daytime basal insulin supplementation or some kind of fixed insulin mixtures containing 70–80% basal insulin. In this context, randomized controlled clinical trials are urgently needed to compare insulin treatment protocols for overweight/obese type 2 diabetic subjects used so far with meal-adapted protocols using fast-acting analogs with respect to units of insulin per day needed to achieve near-normoglycemia and the corresponding effect on weight gain. Based on the nature of the ß-cell defect in the still overweight/obese type 2 diabetes patient, it is tempting to speculate that the protocol using meal-adapted fast-acting insulin analogs might achieve near- normoglycemia with lower total daily insulin dosage accompanied by significantly less weight gain. In this regard, the results of these trails would have a tremendous impact on the insulin-treatment recommendations for the subjects with type 2 diabetes entering this stage of the disease. In addition, to further decrease the exogenous insulin dose in the treatment of overweight/obese insulin-requiring type 2 diabetic subjects, additional therapy with noninsulinotropic agents has been shown to reduce the insulin dose by 20–30%, and the possible clinical benefit should be evaluated in the individual patient (507).

In conclusion, the optimal therapy of patients with type 2 diabetes mellitus requires a multifaceted therapeutic approach including patient education, life style changes, and pharmacological antihyperglycemic and antihypertensive, as well as antihyperlipidemic, therapy. Future efforts should focus on preventive strategies using educational and possibly (dependent upon the outcome of ongoing studies) pharmacological interventions in an attempt to lower the number of patients with the metabolic syndrome, IGT, and overt type 2 diabetes mellitus, thereby reducing the disabling individual and socioeconomic burden for society.

	Footnotes

 
Address reprint requests to: Hans-Ulrich Häring, M.D., Department of Internal Medicine IV, University of Tübingen, Otfried-Müller-Strasse 10, D-72076 Tübingen, Germany. E-mail: Hans-Ulrich.Haering{at}med.uni-tuebingen.de

¹ The work of the authors has been supported by the German Research Foundation (DFG), the European Community (Biomed-Program), the intramural fortüne-program of the University of Tübingen, Aventis (Germany), Bayer Corp. (Germany), NovoNordisk (Denmark), Merck (Germany), Sankyo Co., Ltd. (Japan), and SmithKline Beecham (United Kingdom).

	References

Top Abstract I. Introduction II. Pathophysiology and... III. Pharmacological Treatment IV. Perspectives V. Summary and Conclusion References

 

1. Gerich JE 1998 The genetic basis of type 2 diabetes mellitus: impaired insulin secretion vs. impaired insulin sensitivity. Endocr Rev 19:491–503[Abstract/Free Full Text]
2. DeFronzo RA 1992 Pathogenesis of type 2 (non-insulin dependent) diabetes mellitus: a balanced overview. Diabetologia 35:389–397[CrossRef][Medline]
3. Yki-Järvinen H 1994 Pathogenesis of non-insulin-dependent diabetes mellitus. Lancet 343:91–95[CrossRef][Medline]
4. Ferrannini E 1998 Insulin resistance vs. insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects. Endocr Rev 19:477–490[Abstract/Free Full Text]
5. Kahn CR 1994 Banting Lecture. Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes 4:1066–1084
6. Olefsky JM 1993 Insulin resistance and the pathogenesis of non-insulin-dependent diabetes mellitus: cellular and molecular mechanisms. Adv Exp Med Biol 334:129–150[Medline]
7. Häring HU 1999 Pathogenesis of type II diabetes: are there common causes for insulin resistance and secretion failure? Exp Clin Endocrinol Diabetes 107[Suppl.2]:S17–S23
8. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus 1999 Diabetes Care 22[Suppl 1]:S5–S19
9. Beck Nielsen H, Groop LC 1994 Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 94:1714–1721
10. Kelley DE 1995 Effects of weight loss on glucose homeostasis in NIDDM. Diabetes Rev 3:366–377
11. Schneider SH, Morgado A 1995 Effects of fitness and physical training on carbohydrate metabolism and associated cardiovascular risk factors in patients with diabetes. Diabetes Rev 3:378–407
12. Levy J, Atkinson AB, Bell PM, McCance DR, Hadden DR 1998 Beta-cell deterioration determines the onset and rate of progression of secondary dietary failure in type 2 diabetes mellitus: the 10 year follow-up of the Belfast Diet Study. Diabet Med 15:290–296[CrossRef][Medline]
13. Turner RC, Cull CA, Frighi V, Holman RR 1999 Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 281:2005–2012[Abstract/Free Full Text]
14. Fox C 1999 Diabetes and hypertension: an era of clarity or confusion. J Hum Hypertens 13[Suppl 2]:S9–S17
15. UKPDS-Study Group 1998 Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J 317:703–713[Abstract/Free Full Text]
16. UKPDS-Study Group 1998 Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. Br Med J 317:713–720[Abstract/Free Full Text]
17. Taskinen MR 1999 Strategies for the management of diabetic dyslipidemia. Drugs 58[Suppl 1]:47–51
18. Howard BV 1999 Insulin resistance and lipid metabolism. Am J Cardiol 84 (1A):28J–32J
19. Vague P, Juhan-Vague I 1997 Fibrinogen, fibrinolysis and diabetes mellitus: a comment. Diabetologia 40:738–740[CrossRef][Medline]
20. Tschoepe D, Roesen P 1998 Heart disease in diabetes mellitus: a challenge for early diagnosis and intervention. Exp Clin Endocrinol Diabetes 106:16–24[Medline]
21. Gerich JE 1991 Is muscle the major site of insulin resistance in type 2 (non-insulin-dependent) diabetes mellitus? Diabetologia 34:607–610[CrossRef][Medline]
22. Moller DE, Flier JS 1991 Insulin resistance–mechanisms, syndromes, and implications. N Engl J Med 325:938–948[Medline]
23. Garvey WT, Birnbaum MJ 1993 Cellular insulin action and insulin resistance. Baillieres Clin Endocrinol Metab 7:785–873[CrossRef][Medline]
24. DeFronzo RA, Tobin JD, Andres R 1979 Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 237:E214–E223
25. Mitrakou A, Kelley D, Veneman T, Jenssen T, Pangburn T, Reilly J, Gerich J 1990 Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes 39:1381–1390[Abstract]
26. Kelley D, Mitrakou A, Marsh H, Schwenk F, Benn J, Sonnenberg G, Arcangeli M, Aoki T, Sorensen J, Berger M, Sonksen P, Gerich J 1988 Skeletal muscle glycolysis, oxidation, and storage of an oral glucose load. J Clin Invest 81:1563–1571
27. Ferrannini E, Bjorkman O, Reichard Jr GA, Pilo A, Olsson M, Wahren J, DeFronzo RA 1985 The disposal of an oral glucose load in healthy subjects. A quantitative study. Diabetes 34:580–588[Abstract]
28. Pimenta W, Korytkowski M, Mitrakou A, Jenssen T, Yki-Järvinen H, Evron W, Dailey G, Gerich J 1995 Pancreatic ß-cell dysfunction as the primary genetic lesion in NIDDM. Evidence from studies in normal glucose-tolerant individuals with a first-degree NIDDM relative. JAMA 273:1855–1861[Abstract/Free Full Text]
29. Volk A, Renn W, Overkamp D, Mehnert B, Maerker E, Jacob S, Balletshofer B, Haring HU, Rett K 1999 Insulin action and secretion in healthy, glucose tolerant first degree relatives of patients with type 2 diabetes mellitus. Influence of body weight. Exp Clin Endocrinol Diabetes 107:140–147[Medline]
30. Finegood DT, Bergman RN, Vranic M 1987 Estimation of endogenous glucose production during hyperinsulinemic-euglycemic glucose clamps. Comparison of unlabeled and labeled exogenous glucose infusates. Diabetes 36:914–924[Abstract]
31. Stumvoll M, Meyer C, Mitrakou A, Nadkarni V, Gerich JE 1997 Renal glucose production and utilization: new aspects in humans. Diabetologia 40:749–757[CrossRef][Medline]
32. Perriello G, Pampanelli S, Del-Sindaco P, Lalli C, Ciofetta M, Volpi E, Santeusanio F, Brunetti P, Bolli GB 1997 Evidence of increased systemic glucose production and gluconeogenesis in an early stage of NIDDM. Diabetes 46:1010–1016[Abstract]
33. DeFronzo RA, Simonson D, Ferrannini E 1982 Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia 23:313–319[Medline]
34. Campbell PJ, Mandarino LJ, Gerich JE 1988 Quantification of the relative impairment in actions of insulin on hepatic glucose production and peripheral glucose uptake in non-insulin-dependent diabetes mellitus. Metabolism 37:15–21[CrossRef][Medline]
35. Bogardus C, Lillioja S, Howard BV, Reaven G, Mott D 1984 Relationships between insulin secretion, insulin action, and fasting plasma glucose concentration in nondiabetic and noninsulindependent diabetic subjects. J Clin Invest 74:1238–1246
36. Ferrannini E, Smith JD, Cobelli C, Toffolo G, Pilo A, DeFronzo RA 1985 Effect of insulin on the distribution and disposition of glucose in man. J Clin Invest 76:357–364
37. Mitrakou A, Kelley D, Veneman T, Jenssen T, Pangburn T, Reilly J, Gerich J 1990 Contribution of abnormal muscle and liver glucose metabolism to postprandial hyperglycemia in NIDDM. Diabetes 39:1381–1390
38. Randle PJ, Priestman DA, Mistry SC, Halsall A 1994 Glucose fatty acid interactions and the regulation of glucose disposal. J Cell Biochem 55[Suppl]:1–11
39. Saloranta C, Groop L 1996 Interactions between glucose and FFA metabolism in man. Diabetes Metab Rev 12:15–36[CrossRef][Medline]
40. Boden G 1997 Role of fatty acids in the pathogenesis of insulin resistance and NIDDM [published erratum appears in Diabetes 1997 Mar;46(3):536]. Diabetes 46:3–10[Abstract]
41. Foley JE 1992 Rationale and application of fatty acid oxidation inhibitors in treatment of diabetes mellitus. Diabetes Care 15:773–784[Abstract]
42. Nurjhan N, Consoli A, Gerich J 1992 Increased lipolysis and its consequences on gluconeogenesis in non-insulin-dependent diabetes mellitus. J Clin Invest 89:169–175
43. Campbell PJ, Mandarino LJ, Gerich JE 1988 Quantification of the relative impairment in actions of insulin on hepatic glucose production and peripheral glucose uptake in non-insulin-dependent diabetes mellitus. Metabolism 37:15–21
44. Groop LC, Bonadonna RC, Del Prato S, Ratheiser K, Zyck K, Ferrannini E, DeFronzo RA 1989 Glucose and free fatty acid metabolism in non-insulin-dependent diabetes mellitus. Evidence for multiple sites of insulin resistance. J Clin Invest 84:205–213
45. Bonadonna RC, Groop L, Kraemer N, Ferrannini E, Del Prato S, DeFronzo RA 1990 Obesity and insulin resistance in humans: a dose-response study. Metabolism 39:452–459[CrossRef][Medline]
46. Campbell PJ, Carlson MG, Hill JO, Nurjhan N 1992 Regulation of free fatty acid metabolism by insulin in humans: role of lipolysis and reesterification. Am J Physiol 263:E1063–E1069
47. Campbell PJ, Carlson MG, Nurjhan N 1994 Fat metabolism in human obesity. Am J Physiol 266:E600–E605
48. Nurjhan N, Campbell PJ, Kennedy FP, Miles JM, Gerich JE 1986 Insulin dose-response characteristics for suppression of glycerol release and conversion to glucose in humans. Diabetes 35:1326–1331[Abstract]
49. Groop LC, Bonadonna RC, Simonson DC, Petrides AS, Shank M, DeFronzo RA 1992 Effect of insulin on oxidative and nonoxidative pathways of free fatty acid metabolism in human obesity. Am J Physiol 263:E79–E84
50. Mitrakou A, Kelley D, Mokan M, Veneman T, Pangburn T, Reilly J, Gerich J 1992 Role of reduced suppression of glucose production and diminished early insulin release in impaired glucose tolerance. N Engl J Med 326:22–29[Abstract]
51. Berrish TS, Hetherington CS, Alberti KG, Walker M 1995 Peripheral and hepatic insulin sensitivity in subjects with impaired glucose tolerance. Diabetologia 38:699–704[Medline]
52. Kellerer M, Lammers R, Haring HU 1999 Insulin signal transduction: possible mechanisms for insulin resistance. Exp Clin Endocrinol Diabetes 107:97–106[Medline]
53. Kasuga M, Karlsson FA, Kahn CR 1982 Insulin stimulates the phosphorylation of the 95,000-dalton subunit of its own receptor. Science 215:185–187[Abstract/Free Full Text]
54. Thies RS, Molina JM, Ciaraldi TP, Freidenberg GR, Olefsky JM 1990 Insulin-receptor autophosphorylation and endogenous substrate phosphorylation in human adipocytes from control, obese, and NIDDM subjects. Diabetes 39:250–259[Abstract]
55. Freidenberg GR, Henry RR, Klein HH, Reichart DR, Olefsky JM 1987 Decreased kinase activity of insulin receptors from adipocytes of non-insulin-dependent diabetic subjects. J Clin Invest 79:240–250
56. Caro JF, Sinha MK, Raju SM, Ittoop O, Pories WJ, Flickinger EG, Meelheim D, Dohm GL 1987 Insulin receptor kinase in human skeletal muscle from obese subjects with and without noninsulin dependent diabetes. J Clin Invest 79:1330–1337
57. Klein HH, Vestergaard H, Kotzke G, Pedersen O 1995 Elevation of serum insulin concentration during euglycemic hyperinsulinemic clamp studies leads to similar activation of insulin receptor kinase in skeletal muscle of subjects with and without NIDDM. Diabetes 44:1310–1317[Abstract]
58. Bak JF, Moller N, Schmitz O, Saaek A, Pedersen O 1992 In vivo insulin action and muscle glycogen synthase activity in type 2 (non-insulin-dependent) diabetes mellitus: effects of diet treatment. Diabetologia 35:777–784[Medline]
59. Obermaier-Kusser B, White MF, Pongratz DE, Su Z, Ermel B, Muhlbacher C, Haring HU 1989 A defective intramolecular autoactivation cascade may cause the reduced kinase activity of the skeletal muscle insulin receptor from patients with non-insulin-dependent diabetes mellitus. J Biol Chem 264:9497–9504[Abstract/Free Full Text]
60. Nyomba BL, Ossowski VM, Bogardus C, Mott DM 1990 Insulin-sensitive tyrosine kinase: relationship with in vivo insulin action in humans. Am J Physiol 258:E964–E974
61. Maegawa H, Shigeta Y, Egawa K, Kobayashi M 1991 Impaired autophosphorylation of insulin receptors from abdominal skeletal muscles in nonobese subjects with NIDDM. Diabetes 40:815–819[Abstract]
62. Nolan JJ, Freidenberg G, Henry R, Reichart D, Olefsky JM 1994 Role of human skeletal muscle insulin receptor kinase in the in vivo insulin resistance of noninsulin-dependent diabetes mellitus and obesity. J Clin Endocrinol Metab 78:471–477[Abstract]
63. Freidenberg GR, Reichart D, Olefsky JM, Henry RR 1988 Reversibility of defective adipocyte insulin receptor kinase activity in non-insulin-dependent diabetes mellitus. Effect of weight loss. J Clin Invest 82:1398–1406
64. White MF, Maron R, Kahn CR 1985 Insulin rapidly stimulates tyrosine phosphorylation of a Mr-185,000 protein in intact cells. Nature 318:183–186[CrossRef][Medline]
65. Sun XJ, Rothenberg P, Kahn CR, Backer JM, Araki E, Wilden PA, Cahill DA, Goldstein BJ, White MF 1991 Structure of the insulin receptor substrate IRS-1 defines a unique signal transduction protein. Nature 352:73–77[CrossRef][Medline]
66. Sun XJ, Wang LM, Zhang Y, Yenush L, Myers-MG J, Glasheen E, Lane WS, Pierce JH, White MF 1995 Role of IRS-2 in insulin and cytokine signalling. Nature 377:173–177[CrossRef][Medline]
67. Lavan BE, Fantin VR, Chang ET, Lane WS, Keller SR, Lienhard GE 1997 A novel 160-kDa phosphotyrosine protein in insulin-treated embryonic kidney cells is a new member of the insulin receptor substrate family. J Biol Chem 272:21403–21407[Abstract/Free Full Text]
68. Lavan BE, Lane WS, Lienhard GE 1997 The 60-kDa phosphotyrosine protein in insulin-treated adipocytes is a new member of the insulin receptor substrate family. J Biol Chem 272:11439–11443[Abstract/Free Full Text]
69. Tamemoto H, Kadowaki T, Tobe K, Yagi T, Sakura H, Hayakawa T, Terauchi Y, Ueki K, Kaburagi Y, Satoh S, Sekihara H, Yoshioka S, Horikoshi H, Furuta Y, Ikawa Y, Kasuga M, Yazaki Y, Aizawa S 1994 Insulin resistance and growth retardation in mice lacking insulin receptor substrate-1. Nature 372:182–186[CrossRef][Medline]
70. Araki E, Lipes MA, Patti ME, Bruning JC, Haag B, Johnson RS, Kahn CR 1994 Alternative pathway of insulin signalling in mice with targeted disruption of the IRS-1 gene. Nature 372:186–190[CrossRef][Medline]
71. Withers DJ, Gutierrez JS, Towery H, Burks DJ, Ren JM, Previs S, Zhang Y, Bernal D, Pons S, Shulman GI, Bonner WS, White MF 1998 Disruption of IRS-2 causes type 2 diabetes in mice. Nature 391:900–904[CrossRef][Medline]
72. Alessi DR, James SR, Downes CP, Holmes AB, Gaffney PR, Reese CB, Cohen P 1997 Characterization of a 3-phosphoinositidedependent protein kinase which phosphorylates and activates protein kinase B. Curr Biol 7:261–269[CrossRef][Medline]
73. Marte BM, Downward J 1997 PKB/Akt: connecting phosphoinositide 3-kinase to cell survival and beyond. Trends Biochem Sci 22:355–358[CrossRef][Medline]
74. Chou MM, Hou W, Johnson J, Graham LK, Lee MH, Chen CS, Newton AC, Schaffhausen BS, Toker A 1998 Regulation of protein kinase C zeta by PI 3-kinase and PDK-1. Curr Biol 8:1069–1077[CrossRef][Medline]
75. Le-Good JA, Ziegler WH, Parekh DB, Alessi DR, Cohen P, Parker PJ 1998 Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1. Science 281:2042–2045[Abstract/Free Full Text]
76. Mendez R, Kollmorgen G, White MF, Rhoads RE 1997 Requirement of protein kinase C for stimulation of protein synthesis by insulin. Mol Cell Biol 17:5184–5192[Abstract]
77. Standaert ML, Galloway L, Karnam P, Bandyopadhyay G, Moscat J, Farese RV 1997 Protein kinase C- as a downstream effector of phosphatidylinositol 3-kinase during insulin stimulation in rat adipocytes. Potential role in glucose transport. J Biol Chem 272:30075–30082[Abstract/Free Full Text]
78. Kotani K, Ogawa W, Matsumoto M, Kitamura T, Sakaue H, Hino Y, Miyake K, Sano W, Akimoto K, Ohno S, Kasuga M 1998 Requirement of atypical protein kinase clambda for insulin stimulation of glucose uptake but not for Akt activation in 3T3–L1 adipocytes. Mol Cell Biol 18:6971–6982[Abstract/Free Full Text]
79. Krook A, Roth RA, Jiang XJ, Zierath JR, Wallberg-Henriksson H 1998 Insulin-stimulated Akt kinase activity is reduced in skeletal muscle from NIDDM subjects. Diabetes 47:1281–1286[Abstract]
80. Kim YB, Nikoulina SE, Ciaraldi TP, Henry RR, Kahn BB 1999 Normal insulin-dependent activation of Akt/protein kinase B, with diminished activation of phosphoinositide 3-kinase, in muscle in type 2 diabetes. J Clin Invest 104:733–741[Medline]
81. Bjornholm M, Kawano Y, Lehtihet M, Zierath JR 1997 Insulin receptor substrate-1 phosphorylation and phosphatidylinositol 3-kinase activity in skeletal muscle from NIDDM subjects after in vivo insulin stimulation. Diabetes 46:524–527[Abstract]
82. Goodyear LJ, Giorgino F, Sherman LA, Carey J, Smith RJ, Dohm GL 1995 Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J Clin Invest 95:2195–2204
83. Taylor SI 1992 Lilly Lecture: molecular mechanisms of insulin resistance. Lessons from patients with mutations in the insulin-receptor gene. Diabetes 41:1473–1490[Abstract]
84. Kahn CR, Vicent D, Doria A 1996 Genetics of non-insulin-dependent (type-II) diabetes mellitus. Annu Rev Med 47:509–531[CrossRef][Medline]
85. O’Rahilly S, Choi WH, Patel P, Turner RC, Flier JS, Moller DE 1991 Detection of mutations in insulin-receptor gene in NIDDM patients by analysis of single-stranded conformation polymorphisms. Diabetes 40:777–782[Abstract]
86. Cocozza S, Porcellini A, Riccardi G, Monticelli A, Condorelli G, Ferrara A, Pianese L, Miele C, Capaldo B, Beguinot F, Varrone S 1992 NIDDM associated with mutation in tyrosine kinase domain of insulin receptor gene. Diabetes 41:521–526[Abstract]
87. Hart LM, Stolk RP, Heine RJ, Grobbee DE, van-der-Does FE, Maassen JA 1996 Association of the insulin-receptor variant Met-985 with hyperglycemia and non-insulin-dependent diabetes mellitus in the Netherlands: a population-based study. Am J Hum Genet 59:1119–1125[Medline]
88. Almind K, Bjorbaek C, Vestergaard H, Hansen T, Echwald S, Pedersen O 1993 Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus. Lancet 342:828–832[CrossRef][Medline]
89. Bernal D, Almind K, Yenush L, Ayoub M, Zhang Y, Rosshani L, Larsson C, Pedersen O, White MF 1998 Insulin receptor substrate-2 amino acid polymorphisms are not associated with random type 2 diabetes among Caucasians. Diabetes 47:976–979[Medline]
90. Almind K, Inoue G, Pedersen O, Kahn CR 1996 A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies. J Clin Invest 97:2569–2575[Medline]
91. Clausen JO, Hansen T, Bjorbaek C, Echwald SM, Urhammer SA, Rasmussen S, Andersen CB, Hansen L, Almind K, Winther K, Haraldsdòttir J, Borch-Johnsen K, Pedersen O 1995 Insulin resistance: interactions between obesity and a common variant of insulin receptor substrate-1. Lancet 346:397–402[CrossRef][Medline]
92. Zhang Y, Wat N, Stratton IM, Warren PM, Orho M, Groop L, Turner RC 1996 UKPDS 19: heterogeneity in NIDDM: separate contributions of IRS-1 and beta 3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations. UK Prospective Diabetes Study. Diabetologia 39:1505–1511[CrossRef][Medline]
93. Koch M, Rett K, Volk A, Maerker E, Haist K, Deninger M, Renn W, Häring HU 1999 Amino acid polymorphism Gly972Arg in IRS-1 is not associated to clamp-derived insulin sensitivity in young healthy first degree relatives of patients with Type 2-diabetes. Exp Clin Endocrinol Diabetes 107:318–322[Medline]
94. Porzio O, Federici M, Hribal ML, Lauro D, Accili D, Lauro R, Borboni P, Sesti G 1999 The Gly972–>Arg amino acid polymorphism in IRS-1 impairs insulin secretion in pancreatic beta cells. J Clin Invest 104:357–364[Medline]
95. Bektas A, Warram JH, White MF, Krolewski AS, Doria A 1999 Exclusion of insulin receptor substrate 2 (IRS-2) as a major locus for early-onset autosomal dominant type 2 diabetes. Diabetes 48:640–642[Abstract]
96. Shepherd PR, Withers DJ, Siddle K 1998 Phosphoinositide 3kinase: the key switch mechanism in insulin signalling. Biochem J 333:471–490
97. Shepherd PR, Nave BT, Rincon J, Nolte LA, Bevan AP, Siddle K, Zierath JR, Wallberg HH 1997 Differential regulation of phosphoinositide 3-kinase adapter subunit variants by insulin in human skeletal muscle. J Biol Chem 272:19000–19007[Abstract/Free Full Text]
98. Terauchi Y, Tsuji Y, Satoh S, Minoura H, Murakami K, Okuno A, Inukai K, Asano T, Kaburagi Y, Ueki K, Nakajima H, Hanafusa T, Matsuzawa Y, Sekihara H, Yin Y, Barrett JC, Oda H, Ishikawa T, Akanuma Y, Komuro I, Suzuki M, Yamamura K, Kodama T, Suzuki H, Koyasu S, Aizawa S, Tobe K, Fukni Y, Yazaki Y, Kadowaki T, et al 1999 Increased insulin sensitivity and hypoglycaemia in mice lacking the p85 subunit of phosphoinositide 3-kinase. Nat Genet 21:230–235[CrossRef][Medline]
99. Hansen T, Andersen CB, Echwald SM, Urhammer SA, Clausen JO, Vestergaard H, Owens D, Hansen L, Pedersen O 1997 Identification of a common amino acid polymorphism in the p85alpha regulatory subunit of phosphatidylinositol 3-kinase: effects on glucose disappearance constant, glucose effectiveness, and the insulin sensitivity index. Diabetes 46:494–501[Abstract]
100. Kawanishi M, Tamori Y, Masugi J, Mori H, Ito C, Hansen T, Andersen CB, Pedersen O, Kasuga M 1997 Prevalence of a polymorphism of the phosphatidylinositol 3-kinase p85 alpha regulatory subunit (codon 326 Met–>Ile) in Japanese NIDDM patients [letter]. Diabetes Care 20:1043[Medline]
101. Baier LJ, Wiedrich C, Hanson RL, Bogardus C 1998 Variant in the regulatory subunit of phosphatidylinositol 3-kinase (p85alpha): preliminary evidence indicates a potential role of this variant in the acute insulin response and type 2 diabetes in Pima women. Diabetes 47:973–975[Medline]
102. Kahn CR, Vicent D, Doria A 1996 Genetics of non-insulin-dependent (type-II) diabetes mellitus. Annu Rev Med 47:509–531
103. Prochazka M, Lillioja S, Tait JF, Knowler WC, Mott DM, Spraul M, Bennett PH, Bogardus C 1993 Linkage of chromosomal markers on 4q with a putative gene determining maximal insulin action in Pima Indians. Diabetes 42:514–519[Abstract]
104. Thompson DB, Janssen RC, Ossowski VM, Prochazka M, Knowler WC, Bogardus C 1995 Evidence for linkage between a region on chromosome 1p and the acute insulin response in Pima Indians. Diabetes 44:478–481[Abstract]
105. Hanis CL, Boerwinkle E, Chakraborty R, Ellsworth DL, Concannon P, Stirling B, Morrison VA, Wapelhorst B, Spielman RS, Gogolin EK, Shepard JM, Williams SR, Risch N, Hinds D, Iwasaki N, Ogata M, Omori Y, Petzold C, Rietzch H, Schroder HE, Schulze J, Cox NJ, Menzel S, Boriraj VV, Chen X, Lim LR, Lindner T, Mereu LE, Wang YQ, Xiang K, Yamagata K, Yang Y, Bell GI 1996 A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet 13:161–166[CrossRef][Medline]
106. Stern MP, Duggirala R, Mitchell BD, Reinhart LJ, Shivakumar S, Shipman PA, Uresandi OC, Benavides E, Blangero J, O’Connell P 1996 Evidence for linkage of regions on chromosomes 6 and 11 to plasma glucose concentrations in Mexican Americans. Genome Res 6:724–734[Abstract/Free Full Text]
107. Mahtani MM, Widen E, Lehto M, Thomas J, McCarthy M, Brayer J, Bryant B, Chan G, Daly M, Forsblom C, Kanninen T, Kirby A, Kruglyak L, Munnelly K, Parkkonen M, Reeve DM, Weaver A, Brettin T, Duyk G, Lander ES, Groop LC 1996 Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nat Genet 14:90–94[CrossRef][Medline]
108. Elbein SC, Bragg KL, Hoffman MD, Mayorga RA, Leppert MF 1996 Linkage studies of NIDDM with 23 chromosome 11 markers in a sample of whites of northern European descent. Diabetes 45:370–375[Abstract]
109. Ji L, Malecki M, Warram JH, Yang Y, Rich SS, Krolewski AS 1997 New susceptibility locus for NIDDM is localized to human chromosome 20q. Diabetes 46:876–881[Abstract]
110. Bowden DW, Sale M, Howard TD, Qadri A, Spray BJ, Rothschild CB, Akots G, Rich SS, Freedman BI 1997 Linkage of genetic markers on human chromosomes 20 and 12 to NIDDM in Caucasian sib pairs with a history of diabetic nephropathy. Diabetes 46:882–886[Abstract]
111. Zouali H, Hani EH, Philippi A, Vionnet N, Beckmann JS, Demenais F, Froguel P 1997 A susceptibility locus for early-onset non-insulin dependent (type 2) diabetes mellitus maps to chromosome 20q, proximal to the phosphoenolpyruvate carboxykinase gene. Hum Mol Genet 6:1401–1408[Abstract/Free Full Text]
112. Pratley RE, Thompson DB, Prochazka M, Baier L, Mott D, Ravussin E, Sakul H, Ehm MG, Burns DK, Foroud T, Garvey WT, Hanson RL, Knowler WC, Bennett PH, Bogardus C 1998 An autosomal genomic scan for loci linked to prediabetic phenotypes in Pima Indians. J Clin Invest 101:1757–1764[Medline]
113. Hanson RL, Ehm MG, Pettitt DJ, Prochazka M, Thompson DB, Timberlake D, Foroud T, Kobes S, Baier L, Burns DK, Almasy L, Blangero J, Garvey WT, Bennett PH, Knowler WC 1998 An autosomal genomic scan for loci linked to type II diabetes mellitus and body-mass index in Pima Indians. Am J Hum Genet 63:1130–1138[CrossRef][Medline]
114. Elbein SC, Hoffman MD, Teng K, Leppert MF, and Hasstedt SJ 1999 A genome-wide search for type 2 diabetes susceptibility genes in Utah Caucasians. Diabetes 48:1175–1182[Abstract]
115. Ghosh S, Watanabe RM, Hauser ER, Valle T, Magnuson VL, Erdos MR, Langefeld CD, Balow J, Ally DS, Kohtamaki K, Chines P, Birznieks G, Kaleta HS, Musick A, Te C, Tannenbaum J, Eldridge W, Shapiro S, Martin C, Witt A, So A, Chang J, Shurtleff B, Porter R, Boehnke M, et al 1999 Type 2 diabetes: evidence for linkage on chromosome 20 in 716 Finnish affected sib pairs. Proc Natl Acad Sci USA 96:2198–2203[Abstract/Free Full Text]
116. Stern MP, Mitchell BD, Blangero J, Reinhart L, Krammerer CM, Harrison CR, Shipman PA, O’Connell P, Frazier ML, MacCluer JW 1996 Evidence for a major gene for type II diabetes and linkage analyses with selected candidate genes in Mexican-Americans. Diabetes 45:563–568[Abstract]
117. Hager J, Dina C, Francke S, Dubois S, Houari M, Vatin V, Vaillant E, Lorentz N, Basdevant A, Clement K, Guy GB, Froguel P 1998 A genome-wide scan for human obesity genes reveals a major susceptibility locus on chromosome 10. Nat Genet 20:304–308[CrossRef][Medline]
118. Wolford JK, Bogardus C, Prochazka M 1999 Genome-wide scan for CAG/CTG repeat expansions in Pimas with early onset of type 2 diabetes mellitus. Mol Genet Metab 66:62–67[CrossRef][Medline]
119. Hegele RA, Sun F, Harris SB, Anderson C, Hanley AJ, Zinman B 1999 Genome-wide scanning for type 2 diabetes susceptibility in Canadian Oji-Cree, using 190 microsatellite markers. J Hum Genet 44:10–14[CrossRef][Medline]
120. Goodyear LJ, Kahn BB 1998 Exercise, glucose transport, and insulin sensitivity. Annu Rev Med 49:235–261[CrossRef][Medline]
121. Perseghin G, Price TB, Petersen KF, Roden M, Cline GW, Gerow K, Rothman DL, Shulman GI 1996 Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects. N Engl J Med 335:1357–1362[Abstract/Free Full Text]
122. Hespel P, Vergauwen L, Vandenberghe K, Richter EA 1995 Important role of insulin and flow in stimulating glucose uptake in contracting skeletal muscle. Diabetes 44:210–215[Abstract]
123. Kishi K, Muromoto N, Nakaya Y, Miyata I, Hagi A, Hayashi H, Ebina Y 1998 Bradykinin directly triggers GLUT4 translocation via an insulin-independent pathway [published erratum appears in Diabetes 1998 Jul;47(7):1170]. Diabetes 47:550–558[Abstract]
124. DeFronzo RA, Sherwin RS, Kraemer N 1987 Effect of physical training on insulin action in obesity. Diabetes 36:1379–1385[Abstract]
125. Koivisto VA, Yki-Järvinen H 1987 Effect of exercise on insulin binding and glucose transport in adipocytes of normal humans. J Appl Physiol 63:1319–1323[Abstract/Free Full Text]
126. Stumvoll M, Jacob S 1999 Multiple sites of insulin resistance: muscle, liver and adipose tissue [comment]. Exp Clin Endocrinol Diabetes 107:107–110[Medline]
127. Grassi G, Seravalle G, Cattaneo BM, Bolla GB, Lanfranchi A, Colombo M, Giannattasio C, Brunani A, Cavagnini F, Mancia G 1995 Sympathetic activation in obese normotensive subjects. Hypertension 25:560–563[Abstract/Free Full Text]
128. Scherrer U, Randin D, Tappy L, Vollenweider P, Jequier E, Nicod P 1994 Body fat and sympathetic nerve activity in healthy subjects. Circulation 89:2634–2640[Abstract/Free Full Text]
129. Hilsted J, Richter E, Madsbad S, Tronier B, Christensen NJ, Hildebrandt P, Damkjaer M, Galbo H 1987 Metabolic and cardiovascular responses to epinephrine in diabetic autonomic neuropathy. N Engl J Med 317:421–426[Abstract]
130. Randle PJ, Garland PB, Hales CN, Newsholme EA 1963 The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1:785–789[Medline]
131. Gonzalez MC, Ayuso MS, Parrilla R 1989 Control of hepatic gluconeogenesis: role of fatty acid oxidation. Arch Biochem Biophys 271:1–9[CrossRef][Medline]
132. Felley CP, Felley EM, van-Melle GD, Frascarolo P, Jequier E, Felber JP 1989 Impairment of glucose disposal by infusion of triglycerides in humans: role of glycemia. Am J Physiol 256:E747–E752
133. Boden G, Chen X, Ruiz J, White JV, Rossetti L 1994 Mechanisms of fatty acid-induced inhibition of glucose uptake. J Clin Invest 93:2438–2446
134. Wolfe RR 1998 Metabolic interactions between glucose and fatty acids in humans. Am J Clin Nutr 67:519S–526S
135. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM 1994 Positional cloning of the mouse obese gene and its human homologue [published erratum appears in Nature 1995 Mar 30;374(6521):479] [see comments]. Nature 372:425–432[CrossRef][Medline]
136. Tartaglia LA, Dembski M, Weng X, Deng NH, Culpepper J, Devos R, Richards GJ, Campfield LA, Clark FT, Deeds J, Muir C, Sanker S, Moriarty A, Moore KJ, Smutko JS, Mays GG, Woolf EA, Monroe CA, Tepper RI 1995 Identification and expression cloning of a leptin receptor, OB-R. Cell 83:1263–1271[CrossRef][Medline]
137. White DW, Tartaglia LA 1996 Leptin and OB-R: body weight regulation by a cytokine receptor. Cytokine Growth Factor Rev 7:303–309[CrossRef][Medline]
138. Friedman JM, Halaas JL 1998 Leptin and the regulation of body weight in mammals. Nature 395:763–770[CrossRef][Medline]
139. Chen H, Charlat O, Tartaglia LA, Woolf EA, Weng X, Ellis SJ, Lakey ND, Culpepper J, Moore KJ, Breitbart RE, Duyk GM, Tepper RI, Morgenstern JP 1996 Evidence that the diabetes gene encodes the leptin receptor: identification of a mutation in the leptin receptor gene in db/db mice. Cell 84:491–495[CrossRef][Medline]
140. Cohen B, Novick D, Rubinstein M 1996 Modulation of insulin activities by leptin. Science 274:1185–1188[Abstract/Free Full Text]
141. Berti L, Kellerer M, Capp E, Haring HU 1997 Leptin stimulates glucose transport and glycogen synthesis in C2C12 myotubes: evidence for a PI3-kinase mediated effect. Diabetologia 40:606–609[CrossRef][Medline]
142. Muller G, Ertl J, Gerl M, Preibisch G 1997 Leptin impairs metabolic actions of insulin in isolated rat adipocytes. J Biol Chem 272:10585–10593[Abstract/Free Full Text]
143. Kieffer TJ, Keller RS, Leech CA, Holz GG, Habener JF 1997 Leptin suppression of insulin secretion by the activation of ATP-sensitive K⁺ channels in pancreatic ß-cells. Diabetes 46:1087–1093[Abstract]
144. Shimizu H, Ohtani K, Tsuchiya T, Takahashi H, Uehara Y, Sato N, Mori M 1997 Leptin stimulates insulin secretion and synthesis in HIT-T 15 cells. Peptides 18:1263–1266[CrossRef][Medline]
145. Tanizawa Y, Okuya S, Ishihara H, Asano T, Yada T, Oka Y 1997 Direct stimulation of basal insulin secretion by physiological concentrations of leptin in pancreatic ß cells. Endocrinology 138:4513–4516[Abstract/Free Full Text]
146. Fehmann HC, Berghofer P, Brandhorst D, Brandhorst H, Hering B, Bretzel RG, Goke B 1997 Leptin inhibition of insulin secretion from isolated human islets. Acta Diabetologica 34:249–252[CrossRef][Medline]
147. Harvey J, McKenna F, Herson PS, Spanswick D, Ashford MLJ 1997 Leptin activates ATP-sensitive potassium channels in the rat insulin-secreting cell line, CRI-G1. J Physiol (Lond) 504:527–535[Abstract/Free Full Text]
148. Seufert J, Kieffer TJ, Leech CA, Holz GG, Moritz W, Ricordi C, Habener JF 1999 Leptin suppression of insulin secretion and gene expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus. J Clin Endocrinol Metab 84:670–676[Abstract/Free Full Text]
149. Ookuma M, Ookuma K, York DA 1998 Effects of leptin on insulin secretion from isolated rat pancreatic islets. Diabetes 47:219–223[Abstract]
150. Zhao AZ, Bornfeldt KE, Beavo JA 1998 Leptin inhibits insulin secretion by activation of phosphodiesterase 3B. J Clin Invest 102:869–873[Medline]
151. Clement K, Vaisse C, Lahlou N, Cabrol S, Pelloux V, Cassuto D, Gourmelen M, Dina C, Chambaz J, Lacorte JM, Basdevant A, Bougneres P, Lebouc Y, Froguel P, Guy GB 1998 A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. Nature 392:398–401[CrossRef][Medline]
152. O’Rahilly S 1998 Life without leptin [news; comment]. Nature 392:330–331[CrossRef][Medline]
153. Montague CT, Farooqi IS, Whitehead JP, Soos MA, Rau H, Wareham NJ, Sewter CP, Digby JE, Mohammed SN, Hurst JA, Cheetham CH, Earley AR, Barnett AH, Prins JB, O’Rahilly S 1997 Congenital leptin deficiency is associated with severe early-onset obesity in humans. Nature 387:903–908[CrossRef][Medline]
154. Peraldi P, Spiegelman B 1998 TNF- and insulin resistance: summary and future prospects. Mol Cell Biochem 182:169–175[CrossRef][Medline]
155. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM 1996 IRS-1-mediated inhibition of insulin receptor tyrosine kinase activity in TNF-- and obesity-induced insulin resistance. Science 271:665–668[Abstract]
156. Kanety H, Hemi R, Papa MZ, Karasik A 1996 Sphingomyelinase and ceramide suppress insulin-induced tyrosine phosphorylation of the insulin receptor substrate-1. J Biol Chem 271:9895–9897[Abstract/Free Full Text]
157. Kroder G, Bossenmaier B, Kellerer M, Capp E, Stoyanov B, Muhlhofer A, Berti L, Horikoshi H, Ullrich A, Haring H 1996 Tumor necrosis factor-- and hyperglycemia-induced insulin resistance. Evidence for different mechanisms and different effects on insulin signaling. J Clin Invest 97:1471–1477[Medline]
158. Kellerer M, Rett K, Renn W, Groop L, Haring HU 1996 Circulating TNF- and leptin levels in offspring of NIDDM patients do not correlate to individual insulin sensitivity. Horm Metab Res 28:737–743[Medline]
159. Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R 1996 Effects of an engineered human anti-TNF-alpha antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45:881–885[Abstract]
160. Harris PK, Kletzien RF 1994 Localization of a pioglitazone response element in the adipocyte fatty acid-binding protein gene. Mol Pharmacol 45:439–445[Abstract]
161. Lemberger T, Braissant O, Juge AC, Keller H, Saladin R, Staels B, Auwerx J, Burger AG, Meier CA, Wahli W 1996 PPAR tissue distribution and interactions with other hormone-signaling pathways. Ann NY Acad Sci 804:231–251[Medline]
162. Spiegelman BM 1998 PPAR-: adipogenic regulator and thiazolidinedione receptor. Diabetes 47:507–514[Abstract]
163. Auwerx J 1999 PPAR, the ultimate thrifty gene. Diabetologia 42:1033–1049[CrossRef][Medline]
164. Yen CJ, Beamer BA, Negri C, Silver K, Brown KA, Yarnall DP, Burns DK, Roth J, Shuldiner AR 1997 Molecular scanning of the human peroxisome proliferator activated receptor (hPPAR) gene in diabetic Caucasians: identification of a Pro12Ala PPAR 2 missense mutation. Biochem Biophys Res Commun 241:270–274[CrossRef][Medline]
165. Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J 1998 A Pro12Ala substitution in PPAR2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 20:284–287[CrossRef][Medline]
166. Koch M, Rett K, Maerker E, Volk A, Deninger M, Renn W, Häring HU 1999 The PPAR2 amino acid polymorphism Pro 12 Ala is prevalent in offspring of Type II diabetic patients and is associated to increased insulin sensitvitiy in a subgroup of obese subjects. Diabetologia 42:758–762[CrossRef][Medline]
167. Masuda K, Okamoto Y, Tsuura Y, Kato S, Miura T, Tsuda K, Horikoshi H, Ishida H, Seino Y 1995 Effects of Troglitazone (CS-045) on insulin secretion in isolated rat pancreatic islets and HIT cells: an insulinotropic mechanism distinct from glibenclamide. Diabetologia 38:24–30[Medline]
168. Fujiwara T, Wada M, Fukuda K, Fukami M, Yoshioka S, Yoshioka T, Horikoshi H 1991 Characterization of CS-045, a new oral antidiabetic agent. II. Effects on glycemic control and pancreatic islet structure at a late stage of the diabetic syndrome in C57BL/KsJ-db/db mice. Metabolism 40:1213–1218[CrossRef][Medline]
169. Buckingham RE, Al-Barazanji KA, Toseland CD, Slaughter M, Connor SC, West A, Bond B, Turner NC, Clapham JC 1998 Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats. Diabetes 47:1326–1334[Abstract]
170. Shimabukuro M, Zhou YT, Lee Y, Unger RH 1998 Troglitazone lowers islet fat and restores ß cell function of Zucker diabetic fatty rats. J Biol Chem 273:3547–3550[Abstract/Free Full Text]
171. Rossetti L, Giaccari A, DeFronzo RA 1990 Glucose toxicity. Diabetes Care 13:610–630[Abstract]
172. Yki-Järvinen H 1992 Glucose toxicity. Endocr Rev 13:415–431[Abstract/Free Full Text]
173. Unger RH, Grundy S 1985 Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the mangement of diabetes. Diabetologia 28:119–121[Medline]
174. Cavaghan MK, Ehrmann DA, Byrne MM, Polonsky KS 1997 Treatment with the oral antidiabetic agent troglitazone improves ß cell responses to glucose in subjects with impaired glucose tolerance. J Clin Invest 100:530–537[Medline]
175. Balfour JA, McTavish D 1993 Acarbose. An update of its pharmacology and therapeutic use in diabetes mellitus. Drugs 46:1025–1054[Medline]
176. Clissold SP, Edwards C 1988 Acarbose. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs 35:214–243[Medline]
177. Salvatore T, Giugliano D 1996 Pharmacokinetic-pharmacodynamic relationships of Acarbose. Clin Phamacokinet 30:94–106
178. Bischoff H 1994 Pharmacology of -glucosidase inhibition. Eur J Clin Invest 24[Suppl 3]:3–10
179. Harrower AD 1996 Pharmacokinetics of oral antihyperglycaemic agents in patients with renal insufficiency. Clin Phamacokinet 31:111–119
180. Yee HS, Fong NT 1996 A review of the safety and efficacy of acarbse in diabetes mellitus. Pharmacotherapy 16:792–805[Medline]
181. Campbell LK, White JR, Campbell RK 1996 Acarbose: its role in the treatment of diabetes mellitus. Ann Pharmacother 30:1255–1262[Abstract]
182. Puls W 1996 Phamacology of glucosidase inhibitors. In: Kuhlmann J, Puls W (eds) Handbook of Experimental Pharmacology: Oral Antidiabetics. Springer, Berlin, vol 119:497–525
183. Lebovitz HE 1997 -Glucosidase inhibitors. Endocrinol Metab Clin North Am 26:539–551[CrossRef][Medline]
184. Hanefeld M, Fischer S, Schulze J, Spengler M, Wargenau M, Schollberg K, Fücker K 1991 Therapeutic potentials of acarbose as first-line drug in NIDDM insufficiently treated with diet alone. Diabetes Care 14:732–737[Abstract]
185. Lindstrom J, Tuomilehto J, Spengler M 1996 The effect of acarbose on dietary nutrient intake and metabolic control in NIDDM patients. (Abstract) Diabetologia 39[Suppl 1]:739
186. Coniff RF, Shapiro JA, Seaton TB 1994 Long-term efficacy and safety of acarbose in the treatment of obese subjects with non-insulin-dependent diabetes mellitus. Arch Intern Med 154:2442–2448[Abstract/Free Full Text]
187. Coniff RF, Shapiro JA, Seaton TB, Bray GA 1995 Multicenter, placebo-controlled trial comparing acarbose with placebo, tolbutamde and tolbutamide plus acarbose in non-insulin-dependent diabetes mellitus. Am J Med 98:443–451[CrossRef][Medline]
188. Matsumoto K, Yano M, Miyake S, Ueki Y, Yamaguchi Y, Akazama S, Tominaga Y 1998 Effects of voglibose on glycemic excursions, insulin secretion and insulin sensitivity in non-insulin treated NIDDM patients. Diabetes Care 21:256–260[Abstract]
189. Segal P, Feig PU, Schernthaner G, Ratzmann KP, Rybka J, Petzinna D, Berlin C 1997 The efficacy and safety of miglitol therapy compared with glibenclamide in patients with NIDDM inadequately controlled by diet alone. Diabetes Care 20:687–691[Abstract]
190. Coniff RF, Shapiro JA, Robbins D, Kleinfield R, Seaton TB, Beisswenger P, McGill JB 1995 Reduction in glycosylated hemoglobin and postprandial hyperglycemia by acarbose in patients with NIDDM: a placebo-controlled dose comparison study. Diabetes Care 18:817–824[Abstract]
191. Johnston PS, Feig PU, Coniff RF, Krol A, Kelley DE, Mooradian D 1998 Chronic treatment of African-American type 2 diabeic patients with -glucosidase inhibition. Diabetes Care 21:416–422[Abstract]
192. Braun D, Schonherr U, Mitzkat HJ 1996 Efficacy of acarbose monotherapy in patients with type 2 diabetes: a double-blind study conducted in general practice. Endocrinol Metab 3:275–280
193. Johnston PS, Feig PU, Coniff RF, Krol A, Davidson JA, Haffner SM 1998 Long-term titrated-dose alpha-glucosidase inhibition in non-insulin requiring hispanic NIDDM patients. Diabetes Care 21:409–415[Abstract]
194. Hoffman J, Spengler M 1997 Efficacy of 24 week monotherapy with acarbose, metformin or placebo in dietary-treated NIDDM patients: the Essen II Study. Am J Med 103:483–490[CrossRef][Medline]
195. Pagano G, Marena S, Corgiat-Mansin L, Cravero F, Giordia C, Bozza M, Ross CM 1995 Comparison of miglitol and glibenclamide in diet-treated type 2 diabetic patients. Diabete Metab 21:162–167[Medline]
196. Santeusanio F, Ventura MM, Contandini S, Compagnucci P, Moriconi V, Zaccarini P 1993 Efficacy and safety of two different doses of acarbose in non-insulin-dependent diabetic patients treated by diet alone. Diabetes Nutr Metab 6:147–154
197. Hotta N, Kakutta H, Sano T, Masumae H, Yamada H, Kitazawa S, Sakamoto N 1993 Long-term effect of acarbose on glycemic control in non-insulin-dependent diabetes mellitus: a placebo controlled double-blind study. Diabet Med 10:134–138[Medline]
198. Johnston PS, Lebovitz HE, Coniff RF, Simonson DC, Raskin P, Munera CL 1998 Advantages of -glucosidase inhibition as monotherapy in eldely type 2 diabetic patients. J Clin Endocrinol Metab 83:1515–1522[Abstract/Free Full Text]
199. Hasche H, Mertes G 1998 Efficacy of acarbose in patients receiving dietary training and counselling: a 2-year placebo-controlled, double-blind study (Abstract) Diabetes 47 [Suppl 1]:351
200. Kawagishi T, Nshizawa Y, Taniwaki H, Tanaka S, Okuno Y, Inaba M, Ishimura E, Emoto M, Morii H 1997 Relationship between gastric emptying and -glucosidase inhibitor effect on postprandial hyperglycemia in NIDDM patients. Diabetes Care 20:1529–1532[Abstract]
201. Chiasson JL, Josse RG, Hunt JA, Palmason C, Rodger NW, Ross SA, Ryan EA, Tan MN, Wolever TMS 1994 The efficacy of acarbose in the treatment of patients with non-insulin-dependent diabetes mellitus: a multicenter controlled clinical trial. Ann Intern Med 121:928–935[Abstract/Free Full Text]
202. Hoffmann J, Spengler M 1994 Efficacy of 24 week monotherapy with acabose, glibenclamide or placebo in NIDDM patients. Diabetes Care 17:561–566[Abstract]
203. Mertes G 1998 Efficacy and safety of acarbose in the treatment of Type 2 diabetes: data from a 2-year surveillance study. Diabetes Res Clin Pract 40:63–70[CrossRef][Medline]
204. Lebovitz HE 1998 -Glucosidase inhibitors as agents in the treatment of diabetes. Diabetes Rev 6:132–145
205. Holman RR, Cull C, Turner R 1999 A randomized double-blind trial of acarbose in type 2 diabetes shows improved glycemic control over three years. Diabetes Care 22:960–964[Abstract]
206. Chiasson JL, Josse RG, Leiter L, Mihic M, Nathan DM, Palmason C, Cohen RM, Wolever TMS 1996 The effect of acarbose on insulin sensitivity in subjects with impaired glucose tolerance. Diabetes Care 19:1190–1193[Abstract]
207. Laube H, Linn T, Heyen P 1998 The effects of acarbose on insulin sensitivity and proinsulin in overweight subjects with impaired glucose tolerance. Exp Clin Endocrinol Diabetes 106:231–233[Medline]
208. Shinozaki K, Suzuki M, Ikebuchi M, Hirose J, Hara Y, Harano Y 1996 Improvement of insulin sensitivity and dyslipidemia with a new -glucosidase inhibitor, voglibose, in nondiabetic hyperinsulinemic subjects. Metabolism 45:731–737[CrossRef][Medline]
209. Schnack C, Prager RJF, Winkler J, Klauser RM, Schneider BG, Schernthaner G 1989 Effects of 8-wk -glucosidase inhibition on metabolic control, C-peptide secretion, hepatic glucose output, and peripheral insulin sensitvity in poorly controlled type II diabetic patients. Diabetes Care 12:537–543[Abstract]
210. Reaven GM, Lardinois CK, Greenfield MS, Schwarzt HC, Vreman HJ 1990 Effect of acarbose on carbohydrate and lipid metabolism in NIDDM patients poorly controlled by sufonylureas. Diabetes Care 13[Suppl 3]:32–36
211. Jenney A, Proietto J, O'Dea K, Nankervis A, Traianedes K, D‘Embden H 1993 Low-dose acarbose improves glycemic control in NIDDM patients without changes in insulin sensitivity. Diabetes Care 16:499–502[Abstract]
212. Johnson AB, Taylor R 1996 Does suppression of postprandial blood glucose excursions by the -glucosidase inhibitor miglitol improve insulin sensitivity in diet-treated type II diabetic patients? Diabetes Care 19:559–563[Abstract]
213. Matsumoto K, Yano M, Miyake S, Ueki Y, Yamaguchi Y, Akazawa S, Tominaga Y 1998 Effects of voglibose on glycemic excursions, insulin secretion, and insulin sensitivity in non-insulin-treated NIDDM patients. Diabetes Care 21:256–260
214. Chiasson JL, Gomis R, Hanefeld M, Josse RG, Karasik A, Laakso M and the STOP-NIDDM Trial Research Group 1998 The STOP-NIDDM Trial: an international study on the efficacy of an glucosidase inhibitor to prevent type 2 diabetes in a population with impaired glucose tolerance: rationale, design, and preliminary screening data. Diabetes Care 21:1720–1725[Abstract]
215. Pan X, Li G, Hu YH, Wang J, Yang W, Zuo A, Ze H, Lin J, Xiao JZ, Cao H, Liu PA, Jiang X, Jiang Y, Wang J, Zheng H, Zhang H, Bennett PH, Howard BV 1997 Effects of diet and exercise in preventing NIDDM in people with impaired glucose toleance: the Da Qing IGT and Diabetes Study. Diabetes Care 20:537–544[Abstract]
216. Karunakaran S, Hammersley MS, Morris RJ, Turner RC, Holman RR 1997 The Fasting Hyperglycemia Study. III. Randomized Trial of sulfonylurea therapy in subjects with increased but not diabetic fasting plasma glucose. Metabolism 46[Suppl 1]:55–60
217. Clissold SP, Edwards C 1988 Acarbose. A preliminary review of its pharmacodynamic and pharmacokinetic properties and theapeutic potential. Drugs 35:214–243
218. Spengler M, Cagatay M 1992 Assessment of efficacy and tolerability of acarbose in diabetic patients 5–16 years of age. In: Lefebvre PJ, Standl E (eds) New Aspects in Diabetes. Treatment Strategies with -Glucosidase Inhibitors. De Gruyter, Berlin, pp 290–294
219. Ahr HJ, Boberg M, Krause HP, Maul W, Müller FO 1989 Pharmacokinetics of acarbose. I. Absorption, concentration in plasma metabolism and excretion after single administration of [14C]acarbose to rats, dogs and man. Arzneimittelforschung 39:1254–1260[Medline]
220. Ahr HJ, Krause HP, Siefert HM, Steinke W, Weber H 1989 Pharmacokinetics of acarbose. II. Distributon to and elimination from tissues and organs following single or repeated administration of [14C]acarbose to rats and dogs. Arzneimittelforschung 39:1261–1267[Medline]
221. Hollander PA 1996 Acarbose: adverse events and safety profile. Drug Benefit Trends 8[Suppl E]:46–54
222. Wang PY, Kaneko T, Wang Y, Sato A 1999 Acarbose alone or in combination with ethanol potentiates the hepatotoxicity of carbon tetrachloride and acetaminophen in rats. Hepatology 29:161–165[CrossRef][Medline]
223. Buse J, Hart K, Minasi L 1998 The PROTECT Study: final results of a large multicenter postmarketing study in patients with type 2 diabetes. Precose Resolution of optimal titration to enhance current therapies. Clin Ther 20:257–269[CrossRef][Medline]
224. Andrade RJ, Lucena M, Vega JL, Torres M, Salmeron FJ, Bellot V, Garcia-Escano MD, Moreno P 1998 Acarbose-associated hepatotoxicity [letter]. Diabetes Care 21:2029–2030[Medline]
225. Andrade RJ, Lucena M, Rodriguez-Mendizabal M 1996 Hepatic injury caused by acarbose [letter]. Ann Intern Med 124:931[Free Full Text]
226. Carrascosa M, Pascual F, Aresti S 1997 Acarbose-induced severe hepatotoxicity [letter]. Lancet 349:698–699[Medline]
227. Diaz-Gtierrez FL, Ladero JM, Diaz-Rubio M 1998 Acarboseinduced acute hepatitis [letter]. Am J Gastroenterol 93:481[Medline]
228. Kihara Y, Ogami Y, Tabaru A, Unoki H, Otsuki M 1997 Safe and effective treatment of diabetes mellitus associated with chronic liver disease with an -glucosidase inibitor. J Gastroenterol 32:777–782[Medline]
229. Kono T, Hayami M, Kobayashi H, Ishii M, Taniguchi S 1999 Acarbose-induced generalised erythema multiforme. Lancet 354:396–397[CrossRef][Medline]
230. Johansen K 1999 Efficacy of metformin in the treatment of NIDDM. Diabetes Care. 22:33–37
231. Bailey CJ, Turner RC 1996 Metformin. N Engl J Med 334:574–579[Free Full Text]
232. Dunn CJ, Peters DH 1995 Metformin. A review of its pharmacological properties and therapeutic use in non-insulin-dependent diabetes mellitus. Drugs. 49:721–749
233. Davidson MB, Peters AL 1997 An overview of metformin in the treatment of type 2 diabetes mellitus. Am J Med 102:99–110[CrossRef][Medline]
234. Bailey C J 1992 Biguanides and NIDDM. Diabetes Care 15:755–772[Abstract]
235. Klip A, Leiter L 1990 Cellular mechanism of action of metformin. Diabetes Care 13:696–704[Abstract]
236. Bailey C 1988 Metformin revisited: its actions and indications for use. Diabetic Med 5:315–320[Medline]
237. Hermann L 1990 Biguanides and sulfonylureas as combination therapy in NIDDM. Diabetes Care 13:37–41
238. Bailey C, Nattrass M 1988 Treatment - metformin. Baillieres Clin Endocrinol Metab 2:455–476[CrossRef][Medline]
239. UK Prospective Diabetes Study Group 1998 Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865[CrossRef][Medline]
240. DeFronzo RA, Goodman AM, The Multicenter Metformin Study Group 1995 Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 333:541–549[Abstract/Free Full Text]
241. Hermann LS, Kjellström T, Nilsson-Ehle P 1991 Effects of metformin and glibenclamide alone and in combination on serum lipids and lipoproteins in patients with non-insulin-dependent diabetes mellitus. Diabete Metab 17:174–179[Medline]
242. Ferner RE, Rawlins MD, Alberti K G 1988 Impaired ß-cell responses improve when fasting blood glucose concentration is reduced in non-insulin-dependent diabetes. Q J Med 66:137–146[Abstract/Free Full Text]
243. Yki-Järvinen H 1992 Glucose toxicity. Endocr Rev 13:415–431
244. Dinneen S, Gerich J, Rizza R 1992 Carbohydrate metabolism in non-insulin-dependent diabetes mellitus. N Engl J Med 327:707–713[Medline]
245. DeFronzo RA, Bonadonna RC, Ferrannini E 1992 Pathogenesis of NIDDM. Diabetes Care 15:318–368[Abstract]
246. Nosadini R, Avogaro A, Trevisian R, Valerio A, Tessari P, Duner E, Tiengo A, Velussi M, Del Prato S, De Kreutzenberg S, Muggeo M, Crepaldi G 1987 Effect of metformin on insulin-stimulated glucose turnover and insulin binding to receptors in type II diabetes. Diabetes Care 10:62–67[Abstract]
247. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE 1995 Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 333:550–554
248. Cusi K, Consoli A, DeFronzo RA 1996 Metabolic effects of metformin on glucose and lactate metabolism in noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 81:4059–4067[Abstract/Free Full Text]
249. Prager R, Schernthaner G, Graf H 1986 Effect of metformin on peripheral insulin sensitivity in non-insulin-dependent diabetes mellitus. Diabete Metab 12:346–350[Medline]
250. Jackson RA, Hawa MI, Jaspan JB, Sim BM. Disilvio L, Featherbe D, Kurtz AB 1987 Mechanism of metformin action in noninsulin-dependent diabetes. Diabetes 36:632–640[Abstract]
251. DeFronzo RA, Barzilai N, Simonson DC 1991 Mechanism of metformin action in obese and lean noninsulin-dependent diabetic subjects. J Clin Endocrinol Metab 73:1294–1301[Abstract/Free Full Text]
252. Johnson AB, Webster JM, Sum C-F, Heseltine L, Argyraki M, Cooper BG, Taylor R 1993 The impact of metformin therapy on hepatic glucose production and skeletal muscle glycogen synthase activity in overweight type II diabetic patients. Metabolism 42:1217–1222[CrossRef][Medline]
253. Perriello G, Misericordia P, Volpi E, Santucci A, Santucci C, Ferrannini E, Ventura MM, Santeusanio F, Brunetti P, Bolli GB 1994 Acute antihyperglycemic mechanisms of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production. Diabetes 43:920–928[Abstract]
254. Hother-Nielsen O, Schmitz O, Andersen PH, Beck-Nielsen H, Pedersen O 1989 Metformin improves peripheral but not hepatic insulin action in obese patients with type II diabetes. Acta Endocrinol (Copenh) 120:257–265[Abstract/Free Full Text]
255. Riccio A, Del Prato S, Vigili de Kreutzenberg S, Tiengo A 1991 Glucose and lipid metabolism in non-insulin-dependent diabetes. Effect of metformin. Diabete Metab 17:180–184[Medline]
256. McIntyre HD, Ma A, Bird DM, Paterson CA, Ravenscroft PJ, Cameron DP 1991 Metformin increases insulin sensitivity and basal glucose clearance in type 2 (non-insulin dependent) diabetes mellitus. Aust NZ J Med 21:714–719[Medline]
257. Wu MS, Johnston P, Sheu WH, Hollenbeck CB, Jeng CY, Goldfine ID, Chen YD, Reaven GM 1990 Effect of metformin on carbohydrate and lipoprotein metabolism in NIDDM patients. Diabetes Care. 13:1–8
258. DeFronzo RA 1988 The triumvirate: B-cell, muscle, and liver: a collusion responsible for NIDDM. Diabetes 37:667–687[Medline]
259. Widen EI, Eriksson JG, Groop LC 1992 Metformin normalizes nonoxidative glucose metabolism in insulin-resistant normoglycemic first-degree relatives of patients with NIDDM. Diabetes 41:354–358[Abstract]
260. Wing RR, Koeske R, Epstein LH, Norwalk MP, Gooding W, Becker D 1987 Long-term effects of modest weight loss in type II diabetic patients. Arch Intern Med 147:1749–1753[Abstract/Free Full Text]
261. Morel Y, Golay A, Perneger T, Lehmann T, Vadas L, Pasik C, Reaven GM 1999 Metformin treatment leads to an increase in basal, but not insulin-stimulated, glucose disposal in obese patients with impaired glucose tolerance. Diabet Med 16:650–655[CrossRef][Medline]
262. Scheen AJ, Letiexhe MR, Lefebvre PJ 1995 Short administration of metformin improves insulin sensitivity in android obese subjects with impaired glucose tolerance. Diabet Med 12:985–989[Medline]
263. Diamanti Kandarakis E, Kouli C, Tsianateli T, Bergiele A 1998 Therapeutic effects of metformin on insulin resistance and hyperandrogenism in polycystic ovary syndrome. Eur J Endocrinol 138:269–274[Abstract]
264. Moghetti P, Castello R, Negri C, Tosi F, Perrone F, Caputo M, Zanolin E, Muggeo M 2000 Metformin effects on clinical features endocrine and metabolic pofiles and insulin sensitivity in polycystic ovary syndrome: a randomized double-blind placebo- controlled 6-month trial followed by open long-term clinical evaluation. J Clin Endocrinol Metab 85:139–146
265. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R 1998 Effects of metformin on spontaneous and clomiphen-induced ovulation in the polycystic ovary syndrome. N Engl J Med 338:1876–1880[Abstract/Free Full Text]
266. Hermann LS 1975 Metformin: a review of its pharmacologic properties and therapeutic use. Diabete Metab 5:233–245
267. McLelland J 1985 Recovery from metformin overdose. Diabet Med 2:410–411
268. Mäkimattila S, Nikkilä K, Yki-Järvinen H 1999 Causes of weight gain during insulin therapy with and without metformin in patients with type II diabetes. Diabetologia 42:406–412[CrossRef][Medline]
269. Giugliano D, Quatraro A, Consoli G, Mineai A, Ceriello A, De Rosa N, D’Onofrio F 1993 Metformin for obese, insulin-treated diabetic patients: improvement in glycaemic control and reduction of metabolic risk factors. Eur J Clin Pharmacol 44:107–112[CrossRef][Medline]
270. Robinson AC, Johnston DG, Burke J, Elkeles RS, Robinson S 1998 The effect of metformin on glycemic control and serum lipids in insulin-treated NIDDM patients with suboptimal metabolic control. Diabetes Care 21:701–705[Abstract]
271. Gin H, Messerchmitt C, Brottier E, Aubertin J 1985 Metformin improved insulin resistance in type I, insulin-dependent, diabetic patients. Metabolism. 34:923–925
272. Pagano G, Tagliaferro V, Carta Q, Caselle MT, Bozzo C, vitelli F, Trovati M, Cocuzza E 1983 Metformin reduces insulin requirements in type 1 (insulin-dependent) diabetes. Diabetologia 24:351–354[Medline]
273. Gin H, Slama G, Weissbrodt P, Poynard T, Vexiau P, Klein JC, Tchobroutsky G 1982 Metformin reduces post-prandial insulin needs in type I (insulin-dependent) diabetic patients: assessment by the artificial pancreas. Diabetologia. 23:34–36
274. Abbasi F, Carantoni M, Chen YD, Reaven GM 1998 Further evidence for a central role of adipose tissue in the antihyperglycemic effect of metformin. Diabetes Care 21:1301–1305[Abstract]
275. Cigolini M, Bosello O, Zancanaro C, Orlandi PG, Fezzi O, Smith U 1984 Influence of metformin on metabolic effects of insulin in human adipose tisssue in vitro. Diabete Metab 10:311–315[Medline]
276. Puhakainen I, Yki-Järvinen H 1993 Inhibition of lipolysis decreases lipid oxidation and gluconeogenesis from lactate but not fasting hyperglycemia or total hepatic glucose production. Diabetes 42:1694–1699[Abstract]
277. Saloranta C, Taskinen M, Widen E, Harkonen M, Melander A, Groop L 1993 Metabolic consequences of sustainded suppression of free fatty acids by acipimox in patients with NIDDM. Diabetes 42:1559–1566[Abstract]
278. Wilcock C, Bailey C J 1990 Sites of metformin-stimulated glucose metabolism. Biochem Pharmacol 39:1831–1834[CrossRef][Medline]
279. Penicaud L, Hitier Y, Ferre P, Girard J 1989 Hypoglycaemic effect of metformin in genetically obese (fa/fa) rats results from an increased utilization of blood glucose by intestine. Biochem J 262:881–885[Medline]
280. Bailey CJ, Mynett KJ, Page T 1994 Importance of the intestine as a site of metformin-stimulated glucose utilization. Br J Pharmacol 112:671–675[Medline]
281. Wilcock C, Bailey CJ 1994 Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 24:49–57[Medline]
282. Bellomo R, McGrath B, Boyce N 1991 In vivo catecholamine extraction during continuous hemofiltration in inotrope-dependent patients. ASAIO Trans 37:M324–M325
283. Lee A, Morley JE 1998 Metformin decreases food consumption and induces weight loss in subjects with obesity with type II non-insulin-dependent diabetes. Obes Res 6:47–53[Medline]
284. Leslie P, Jung RT, Isles TE, Baty J 1987 Energy expenditure in non-insulin dependent diabetic subjects on metformin or sulfonylurea therapy. Clin Sci 73:41–45[Medline]
285. Stumvoll M, Meyer C, Mitrakou A, Nadkarni V, Gerich J 1997 Renal glucose production and utilzation. New aspects in humans. Diabetologia. 40:749–757
286. Meyer C, Stumvoll M, Nadkarni V, Dostou J, Mitrakou A, Gerich J 1998 Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus. J Clin Invest. 102:619–624
287. Matthaei S, Hamann A, Klein HH, Benecke H, Kreymann G, Flier JS, Greten H 1991 Association of Metformin’s effect to increase insulin-stimulated glucose transport with potentiation of insulin-induced translocation of glucose transporters from intracellular pool to plasma membrane in rat adipocytes. Diabetes 40:850–857[Abstract]
288. Matthaei S, Reibold JP, Hamann A, Benecke H, Haring HU, Greten H, Klein HH 1993 In vivo metformin treatment ameliorates insulin resistance: evidence for potentiation of insulin-induced translocation and increased functional activity of glucose transporters in obese (fa/fa) Zucker rat adipocytes. Endocrinology 133:304–311[Abstract/Free Full Text]
289. Lalor BC, Bhatnagar D, Winocour PH, Ishola M, Arrol S, Brading M, Durrington PN 1990 Placebo-controlled trial of the effects of guar gum and metformin on fasting blood glucose and serum lipids in obese, type 2 diabetic patients. Diabet Med 7:242–245[Medline]
290. Teupe B, Bergis K 1991 Prospective randomized two-years clinical study comparing additional metformin treatment with reducing diet in type 2 diabetes. Diabete Metab 17:213–217[Medline]
291. Dornan T, Heller S, Peck G, Tattersall R 1991 Double-blind evaluation of efficacy and tolerability of metformin in NIDDM. Diabetes Care 14:342–344[Abstract]
292. Nagi D, Yudkin J 1993 Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects. Diabetes Care 16:621–629[Abstract]
293. Tessari P, Biolo G, Bruttomesso D, Inchiostro S, Panebianco G, Vedovato M, Fongher C, Tiengo A 1994 Effects of metformin treatment on whole-body and splanchnic amino acid turnover in mild type 2 diabetes. J Clin Endocrinol Metab 79:1553–1560[Abstract]
294. Grant PJ 1996 The effects of high- and medium-dose metformin therapy on cardiovascular risk factors in patients with type II diabetes. Diabetes Care 19:64–66[Abstract]
295. Rains S, Wilson G, Richmond W, Elkeles R 1988 The effect of glibenclamide and metformin on serum lipoproteins in type 2 diabetes. Diabet Med 5:653–658[Medline]
296. Collier A, Watson HH, Patrick AW, Ludlam CA, Clarke BF 1989 Effect of glycaemic control, metformin and gliclazide on platelet density and aggregability in recently diagnosed type 2 (non-insulin-dependent) diabetic patients. Diabete Metab 15:420–425[Medline]
297. Josephkutty S, Potter JM 1990 Comparison of tolbutamide and metformin in elderly diabetic patients. Diabet Med 7:510–514[Medline]
298. Noury J, Nandeuil A 1991 Comparative three-month study of the efficacies of metformin and gliclazide in the treatment of NIDD. Diabete Metab 17:209–212[Medline]
299. Boyd K, Rogers C, Boreham C, Andrews WJ, Hadden DR 1992 Insulin, glibenclamide or metformin treatment for non insulin dependent diabetes: heterogenous responses of standard measures of insulin action and insulin secretion before and after differing hypoglycaemic therapy. Diabetes Res 19:69–76[Medline]
300. Hermann LS, Kjellström T, Schersten B, Lindgärde F, Bitzen P, Melander A 1994 Therapeutic comparison of metformin and sulfonylurea, alone and in various combinations. Diabetes Care 17:1100–1109[Abstract]
301. Campbell IW, Menzies DG, Chalmers J, McBain AM, Brown IR 1994 One year comparative trial of metformin and glipizide in type 2 diabetes mellitus. Diabete Metab 20:394–400[Medline]
302. Selby JV, Ettinger B, Swain BE, Brown JB 1999 First 20 months’ experience with use of metformin for type 2 diabetes in a large health maintenance organization. Diabetes Care 22:38–44[Abstract/Free Full Text]
303. Reaven G, Johnston P, Hollenbeck CB, Skowronski R, Zhang JC, Goldfine ID, Chen YD 1992 Combined metformin-sulfonylurea treatment of patients with noninsulin-dependent diabetes in fair to poor glycemic control. J Clin Endocrinol Metab 74:1020–1026[Abstract]
304. Giugliano D, De Rosa N, Di Maro G, Marfella R, Acampora R, Buoninconti R, D’Onofrio F 1993 Metformin improves glucose, lipid metabolism, and reduces blood pressure in hypertensive, obese women. Diabetes Care 16:1387–1390[Abstract]
305. Landin K, Tengborn L, Smith U 1991 Treating insulin resistance in hypertension with metformin reduces both blood pressure and metabolic risk factors. J Intern Med 229:181–187[Medline]
306. Schneider J, Erren T, Zöfel P, Kaffarnik H 1990 Metformininduced changes in serum lipids, lipoproteins, and apoproteins in non-insulin-dependent diabetes mellitus. Atherosclerosis 82:97–103[CrossRef][Medline]
307. Landin K, Tengborn L, Smith U 1994 Metformin and metoprolol CR treatment in non-obese men. J Intern Med 235:335–341[Medline]
308. Landin K, Tengborn L, Smith U 1994 Effects of metformin and metoprolol CR on hormones and fibrinolytic variables during a hyperinsulinemic, euglycemic clamp in man. Thromb Haemost 71:783–787[Medline]
309. Pentikainen PJ, Voutilainen E, Aro A, Uusitupa M, Penttila I, Vapaatalo H 1990 Cholesterol lowering effect of metformin in combined hyperlipidemia: placebo controlled double blind trial. Ann Med 22:307–312[Medline]
310. Grant PJ, Stickland MH, Booth NA, Prentice CR 1991 Metformin causes a reduction in basal and post-venous occlusion plasminogen activator inhibitor-1 in type 2 diabetic patients. Diabet Med 8:361–365[Medline]
311. Gin H, Freyburger G, Boisseau M, Aubertin J 1989 Study of the effect of metformin on platelet aggregation in insulin-dependent diabetics. Diabetes Res Clin Pract 6:61–67[CrossRef][Medline]
312. Marena S, Tagliaferro V, Montegrosso G, Pagano A, Scaglione L, Pagano G 1994 Metabolic effects of metformin addition to chronic glibenclamide treatment in type 2 diabetes. Diabete Metab 20:15–19[Medline]
313. Groop L, Widen E 1991 Treatment strategies for secondary sulfonylurea failure. Should we start insulin or add metformin? Is there a place for intermittent insulin therapy? Diabete Metab 17:218–223[Medline]
314. Hanuschak LN 1996 Metformin useful in combination with exogenous insulin [letter]. Diabetes Care 19:671–672
315. Aviles-Santa A, Sinding J, Raskin P 1999 Effects of metformin in patients with poorly controlled, insulin treated type 2 diabetes. Ann Intern Med 131:182–188[Abstract/Free Full Text]
316. Yki-Järvinen H, Ryysy L, Nikkilä K, Tulokas T, Vanamo R, Heikkilä M 1999 Comparison of bedtime insulin regimens in patients with type 2 diabetes mellitus. Ann Intern Med 130:389–396[Abstract/Free Full Text]
317. Misbin RI, Green L, Stadel BV, Gueriguian JL, Gubbi A, Fleming GA 1998 Lactic acidosis in patients with diabetes treated with metformin. N Engl J Med 338:265–266[Free Full Text]
318. Oates NS, Shah RR, Idle JR, Smith R L 1983 Influence of oxidation polymorphism on phenformin kinetics and dynamics. Clin Pharmacol Ther 34:827–834[Medline]
319. Kreisberg R, Pennington L, Boshell B 1970 Lactate turnover and gluconeogenesis in obesity: effect of phenformin. Diabetes 19:64–69[Medline]
320. Lalau JD, Lacroix C, Compagnon P, de Cagny B, Rigaud JP, Bleichner G, Chauveau P, Dulbecco P, Guerin C, Haegy JM 1995 Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care 18:779–784[Abstract]
321. Nathan DM 1999 Some answers, more questions, from UKPDS. Lancet 352:832–833
322. The Diabetes Prevention Program Diabetes Group 1999 The Diabetes Prevention Program. Design and methods for a clinical trial in the prevention of type 2 diabetes. Diabetes Care 22:623–634[Abstract]
323. Yoshioka T, Fujita T, Kanai T, Aizawa Y, Kurumada T, Hasegawa K, Horikoshi H 1989 Studies on hindered phenols and analogues. 1. Hypolipidemic and hypoglycemic agents with ability to inhibit lipid peroxidation. J Med Chem 32:421–428[CrossRef][Medline]
324. Fujita T, Sugiyama Y, Taketomi S, Sohda T, Kawamatsu Y, Iwatsuka H, Suzuoki Z 1983 Reduction of insulin resistance in obese and/or diabetic animals by 5-[4-(1-methylcyclohexylmethoxy)benzyl]-thiazolidine-2,4-dione (ADD-3878, U-63, 287, ciglitazone), a new antidiabetic agent. Diabetes 32:804–810[Abstract]
325. Fujiwara T, Okuno A, Yoshioka S, Horikoshi H 1995 Suppression of hepatic gluconeogenesis in long-term Troglitazone treated diabetic KK and C57BL/KsJ-db/db mice. Metabolism 44:486–490[CrossRef][Medline]
326. Fujiwara T, Wada M, Fukuda K, Fukami M, Yoshioka S, Yoshioka T, Horikoshi H 1991 Characterization of CS-045, a new oral antidiabetic agent. II. Effects on glycemic control and pancreatic islet structure at a late stage of the diabetic syndrome in C57BL/KsJ-db/db mice. Metabolism 40:1213–1218
327. Tominaga M, Igarashi M, Daimon M, Eguchi H, Matsumoto M, Sekikawa A, Yamatani K, Sasaki H 1993 Thiazolidinediones (AD-4833 and CS-045) improve hepatic insulin resistance in streptozotocin-induced diabetic rats. Endocr J 40:343–349[Medline]
328. Schoonjans K, Martin G, Staels B, Auwerx J 1997 Peroxisome proliferator-activated receptors, orphans with ligands and functions. Curr Opin Lipidol 8:159–166[Medline]
329. Spiegelman BM 1998 PPAR-: adipogenic regulator and thiazolidinedione receptor. Diabetes 47:507–514
330. Teboul L, Gaillard D, Staccini L, Inadera H, Amri EZ, Grimaldi PA 1995 Thiazolidinediones and fatty acids convert myogenic cells into adipose-like cells. J Biol Chem 270:28183–28187[Abstract/Free Full Text]
331. Tontonoz P, Hu E, Spiegelman BM 1994 Stimulation of adipogenesis in fibroblasts by PPAR gamma 2, a lipid-activated transcription factor. Cell 79:1147–1156[CrossRef][Medline]
332. Tafuri SR 1996 Troglitazone enhances differentiation, basal glucose uptake, and Glut1 protein levels in 3T3–L1 adipocytes. Endocrinology 137:4706–4712[Abstract]
333. Burant CF, Sreenan S, Hirano K, Tai TA, Lohmiller J, Lukens J, Davidson NO, Ross S, Graves RA 1997 Troglitazone action is independent of adipose tissue. J Clin Invest 100:2900–2908[Medline]
334. Kellerer M, Kroder G, Tippmer S, Berti L, Kiehn R, Mosthaf L, Haring H 1994 Troglitazone prevents glucose-induced insulin resistance of insulin receptor in rat-1 fibroblasts. Diabetes 43:447–453[Abstract]
335. Saloranta C, Groop L 1996 Interactions between glucose and FFA metabolism in man. Diabetes Metab Rev 12:15–36
336. Randle PJ, Priestman DA, Mistry SC, Halsall A 1994 Glucose fatty acid interactions and the regulation of glucose disposal. J Cell Biol 55S:1–11
337. Hofmann C, Lorenz K, Braithwaite SS, Colca JR, Palazuk BJ, Hotamisligil GS, Spiegelman BM 1994 Altered gene expression for tumor necrosis factor and its receptor during drug and dietary modulation of insulin resistance. Endocrinology 134:264–270[Abstract/Free Full Text]
338. De Vos P, Lefebvre AM, Miller SG, Guerre-Millo M, Wong K, Saladin R, Hamann LG, Staels B, Briggs MR, Auwerx J 1996 Thiazolidinediones repress ob gene expression in rodents via activation of peroxisome proliferator-activated receptor gamma. J Clin Invest 98:1004–1009[Medline]
339. Kallen CB, Lazar MA 1996 Antidiabetic thiazolidinediones inhibit leptin (ob) gene expression in 3T3–L1 adipocytes. Proc Natl Acad Sci USA 93:5793–5796[Abstract/Free Full Text]
340. Kroder G, Bossenmaier B, Kellerer M, Capp E, Stoyanov B, Muhlhofer A, Berti L, Horikoshi H, Ullrich A, Haring H 1996 Tumor necrosis factor-- and hyperglycemia-induced insulin resistance. Evidence for different mechanisms and different effects on insulin signaling. J Clin Invest 97:1471–1477
341. Muller G, Ertl J, Gerl M, Preibisch G 1997 Leptin impairs metabolic actions of insulin in isolated rat adipocytes. J Biol Chem 272:10585–10593
342. Wang M, Wise SC, Leff T, Su T 1999 Troglitazone, an antidiabetic agent, inhibits cholesterol biosynthesis through a mechanism independent of peroxisome proliferator-activated receptor-. Diabetes 48:254–260[Abstract]
343. Patel J, Anderson RJ, Rappaport EB 1999 Rosiglitzone monotherapy improves glycaemic control in patients with type 2 diabetes: a twelve-week, randomized, placebo-controlled study. Diab Obes Metab 1:165–172
344. Grunberger G, Weston WM, Patwardhan R, Rappaport EB 1999 Rosiglitazone once or twice daily improves glycemic control in patients with type 2 diabetes. Diabetes 48[Suppl 1]:A102; 0439
345. Mathisen A, Geerlof J, Houser V 1999 The effect of pioglitazone on glucose control and lipid profile in patients with type 2 diabetes. Diabetes 48[Supp l]:A102; 0441
346. Egan J, Rubin C, Mathisen A on behalf of the Pioglitazone 027 Study Group 1999 Combination therapy with pioglitazone and metformin in patients with type 2 diabetes. Diabetes 48[Suppl 1]:A117
347. Horton ES, Whitehouse F, Ghazzi MN, Venable TC, Whitcomb RW 1998 Troglitazone in combination with sulfonylurea restores glycemic control in patients with type 2 diabetes. The Troglitazone Study Group. Diabetes Care 21:1462–1469[Abstract]
348. Kumar S, Boulton AJ, Beck Nielsen H, Berthezene F, Muggeo M, Persson B, Spinas GA, Donoghue S, Lettis S, Stewart-Long P 1996 Troglitazone, an insulin action enhancer, improves metabolic control in NIDDM patients. Troglitazone Study Group. Diabetologia 39:701–709[Medline]
349. Ghazzi MN, Perez JE, Antonucci TK, Driscoll JH, Huang SM, Faja BW, Whitcomb RW 1997 Cardiac and glycemic benefits of troglitazone treatment in NIDDM. The Troglitazone Study Group. Diabetes 46:433–439[Abstract]
350. Mimura K, Umeda F, Hiramatsu S, Taniguchi S, Ono Y, Nakashima N, Kobayashi K, Masakado M, Sako Y, Nawata H 1994 Effects of a new oral hypoglycaemic agent (CS-045) on metabolic abnormalities and insulin resistance in type 2 diabetes. Diabet Med 11:685–691[Medline]
351. Cominacini L, Young MMR, Capriati A, Garbin U, Fratta Pasini A, Campagnola M, Davoli A, Rigoni A, Contessa GB, Lo Cascio V 1997 Troglitazone increases the resistance of low density lipoprotein to oxidation in healthy volunteers. Diabetologia 40:1211–1218[CrossRef][Medline]
352. Steinberg D, Parthasarathy S, Carew TE, Khoo JC, Witztum JL 1989 Beyond cholesterol. Modifications of low-density lipoprotein that increase its atherogenicity. N Engl J Med 320:915–924[Medline]
353. Schneider R, Egan J, Houser V 1999 Combination therapy with pioglitazone and sulfonylurea in patients with type 2 diabetes. Diabetes 48[Suppl 1]:A106
354. Schwartz S, Raskin P, Fonseca V, Graveline J 1998 Effect of troglitazone in insulin-treated patients with type II diabetes mellitus. N Engl J Med. 338:861–866
355. Rubin C, Egan J, Schneider R on behalf of the Pioglitazone 014 Study Group 1999 Combination therapy with pioglitazone and insulin in patients with Type 2 diabetes. Diabetes 48[Suppl 1]:A110
356. Inzucchi SE, Maggs DG, Spollett GR, Page SL, Rife FS, Walton V, Shulman GI 1998 Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med 338:867–872[Abstract/Free Full Text]
357. Fonseca V, Biswas N, Salzman A 1999 Once-daily rosiglitazone (RSG) in combination with metformin (MET) effectively reduces hyperglycemia in patients with type 2 diabetes. Diabetes 48[Suppl 1]:A100
358. Bowen L, Stein PP, Stevenson R, Shulman GI 1991 The effect of CP 68,722, a thiozolidinedione derivative, on insulin sensitivity in lean and obese Zucker rats. Metabolism 40:1025–1030[CrossRef][Medline]
359. Lee MK, Olefsky JM 1995 Acute effects of troglitazone on in vivo insulin action in normal rats. Metabolism 44:1166–1169[CrossRef][Medline]
360. Ciaraldi TP, Gilmore A, Olefsky JM, Goldberg M, Heidenreich KA 1990 In vitro studies on the action of CS-045, a new antidiabetic agent. Metabolism 39:1056–1062[CrossRef][Medline]
361. Murano K, Inoue Y, Emoto M, Kaku K, Kaneko T 1994 CS-045, a new oral antidiabetic agent, stimulates fructose-2,6-bisphosphate production in rat hepatocytes. Eur J Pharmacol 254:257–262[CrossRef][Medline]
362. Fulgencio JP, Kohl C, Girard J, Pegorier JP 1996 Troglitazone inhibits fatty acid oxidation and sterification, and gluconeogenesis in isolated hepatocytes from starved rats. Diabetes 45:1556–1562[Abstract]
363. Suter SL, Nolan JJ, Wallace P, Gumbiner B, Olefsky JM 1992 Metabolic effects of new oral hypoglycemic agent CS-045 in NIDDM subjects. Diabetes Care 15:193–203[Abstract]
364. Maggs DG, Buchanan TA, Burant CF, Cline G, Gumbiner B, Hseuh WM, Inzucchi S, Kelley D, Nolan J, Olefsky JM, Polonsky KS, Silver D, Valiquett TR, Shulman GI 1998 Metabolic effects of troglitazone monotherapy in type 2 diabetes mellitus. A randomized, double-blind, placebo-controlled trial. Ann Intern Med 128:176–185[Abstract/Free Full Text]
365. Nolan JJ, Ludvik B, Beerdsen P, Joyce M, Olefsky J 1994 Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone. N Engl J Med 331:1188–1193[Abstract/Free Full Text]
366. Antonucci T, Whitcomb R, McLain R, Lockwood D 1997 Impaired glucose tolerance is normalized by treatment with the thiazolidinedione troglitazone. Diabetes Care 20:188–193[Abstract]
367. Dunaif A, Scott D, Finegood D, Quintana B, Whitcomb R 1996 The insulin-sensitizing agent troglitazone improves metabolic and reproductive abnormalities in the polycystic ovary syndrome. J Clin Endocrinol Metab 81:3299–3306[Abstract]
368. Schneider R, Lessem J, Lekich R 1999 Pioglitazone is effective in the treatment of patients with type 2 diabetes. Diabetes 48[Suppl 1]:A109
369. Beebe K, Patel J 1999 Rosiglitazone is effective and well tolerated in patients > 65 with type 2 diabetes. Diabetes 48[Suppl 1]:A111 (Abstract)
370. Watkins PB, Whitcomb RW 1998 Hepatic dysfunction associated with troglitazone. N Engl J Med 338:916–917[Free Full Text]
371. Food and Drug Administrationwww.fda.gov\/medwatch\/ safety\/1997\/dec97.htm rezuli
372. Gitlin N, Julie NL, Spurr CL, Lim KN, Juarbe HM 1998 Two cases of severe clinical and histologic hepatotoxicity associated with troglitazone. Ann Intern Med 129:36–38[Free Full Text]
373. Neuschwander Tetri BA, Isley WL, Oki JC, Ramrakhiani S, Quiason SG, Phillips NJ, Brunt EM 1998 Troglitazone-induced hepatic failure leading to liver transplantation. A case report. Ann Intern Med 129:38–41[Abstract/Free Full Text]
374. Freid J, Everitt D, Boscia J 2000 Rosiglitazone and hepatic failure. Ann Intern Med 132:164[Free Full Text]
375. Al-Salman J, Arjomand H, Kemp DG, Mittal M 2000 Hepatocellular injury in a patient receiving rosiglitazone. A case report. Ann Intern Med 132:121–124[Abstract/Free Full Text]
376. Salzman A, Patel J 1999 Rosiglitazone is not associated with hepatotoxicity. Diabetes 48[Suppl 1]:A95
377. Hallakou S, Doare L, Foufelle F, Kergoat M, Guerre-Millo M, Berthault MF, Dugail I, Morin J, Auwerz J, Ferre P 1997 Pioglitazone induces in vivo adipocyte differentiation in the obese Zucker fa/fa rat. Diabetes 46:1393–1399[Abstract]
378. Buse JB, Gumbiner B, Mathias NP, Nelson DM, Faja BW, Whitcomb RW 1998 Troglitazone use in insulin-treated type 2 diabetic patients. Diabetes Care 21:1455–1461[Abstract]
379. Gimble JM, Robinson CE, Wu X, Kelly KA, Rodriguez BR, Kliewer SA, Lehmann JM, Morris DC 1996 Peroxisome proliferator-activated receptor- activation by thiazolidinediones induces adipogenesis in bone marrow stromal cells. Mol Pharmacol 50:1087–1094[Abstract]
380. Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK 1998 The peroxisome proliferator-activated receptor- is a negative regulator of macrophage activation. Nature 391:79–82[CrossRef][Medline]
381. Nagy L, Tontonoz P, Alvarez JGA, Chen HW, Evans RM 1998 Oxidized LDL regulates macrophage gene expression through ligand activation of PPAR. Cell 93:229–240[CrossRef][Medline]
382. Tontonoz P, Nagy L, Alvarez JGA, Thomazy VA, Evans RM 1998 PPAR promotes monocyte/macrophage differentiation and uptake of oxidized LDL. Cell 93:241–252[CrossRef][Medline]
383. Lefebvre AM, Chen I, Desreumaux P, Najib J, Fruchart JC, Geboes K, Briggs M, Heyman R, Auwerz J 1998 Activation of the peroxisome proliferator-activated receptor gamma promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat Med 4:1053–1057[CrossRef][Medline]
384. Saez E, Tontonoz P, Nelson MC, Alvarez JG, Ming UT, Baird SM, Thomazy VA, Evans RM 1998 Activators of the nuclear receptor PPARgamma enhance colon polyp formation. Nat Med 4:1058–1061[CrossRef][Medline]
385. Sarraf P, Mueller E, Jones D, King FJ, DeAngelo DJ, Partridge JB, Holden SA, Chen LB, Singer S, Fletcher C, Spiegelman BM 1998 Differentiation and reversal of malignant changes in colon cancer through PPAR. Nat Med 4:1046–1052[CrossRef][Medline]
386. Seed B 1998 PPARgamma and colorectal carcinoma: conflicts in a nuclear family. Nat Med 4:1004–1005[CrossRef][Medline]
387. Berkowitz K, Peters R, Kjos SL, Goico J, Marroquin A, Dunn ME, Xiang A, Azen S, Buchanan TA 1996 Effect of troglitazone on insulin sensitivity and pancreatic ß-cell function in women at high risk for NIDDM. Diabetes 45:1572–1579[Abstract]
388. Patel J, Miller E, Patwardhan R 1998 Rosiglitazone improves glycaemic control when used as a monotherapy in type 2 diabetic patients. Diabetic Med 15[Suppl 2]:S37–38
389. Raskin P, Rappaport EB 1999 Rosiglitazone (RSG) improves fasting and post-prandial plasma glucose in type 2 diabetes. Diabetes 48[Suppl 1]:A95
390. Raskin P, Dole JF, Rappaport EB 1999 Rosiglitazone improves glycemic control in poorly controlled, insulin-treated type 2 diabetes. Diabetes 48[Suppl 1]:A94
391. Chabonnel B, Lönnqvist F, Jones NP, Abel MG, Patwardhan R 1999 Rosiglitazone is superior to glyburide in reducing fasting plasma glucose after 1 year of treatment in type 2 diabetic patients. Diabetes 48[Suppl 1]:A114
392. Mathews DR, Bakst A, Weston WM, Hemyari P 1999 Rosiglitazone decreases insulin resistance and improves ß-cell function in patients with type 2 diabetes. Diabetologia 42[Suppl 1]:A228
393. Franke H, Fuchs J 1955 Ein neues antidiabetisches Prinzip. Dtsch Med Wochenschr 80:1449–1453
394. Skillman TG, Feldman JM 1981 The pharmacology of sulfonylureas. Am J Med 70:361–372[CrossRef][Medline]
395. Prendergast BD 1984 Glyburide and glipizide, second-generation oral sulfonylurea hypoglycemic agents. Clin Pharm 3:473–485[Medline]
396. Feldman JM 1985 Glyburide: a second-generation sulfonylurea hypoglycemic agent. History, chemistry, metabolism, pharmacokinetics, clinical use and adverse effects. Pharmacotherapy 5:43–62[Medline]
397. Lebovitz HE 1985 Glipizide: a second-generation sulfonylurea hypoglycemic agent. Pharmacology, pharmacokinetics and clinical use. Pharmacotherapy 5:63–77[Medline]
398. Kuhn T 1988 The second generation oral sulfonylureas: glyburide and glipizide. Am Pharm NS28:55–61
399. Groop L 1983 Metabolic effects of sulfonylurea drugs. A review. Ann Clin Res 15[Suppl 37]:16–20
400. Lebovitz HE 1984 Cellular loci of sulfonylurea actions. Diabetes Care 7[Suppl 1]:67–71
401. Kolterman OG 1987 The impact of sulfonylureas on hepatic glucose metabolism in type II diabetics. Diabetes Metab Rev 3:399–414[Medline]
402. Kolterman OG, Olefsky JM 1984 The impact of sulfonylurea treatment upon the mechanisms responsible for the insulin resistance in type II diabetes. Diabetes Care 7 [Suppl 1]:81–88
403. Ammon HP 1988 Molecular mechanism of action of sulfonylureas. Dtsch Med Wochenschr 113:864–870[Medline]
404. Panten U 1989 Mechanism of insulin secretion and ist modulation by sulfonylureas. Contrib Nephrol 73:16–21[Medline]
405. Malaisse WJ, Lebrun P 1990 Mechanisms of sulfonylurea-induced insulin release. Diabetes Care 13[Suppl 3]:9–17
406. Caro JF 1990 Effects of glyburide on carbohydrate metabolism and insulin action in the liver. Am J Med 89[Suppl 2A]:17S–25S
407. Boyd AE, Aguilar-Bryan L, Nelson DA 1990 Molecular mechanisms of action of glyburide on the ß cell. Am J Med 89[Suppl 2A]:3S–10S
408. Smith RJ 1990 Effects of the sulfonylureas on muscle glucose homeostasis. Am J Med 89[Suppl 2A]:38S–43S
409. Del Prato S, Vigili de Kreutzenberg S, Riccio A, Tiengo A 1991 Hepatic sensitivity to insulin: effects of sulfonylurea drugs. Am J Med 90[Suppl 6A]:29S–36S
410. Panten U, Schwanstecher M, Schwanstecher C 1992 Pancreatic and extrapancreatic sulfonylurea receptors. Horm Metab Res 24:549–554[Medline]
411. Kramer W, Müller G, Girbig F, Gutjahr U, Kowalewski S, Hartz D, Summ HD 1995 The molecular interaction of sulfonylureas with ß-cell ATP-sensitive K(+)-channels. Diabetes Res Clin Pract Suppl:S67–80
412. Panten U, Schwanstecher M, Schwanstecher C 1996 Sulfonylurea receptors and mechanism of sulfonylurea action. Exp Clin Endocrinol Diabetes 104:1–9[Medline]
413. Groop L 1983 Metabolic effects of sulfonylurea drugs. Ann Clin Res 15:16–20
414. Kolterman OG, Prince MJ, Olefsky JM 1983 Insulin resistance in noninsulin-dependent diabetes mellitus: impact of sulfonylurea agents in vivo and in vitro. Am J Med 82:82–101
415. Bak JF, Pedersen O 1991 Gliclazide and insulin action in human muscle. Diabetes Res Clin Pract 14:S61–S64
416. Zimmerman BR 1997 Sulfonylureas. Endocrinol Metab Clin North Am 26:511–522[CrossRef][Medline]
417. Gerich JE 1985 Sulfonylureas in the treatment of diabetes mellitus–1985. Mayo Clin Proc 60:439–443[Medline]
418. Melander A, Lebovitz HE, Faber OK 1990 Sulfonylureas. Why, which, and how. Diabetes Care 13[Suppl 3]:18–25
419. Kolterman OG 1992 Glyburide in non-insulin-dependent diabetes: an update. Clin Ther 14:196–213[Medline]
420. Martz A, Jo I, Jung CY 1989 Sulfonylurea binding to adipocyte membranes and potentiation of insulin-stimulated hexose transport. J Biol Chem 264:13672–13678[Abstract/Free Full Text]
421. Maloff BL, Lockwood DH 1981 In vitro effects of a sulfonylurea on insulin action in adipocytes. Potentiation of insulin-stimulated hexose transport. J Clin Invest 68:85–90
422. Wang PH, Moller D, Flier JS, Nayak C, Smith RJ 1989 Coordinate regulation of glucose transporter function, number, and gene expression by insulin and sulfonylureas in L6 rat skeletal muscle cells. J Clin Invest 84:62–67
423. Wang PH, Beguinot F, Smith RJ 1987 Augmentation of the effects of insulin and insulin-like growth factors I and II on glucose uptake in cultured rat skeletal muscle cells by sulfonylureas. Diabetologia 30:797–803[Medline]
424. Cooper DR, Vila MC, Watson JE, Nair G, Pollet RJ, Standaert M, Farese RV 1990 Sulfonylurea-stimulated glucose transport associaton with diacylglycerollike activation of protein kinase C in BC3H1 myocytes. Diabetes 39:1399–1407[Abstract]
425. Rogers BJ, Standaert ML, Pollet RJ 1987 Direct effects of sulfonylurea agents on glucose transport in the BC3H-1 myocyte. Diabetes 36:1292–1296[Abstract]
426. Pedersen O, Hother-Nielsen O, Bak J, Hjollund E, Beck-Nielsen H 1991 Effects of sulfonylureas on adipocyte and skeletal muscle insulin action in patients with non-insulin-dependent diabetes mellitus. Am J Med 90 [Suppl 6A]:22S–28S
427. Farese RV, Ishizuka T, Standaert ML, Cooper DR 1991 Sulfonylureas activate glucose transport and protein kinase C in rat adipocytes. Metabolism 40:196–200[CrossRef][Medline]
428. Maloff BL, Drake L, Riedy DK, Lockwood DH 1984 Effects of sulfonylureas on the actions of insulin and insulin-mimickers: potentiation of stimulated hexose transport in adipocytes. Eur J Pharmacol 17:319–326[CrossRef]
429. McCaleb ML, Maloff BL, Nowak SM, Lockwood DH 1984 Sulfonylurea effects on target tissues for insulin. Diabetes Care 7[Suppl 1]:42–46
430. Bähr M, von Holtey M, Müller G, Eckel J 1994 Direct stimulation of myocardial glucose transport and glucose transporter-1 (GLUT1) and GLUT4 protein expression by the sulfonylurea glimepiride. Endocinology 136:2547–2553[Abstract]
431. Jacobs DB, Jung CY 1985 Sulfonylurea potentiates insulin-induced recruitment of glucose transport carrier in rat adipocytes. J Biol Chem 260:2593–2596[Abstract/Free Full Text]
432. Müller G, Wied S 1993 The sulfonylurea drug, glimepiride, stimulates glucose transport, glucose transporter translocation, and dephosphorylation in insulin-resistant rat adipocytes in vitro. Diabetes 42:1852–1867[Abstract]
433. Salhanick AI, Konowitz P, Amatruda JM 1982 Potentiation of insulin action by a sulfonylurea in primary cultures of hepatocytes from normal and diabetic rats. Diabetes 32:206–212[Abstract]
434. Caren R, Corbo L 1957 The potentiation of exogenous insulin by tolbutamide in depancreatized dogs. J Clin Invest 36:1546–1550
435. Ricketts H, Wildberger HL Schmid H Long-term studies of sulphonylureas in totally depancreatectomized dogs. Ann NY Acad Sci 71:170–176
436. Best JD, Judzewitsch RG, Pfeifer MA, Beard JC, Halter JB, Porte D 1982 The effect of chronic sulfonylurea therapy on hepatic glucose production in non-insulin-dependent diabetes. Diabetes 31:333–338[Abstract]
437. Simonson DC, Del Prato S, Castellino P, Groop L, DeFronzo RA 1987 Effect of glyburide on glycemic control, insulin requirement, and glucose metabolism in insulin-treated diabetic patients. Diabetes 36:136–146[Abstract]
438. Lisato G, Riccio A, Vigili de Kreutzenberg S, Tiengo A, Del Prato S 1987 Hepatic action of gliclazide treatment in type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 30:550A (Abstract)
439. Simonson DC 1990 Effects of glyburide on in vivo insulin-mediated glucose disposal. Am J Med 89[Suppl 2A]:44S–50S
440. Pontiroli AE, Alberetto M, Bertoletti A, Baio G, Pozza G 1984 Sulfonylureas enhance in vivo the effectiveness of insulin in type 1 (insulin dependent) diabetes mellitus. Horm Metab Res 16:167–170
441. Pernet A, Trimble ER, Kuntschen F, Assal JP, Hahn C, Renold AE 1985 Sulfonylureas in insulin-dependent (type I) diabetes: evidence for an extrapancreatic effect in vivo. J Clin Endocrinol Metab 61:247–251[Abstract/Free Full Text]
442. Keller U, Müller R, Berger W 1986 Sulfonylurea therapy fails to diminish insulin resistance in type I-diabetic subjects. Horm Metab Res 18:599–603[Medline]
443. Leblanc H, Thote A, Chatellier G, Passa P 1990 Effect of glipizide on glycemic control and peripheral insulin sensitivity in type 1 diabetics. Diabete Metab 16:93–97[Medline]
444. Schulz B, Ratzmann KP, Heinke P, Besch W 1983 A stimulatory effect of tolbutamide on the insulin-mediated glucose uptake in subjects with impaired glucose tolerance (IGT). Exp Clin Endocrinol 82:222–231[Medline]
445. Kolterman OG, Olefsky JM 1984 The impact of sulfonylurea treatment upon the mechanism responsible for the insulin resistance in type II diabetes. Diabetes Care 7 [Suppl 1]:81–88
446. Greenfield MS, Doberne L, Rosenthal M, Schulz B, Widstrom A, Reaven GM 1982 Effect of sulfonylurea treatment on in vivo insulin secretion and action in patients with non-insulin-dependent diabetes mellitus. Diabetes 31:307–312[Abstract]
447. Kolterman OG 1985 Longituinal evaluation of the effects of sulfonylurea therapy in subjects with type II diabetes mellitus. Am J Med 79(3B):23–33
448. Ward G, Harrison LC, Proietto J, Aitken P, Nankervis A 1985 Gliclazide therapy is associated with potentiation of postbinding insulin action in obese, non-insulin-dependent diabetic subjects. Diabetes 34:241–245[Abstract]
449. Langtry HD, Balfour JA 1998 Glimepiride: a review of its use in the management of type 2 diabetes mellitus. Drugs 55:563–584[CrossRef][Medline]
450. Rosenkranz B, Profozic V, Metelko Z, Mrzljak V, Lange C, Malerczyk V 1996 Pharmacokinetics and safety of glimepiride at clinically effective doses in diabetic patients with renal impairment. Diabetologia 39:1617–1624[CrossRef][Medline]
451. Kramer W, Müller G, Geisen K 1996 Characterization of the molecular mode of action of the sulfonylurea, glimepiride, at ß-cells. Horm Metab Res 28:464–468[Medline]
452. Müller G, Geisen K 1996 Characterization of the molecular mode of action of the sulfonylurea, glimepiride, at adipocytes. Horm Metab Res 28:469–487[Medline]
453. Ashcroft FM 1996 Mechanism of the glycaemic effects of sulfonylureas. Horm Metab Res 28:456–463[Medline]
454. Müller G, Satoh Y, Geisen K 1995 Extrapancreatic effects of sulfonylureas—a comparison between glimepiride and conventional sulfonylureas. Diabetes Res Clin Pract 28[Suppl]:S115–S137
455. Clark HE, Matthews DR 1996 The effect of glimepiride on pancreatic beta-cell function under hyperglycaemic clamp and hyperinsulinaemic, euglycaemic clamp conditions in non-insulin-dependent diabetes mellitus. Horm Metab Res 28:445–450[Medline]
456. Rosenstock J, Samolis E, Muchmore DB, Schneider J 1996 Glimepiride, a new once-daily sulfonylurea. Diabetes Care 19:1194–1199[Abstract]
457. Dills DG, Schneider J 1996 Clinical evaluation of glimepiride vs. glyburide in NIDDM in a double-blind comparative study. Horm Metab Res 28:426–429[Medline]
458. Draeger KE, Wernicke-Panten K, Lomp HJ, Schüler E, Roßkamp R 1996 Long-term treatment of type 2 diabetic patients with the new oral antidiabetic agent glimepiride (Amaryl ^®): a double-blind comparison with glibenclamide. Horm Metab Res 28:419–425[Medline]
459. Riddle MC 1996 Combined therapy with a sulfonylurea plus evening insulin: safe, reliable, and becoming routine. Horm Metab Res 28:430–433[Medline]
460. Goldberg RB, Holvey SM, Schneider J 1996 A dose-response study of glimepiride in patients with NIDDM who have previously received sulfonylurea agents. Diabetes Care 19:849–856[Abstract]
461. Roßkamp R, Wernicke-Panten K, Draeger E 1996 Clinical profile of the novel sulphonylurea glimepiride. Diabetes Res Clin Pract 31[Suppl]:S33–S42
462. Campbell RK 1998 Glimepiride: role of a new sulfonylurea in the treatment of type 2 diabetes mellitus. Ann Pharmacother 32:1044–1052[Abstract]
463. Massi-Benedetti M, Herz M, Pfeiffer C 1996 The effects of acute exercise on metabolic control in type II diabetic patients treated with glimepiride or glibenclamide. Horm Metab Res 28:451–455[Medline]
464. Geisen K, Vegh A, Krause E, Papp JG 1996 Cardiovascular effects of conventional sulfonylureas and glimepiride. Horm Metab Res 28:496–507[Medline]
465. Rosskamp R 1996 Safety aspects of oral hypoglycemic agents. Diabetologia 39:1668–1672[CrossRef][Medline]
466. Schneider J 1996 An overview of the safety and tolerance of glimepiride. Horm Metab Res 28:413–418[Medline]
467. Paice BJ, Patterson KR, Lawson DH 1985 Undesired effects of sulfonylurea drugs. Adverse Drug React Acute Poisoning Rev 1:23–36
468. UKPDS Group 1998 Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352:837–853[CrossRef][Medline]
469. Schneider J, Chaikin P 1997 Glimepiride safety: results of placebo-controlled, dose-regimen, and active-controlled trials [special report]. Postgrad Med 33–44
470. Dills DG, Schneider J and the Glimepiride/Glyburide Research Group 1996 Clinical evaluation of glimepiride vs. glyburide in NIDDM in a double-blind comparative study. Horm Metab Res 28:426–429
471. Bijlstra PJ, Lutterman JA, Russel FGM, Thien T, Smits P 1996 Interaction of sulfonylurea derivatives with vascular ATP-sensitive potassium channels in humans. Diabetologia 39:1083–1090[Medline]
472. Campbell IW 1985 Metformin and the sulphonylureas: the comparative risk. Horm Metab Res Suppl 15:105–111[Medline]
473. Yki-Järvinen H, Koivisto VA 1984 Continuous subcutaneous insulin infusion therapy decreases insulin resistance in type 1 diabetes. J Clin Endocrinol Metab 58:659–666[Abstract/Free Full Text]
474. Lager I, Lönnroth P, von Schenck H, Smth U 1983 Reversal of insulin resistance in type I diabetes after treatment with continuous subcutaneous insulin infusion. Br Med J (Clin Res Ed) 287:1661–1664
475. Scarlett JA, Gray RS, Griffin J, Olefsky JM, Kolterman OG 1982 Insulin treatment reverses the insulin resistance of type II diabetes mellitus. Diabetes Care 5:353–363[Medline]
476. Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG 1985 The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes 34:222–234[Abstract]
477. Andrews WJ, Vasquez B, Nagulesparan M, Klimes I, Foley J, Unger R, Reaven GM 1984 Insulin therapy in obese non-insulin-dependent diabetes induces improvements in insulin action and secretion that are maintained for two weeks after insulin withdrawal. Diabetes 33:634–642[Abstract]
478. Henry RR, Gumbiner B, Ditzler T, Wallace P, Lyon R, Glauber HS 1993 Intensive conventional insulin therapy for type II diabetes. Diabetes Care 16:21–31[Abstract]
479. Laakso M, Uusitupa M, Takala J, Majander H, Reijonen T, Penttila I 1988 Effects of hypocaloric diet and insulin therapy on metabolic control and mechanisms of hyperglycaemia in obese non-insulin-dependent diabetic subjects. Metabolism 37:1092–1100[CrossRef][Medline]
480. Ginsberg H, Rayfield EJ 1981 Effect of insulin therapy on insulin resistance in type II diabetic subjects. Evidence for heterogeneity. Diabetes 30:739–745[Medline]
481. Yki-Järvinen H, Nikkilä E, Helve E, Taskinen MR 1988 Clinical benefits and mechanisms of a sustained response to intermittent insulin therapy in type 2 diabetic patients with secondary drug failure. Am J Med 84:185–192[CrossRef][Medline]
482. UKPDS Group 1999 Tight blood pressure control and risk of macrovasclar and microvascular complications in type 2 diabetes (UKPDS 38). Br Med J 317:703–713
483. Pyörälä K, Pedersen TR, Kjekshus J, Faergeman O, Olsson AG, Thorgeirsson G and the 4S-Group 1997 Cholesterol lowering with simvastatin improves prognosis of diabetic patients with coronary heart disease. Diabetes Care 20:614–620[Abstract]
484. Meyerovitch J, Rothenberg P, Shechter Y, Bonner-Weir SA, Kahn CR 1991 Vanadate normalises hyperglycaemia in two mouse mdels of non-insulin dependent diabetes mellitus. J Clin Invest 87:1286–1294
485. Brichard SM, Ongemba LN, Henquin JC 1992 Oral vanadate decreases muscle insulin resistance in obese fa/fa rats. Diabetologia 35:522–527[CrossRef][Medline]
486. Goldfine AB, Simonson SC, Folli F, Patti ME, Katin CR 1995 Metabolic effects of sodium metavanadate in humans with insulin-dependent and non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metab 80:3311–3320[Abstract]
487. Cohen N, Halberstam M, Stilimovich P, Chang CJ, Shamoon H, Rosetti L 1995 Oral vanadyl sulfate improves hepatic and peripheral insulin sensitivity in patients with non-insulin-dependent diabetes mellitus. J Clin Invest 95:2501–2509
488. Halberstam M, Cohen N, Shlimovich P, Rosetti L, Shamoon H 1996 Oral vanadyl sulfate improves insulin sensitivity in NIDDM but not in obese nondiabetic subjects. Diabetes 45:659–666[Abstract]
489. McNeill JH, Yuen VG, Hoveyda HR, Orvig C 1992 Bis-(maltolato)-oxovanadium (IV) is a potential mimic. J Med Chem 35:1489–1491[CrossRef][Medline]
490. Zhang B, Salituro G, Szalkowski D, Li Z, Zhang Y, Royo I, Vilella D, Diez MT, Pelaez F, Ruby C, Kendall R, Mao X, Griffin P, Calaycay J, Zierath JR, Heck JV, Smith RG, Moller DE 1999 Discovery of a small molecule insulin mimetic with antidiabetic activity in mice. Science 284:974–977[Abstract/Free Full Text]
491. Nauck M, Wollschläger D, Werner J, Holst J, Orskov C, Creutzfeldt W, Willms B 1996 Effects of subcutaneous glucagon-like peptide 1 (GLP-1[7–36 amide]) in patients with NIDDM. Diabetologia 39:1546–1553[CrossRef][Medline]
492. Skillman CA, Raskin P 1997 A double-masked placebo-controlled trial assessing effects of various doses of BTS 67582, a novel insulinotropic agent on fasting hyperglycaemia in NIDDM patients. Diabetes Care 20:591–596[Abstract]
493. Jones RB, Dickinson K, Anthny DM, Marita AR, Kaul CL, Buckett WR 1997 Evaluation of BTS 67582, a novel antidiabetic agent, in normal and diabetic rats. Br J Pharmacol 120:1135–1143[CrossRef][Medline]
494. Page T, Bailey CJ 1997 Glucose-lowering effect of BTS 67 582. Br J Pharmacol 122:1464–1468[CrossRef][Medline]
495. Ratheiser K, Schneeweis B, Waldhäusl W, Fasching P, Korn A, Nowoty P, Rohac M, Wolf HPO 1991 Inhibition by etomoxir of carnitine palmitoyltransferase 1 reduces hepatic glucose production and plasma lipids in non-insulin-dependent diabetes mellitus. Metabolism 40:1185–1190[CrossRef][Medline]
496. Swislocki A, Eason T 1994 Glucose tolerance and blood pressure are improved in the spontaneously hypertensive rat by ethyl-2-(6-(4-chlorophenoxy)-hexyl)oxirane-2-carboxylate (etomoxir), an inhibitor of fatty acid oxidation. Am J Hypertens 7:739–744[Medline]
497. Hubinger A, Knode O, Susanto F, Reinauer H, Gries FA 1997 Effects of carnitine-acyltransferase inhibitot etomoxir on insulin sensitivity, energy expenditure and substrate oxidation in NIDDM. Horm Metab Res 29:436–439[Medline]
498. Bailey CJ 1999 New pharmacological approaches to glycemic control. Diabetes Rev 7:94–113
499. Iwamoto Y, Kosaka K, Kuzuya T, Akanuma Y, Shigeta Y, Kaneko T 1996 Effect of combination therapy of troglitazone and sulphonylureas in patients with Type 2 diabetes who were poorly controlled by sulphonylurea therapy alone. Diabet Med. 13:365–370
500. Haupt E, Knick B, Koschinsky T, Liebemeister H, Schneider J, Hirche H 1991 Oral antidiabetic combination therapy with sulphonylureas and metformin. Diabete Metab 17:224–231[Medline]
501. Simonson DC, Ferrannini E, Bevilacqua S, Smith D, Barrett E, Carlson R, DeFronzo RA 1984 Mechanism of improvement in glucose metabolism after chronic glyburide therapy. Diabetes 33:838–845[Abstract]
502. Kolterman OG, Gray RS, Shapiro G, Scarlett JA, Griffin J, Olefsky JM 1984 The acute and chronic effects of sulfonylurea therapy in type II diabetic subjects. Diabetes 33:346–354[Abstract]
503. Mandarino LJ, Gerich JE 1984 Prolonged sulphonylurea administration decreases insulin resistance and increases insulin secretion in non-insulin-dependent diabetes mellitus: evidence for improved insulin action at a postreceptor site in hepatic as well as extrahepatic tissues. Diabetes Care 7[Suppl 1]:89–94
504. Hother-Nielsen O, Schmitz O, Andersen PH, Pedersen O, Beck-Nielsen H 1988 In vivo action of glibenclamide in obese subjects with mild type 2 (non-insulin dependent) diabetes. Diabetes Res 8:63–70[Medline]
505. Firth RG, Bell PM, Rizza RA 1986 Effects of tolazamide and exogenous insulin on insulin action in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 314:1280–1286[Abstract]
506. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM 1995 Increased adipose tissue expression of tumor necrosis factor- in human obesity and insulin resistance. J Clin Invest 95:2409–2415
507. Buse J 2000 Combining insulin and oral agents. Am J Med 108[Suppl 1]:23–32

This article has been cited by other articles:

				H. Staiger, F. Machicao, A. Fritsche, and H.-U. Haring Pathomechanisms of Type 2 Diabetes Genes Endocr. Rev., October 1, 2009; 30(6): 557 - 585. [Abstract] [Full Text] [PDF]

				G. E. Umpierrez, D. Smiley, G. Robalino, L. Peng, A. E. Kitabchi, B. Khan, A. Le, A. Quyyumi, V. Brown, and L. S. Phillips Intravenous Intralipid-Induced Blood Pressure Elevation and Endothelial Dysfunction in Obese African-Americans with Type 2 Diabetes J. Clin. Endocrinol. Metab., February 1, 2009; 94(2): 609 - 614. [Abstract] [Full Text] [PDF]

				S. M Nelson Obesity, insulin resistance and assisted conception The British Journal of Diabetes & Vascular Disease, January 1, 2009; 9(1): 23 - 26. [Abstract] [PDF]

				N. Stefan, K. Kantartzis, and H.-U. Haring Causes and Metabolic Consequences of Fatty Liver Endocr. Rev., December 1, 2008; 29(7): 939 - 960. [Abstract] [Full Text] [PDF]

				F. Chiarelli and M. L. Marcovecchio Insulin resistance and obesity in childhood Eur. J. Endocrinol., December 1, 2008; 159(suppl_1): S67 - S74. [Abstract] [Full Text] [PDF]

				C. X. Fang, F. Dong, D. P. Thomas, H. Ma, L. He, and J. Ren Hypertrophic cardiomyopathy in high-fat diet-induced obesity: role of suppression of forkhead transcription factor and atrophy gene transcription Am J Physiol Heart Circ Physiol, September 1, 2008; 295(3): H1206 - H1215. [Abstract] [Full Text] [PDF]

				K. Azuma, Z. Radikova, J. Mancino, F. G. S. Toledo, E. Thomas, C. Kangani, C. Dalla Man, C. Cobelli, J. J. Holst, C. F. Deacon, et al. Measurements of Islet Function and Glucose Metabolism with the Dipeptidyl Peptidase 4 Inhibitor Vildagliptin in Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., February 1, 2008; 93(2): 459 - 464. [Abstract] [Full Text] [PDF]

				J. Movassat, D. Bailbe, C. Lubrano-Berthelier, F. Picarel-Blanchot, E. Bertin, J. Mourot, and B. Portha Follow-up of GK rats during prediabetes highlights increased insulin action and fat deposition despite low insulin secretion Am J Physiol Endocrinol Metab, January 1, 2008; 294(1): E168 - E175. [Abstract] [Full Text] [PDF]

				F. Dong, Q. Li, N. Sreejayan, J. M. Nunn, and J. Ren Metallothionein Prevents High-Fat Diet Induced Cardiac Contractile Dysfunction: Role of Peroxisome Proliferator Activated Receptor {gamma} Coactivator 1{alpha} and Mitochondrial Biogenesis Diabetes, September 1, 2007; 56(9): 2201 - 2212. [Abstract] [Full Text] [PDF]

				J. J. Hernandez-Morante, F. Milagro, J. A. Gabaldon, J. A. Martinez, S. Zamora, and M. Garaulet Effect of DHEA-sulfate on adiponectin gene expression in adipose tissue from different fat depots in morbidly obese humans. Eur. J. Endocrinol., October 1, 2006; 155(4): 593 - 600. [Abstract] [Full Text] [PDF]

				B. Desvergne, L. Michalik, and W. Wahli Transcriptional Regulation of Metabolism Physiol Rev, April 1, 2006; 86(2): 465 - 514. [Abstract] [Full Text] [PDF]

				Y. Kawamura, Y. Tanaka, R. Kawamori, and S. Maeda Overexpression of Kruppel-Like Factor 7 Regulates Adipocytokine Gene Expressions in Human Adipocytes and Inhibits Glucose-Induced Insulin Secretion in Pancreatic {beta}-Cell Line Mol. Endocrinol., April 1, 2006; 20(4): 844 - 856. [Abstract] [Full Text] [PDF]

				X. C. Li, O. A. Carretero, Y. Shao, and J. L. Zhuo Glucagon Receptor-Mediated Extracellular Signal-Regulated Kinase 1/2 Phosphorylation in Rat Mesangial Cells: Role of Protein Kinase A and Phospholipase C Hypertension, March 1, 2006; 47(3): 580 - 585. [Abstract] [Full Text] [PDF]

				B. J Geesaman Genetics of aging: implications for drug discovery and development Am. J. Clinical Nutrition, February 1, 2006; 83(2): 466S - 469S. [Abstract] [Full Text] [PDF]

				T. Tang, J. Glanville, C. J. Hayden, D. White, J. H. Barth, and A. H. Balen Combined lifestyle modification and metformin in obese patients with polycystic ovary syndrome. A randomized, placebo-controlled, double-blind multicentre study Hum. Reprod., January 1, 2006; 21(1): 80 - 89. [Abstract] [Full Text] [PDF]

				S. Kralisch, J. Klein, U. Lossner, M. Bluher, R. Paschke, M. Stumvoll, and M. Fasshauer Hormonal regulation of the novel adipocytokine visfatin in 3T3-L1 adipocytes J. Endocrinol., June 1, 2005; 185(3): R1 - R8. [Abstract] [Full Text] [PDF]

				S. Rice, N. Christoforidis, C. Gadd, D. Nikolaou, L. Seyani, A. Donaldson, R. Margara, K. Hardy, and S. Franks Impaired insulin-dependent glucose metabolism in granulosa-lutein cells from anovulatory women with polycystic ovaries Hum. Reprod., February 1, 2005; 20(2): 373 - 381. [Abstract] [Full Text] [PDF]

				G. Schernthaner, D. R. Matthews, B. Charbonnel, M. Hanefeld, P. Brunetti, and on Behalf of the Quarter Study Group Efficacy and Safety of Pioglitazone Versus Metformin in Patients with Type 2 Diabetes Mellitus: A Double-Blind, Randomized Trial J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6068 - 6076. [Abstract] [Full Text] [PDF]

				J. Klein, S. Westphal, D. Kraus, B. Meier, N. Perwitz, V. Ott, M. Fasshauer, and H H. Klein Metformin inhibits leptin secretion via a mitogen-activated protein kinase signalling pathway in brown adipocytes J. Endocrinol., November 1, 2004; 183(2): 299 - 307. [Abstract] [Full Text] [PDF]

				R. Z. Lewanczuk, B. W. Paty, and E. L. Toth Comparison of the [13C]Glucose Breath Test to the Hyperinsulinemic-Euglycemic Clamp When Determining Insulin Resistance Diabetes Care, February 1, 2004; 27(2): 441 - 447. [Abstract] [Full Text] [PDF]

				V. De Leo, A. la Marca, and F. Petraglia Insulin-Lowering Agents in the Management of Polycystic Ovary Syndrome Endocr. Rev., October 1, 2003; 24(5): 633 - 667. [Abstract] [Full Text] [PDF]

				M. Stumvoll, P. A. Tataranni, N. Stefan, B. Vozarova, and C. Bogardus Glucose Allostasis Diabetes, April 1, 2003; 52(4): 903 - 909. [Abstract] [Full Text] [PDF]

				J. E. Gunton, P. J. D. Delhanty, S.-I. Takahashi, and R. C. Baxter Metformin Rapidly Increases Insulin Receptor Activation in Human Liver and Signals Preferentially through Insulin-Receptor Substrate-2 J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1323 - 1332. [Abstract] [Full Text] [PDF]

				S. P. Marso Optimizing the diabetic formulary: beyond aspirin and insulin J. Am. Coll. Cardiol., August 21, 2002; 40(4): 652 - 661. [Abstract] [Full Text] [PDF]

				Y. Ido, D. Carling, and N. Ruderman Hyperglycemia-Induced Apoptosis in Human Umbilical Vein Endothelial Cells: Inhibition by the AMP-Activated Protein Kinase Activation Diabetes, January 1, 2002; 51(1): 159 - 167. [Abstract] [Full Text] [PDF]

				H. Cho, J. Mu, J. K. Kim, J. L. Thorvaldsen, Q. Chu, E. B. Crenshaw III, K. H. Kaestner, M. S. Bartolomei, G. I. Shulman, and M. J. Birnbaum Insulin Resistance and a Diabetes Mellitus-Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKBbeta ) Science, June 1, 2001; 292(5522): 1728 - 1731. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Matthaei, S. Articles by Häring, H.-U. Search for Related Content PubMed PubMed Citation Articles by Matthaei, S. Articles by Häring, H.-U.