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Endocrine Reviews 21 (6): 585-618
Copyright © 2000 by The Endocrine Society

Pathophysiology and Pharmacological Treatment of Insulin Resistance1

Stephan Matthaei, Michael Stumvoll, Monika Kellerer and Hans-Ulrich Häring

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., {alpha}-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. {alpha}-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. 1Go) 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.



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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 ).

 
Until the importance of screening for, as well as treating, the early stage of the metabolic syndrome is appreciated by health insurance companies and physicians, the optimal treatment of patients with type 2 diabetes mellitus to avoid diabetic complications and to preserve quality of life is a major focus in today’s medical world. Although nonpharmacological treatment modalities such as reduced caloric intake and increased physical activity represent the basis of the treatment of insulin resistance and their efficacy have been demonstrated in numerous studies and summarized in recent reviews (10, 11), the actual number of patients sufficiently treated without pharmacological agents is comparatively low. The United Kingdom Prospective Diabetes Study (UKPDS) has recently demonstrated that nonpharmacological treatment is sufficient only in 25% of patients with a 3-yr duration of diabetes (time after diagnosis). With advancing duration of the disease, which is associated with progressive deterioration in ß-cell function (12), this number fell to less than 10% after 9 yr (13). Thus, these data implicate that pharmacological treatment is required in the vast majority of type 2 diabetic patients.

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. 1Go). 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. 2Go). 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.



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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.

 
1. The insulin-signaling chain: alterations found in insulin resistance and type 2 diabetes. Figure 3Go shows a simplified draft of the signaling steps from insulin receptor binding to glucose transport activation. Insulin signaling at the cellular level is mediated by binding of insulin to a specific receptor. Insulin binding to the receptor stimulates autophosphorylation of the intracellular region of the receptor ß-subunit (53). A reduced autoactivation status of the insulin receptor from skeletal muscle and adipocytes of type 2 diabetic patients has been described by several but not all investigators (54, 55, 56, 57, 58, 59, 60, 61, 62). Some of these studies have shown that obesity was a major contributory factor for the development of a reduced insulin receptor activity (56, 63). This could suggest that the defective insulin receptor kinase activity is secondarily acquired due to obesity and metabolic changes such as hyperinsulinemia and hyperglycemia.



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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.

 
a. Insulin receptor substrates.
The first substrate of the insulin receptor was described by White et al. in 1985 (64). Subsequently, this intracellular protein was cloned by Sun et al. (65) and named insulin receptor substrate-1 (IRS-1). IRS-1 and other recently cloned IRS proteins (IRS-2, -3, -4) are phosphorylated upon insulin stimulation and have adaptor function between the insulin receptor and other cellular substrates such as the phosphatidylinositol 3-kinase (PI 3kinase) (65, 66, 67, 68). The contribution of IRS-1 and IRS-2 to insulin resistance and diabetes was recently tested by targeted disruption of the respective gene in mice. IRS-1 knockout mice were insulin resistant but not hyperglycemic (69). It has been shown that the recently cloned IRS-2 was at least partially able to compensate for the lack of IRS-1, which could explain the mild and nondiabetic phenotype of IRS-1 knockout mice (70). In the meantime, IRS-2 knockout mice have also been generated. Although IRS-1 and IRS-2 are highly homologous proteins and share many signaling properties, the phenotype of IRS-2 knockout mice is markedly different from that of IRS-1 knockout mice (71). IRS-2-deficient mice are severely hyperglycemic due to abnormalities of peripheral insulin action and failure of ß-cell secretion (71). This phenotype with severe hyperglycemia as a consequence of peripheral insulin resistance and insufficient insulin secretion due to a significantly reduced ß-cell mass reveals many similarities to type 2 diabetes in man and outlines the role of IRS proteins for the development of cellular insulin resistance and ß-cell function.

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{zeta} isoform has been demonstrated recently (76). Recent evidence suggests that PDK-1 mediates insulin-dependent activation of atypical PKC{zeta} through phosphorylation on threonine410 in the activation loop (74, 75). In addition, insulin-dependent stimulation of atypical PKC{zeta} has been shown to mediate insulin effects on protein synthesis (76). Moreover, there is evidence that the atypical PKC isoforms {zeta} and {lambda} 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{alpha} 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{alpha} subunit of PI 3-kinase are surprisingly more insulin sensitive and mildly hypoglycemic (98). This has been explained by a switch from p85{alpha} to the p50{alpha} 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{alpha} 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 1Go 103–115). The chromosomal loci are partially located in the vicinity of known genes such as the hepatic nuclear factor 1{alpha} (HNF 1{alpha}), 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.


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Table 1. Genome scan studies for susceptibility of insulin resistance and type 2-diabetes

 
D. Inactivity-related insulin resistance
Obesity and lack of physical exercise are major contributory factors to insulin resistance. It has been demonstrated that insulin sensitivity could be improved by exercise independently from weight reduction and changes in body composition. Most of these studies refer to the effect of exercise on skeletal muscle. There is evidence that skeletal muscle training leads to altered expression of insulin signaling elements, in particular glucose transporters (reviewed in Ref. 120). In insulin-resistant offspring of type 2 diabetic patients, 6 weeks of training caused increased glucose uptake and glycogen synthesis, which led to improved insulin sensitivity 21). In addition to the effect of physical exercise on glucose transporter molecules, increased blood flow and availability of insulin in target tissues may contribute to metabolic improvement during training (122). Another non-insulindependent effect by exercise is release of local bradykinin, which has been shown to have stimulatory effects on glucose uptake (123). In addition to the effects on skeletal muscle, there is evidence that insulin resistance of liver can be improved as well. This has been demonstrated by a significant reduction of hepatic glucose production after endurance training (124). Moreover, insulin responsiveness toward glucose uptake can be enhanced in adipocytes after acute exercise (125). Thus, it is generally accepted that muscle, liver, and fat contribute to the improvement of insulin sensitivity induced by physical exercise.

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-{alpha} (TNF{alpha}) in obesity-related insulin resistance. A great number of studies have been performed in the last years to elucidate the role of TNF{alpha} for obesity-related insulin resistance. Spiegelman and co-workers recently proposed that TNF{alpha} may contribute to insulin resistance in obese subjects (reviewed in Ref. 154). Several studies have shown that TNF{alpha} 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{alpha}-induced insulin resistance, clinical results from different insulin-resistant populations so far do not support a major role of TNF{alpha} on insulin resistance in humans (158, 159). However, one study has shown increased adipose tissue expression of TNF{alpha} in obese premenopausal women when compared with control subjects (506).

4. The peroxisome proliferator-activated receptor-{gamma} (PPAR{gamma}): 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 PPAR{gamma}2 (160). PPAR{gamma}2 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{gamma} 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 PPAR{gamma}2-dependent genes (reviewed in Refs. 162, 163). Recently, the Pro12Ala and two other polymorphisms were described in the PPAR{gamma}2 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 PPAR{gamma}2 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 PPAR{gamma}2 polymorphism directly interferes with ß-cell function. In agreement with this, direct effects of PPAR{gamma} 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{gamma} 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{gamma} 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{gamma} agonists may directly improve ß-cell dysfunction in humans. However, clearly more studies are needed to investigate direct effects of PPAR{gamma} 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. {alpha}-Glucosidase inhibitors
1. Mechanism of action. These agents delay digestion of complex carbohydrates and disaccharides (starch, dextrin, sucrose) to absorbable monosaccharides by reversibly inhibiting {alpha}-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 {alpha}-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 {alpha}-glucosidase inhibitors on hyperglycemia in patients with type 2 diabetes mellitus. The effect of monotherapy with {alpha}-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 {alpha}-glucosidase inhibitors on fasting plasma glucose levels is less pronounced and averages -1.3 mmol/liter. The overall effect of {alpha}-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 {alpha}-glucosidase-inhibitors on insulin sensitivity. Eight randomized placebo-controlled studies have been published examining the effect of {alpha}-glucosidase inhibitors on insulin sensitivity in patients with IGT or type 2 diabetes mellitus (Table 2Go). 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 {alpha}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 {alpha}-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 {alpha}-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 {alpha}-glucosidase inhibitors improve insulin sensitivity in subjects with IGT but have no effect on insulin sensitivity in subjects with overt type 2 diabetes.


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Table 2. Effect of {alpha}-glucosidase inhibitors on insulin sensitivity

 
4. {alpha}-Glucosidase inhibitors in type 2 diabetes prevention studies. Currently, three type 2 diabetes prevention trials examining the effect of acarbose on the conversion rate from IGT to type 2 diabetes are under way. The Early Diabetes Intervention Trial (EDIT), the Dutch Acarbose Intervention Trial (DAISI), and the Study to Prevent NIDDM (STOP-NIDDM). The STOP-NIDDM is the largest trial including more than 1,400 IGT-subjects recruited until February 1998. The study has a randomized double-blind placebo-controlled design, and the recently published preliminary screening data (214) provide interesting information on the population under study. In a preliminary subset of 3,919 screened subjects, preselected by known risk factors to develop type 2 diabetes (BMI > 27 kg/m2, history of diabetes, hypertension, dyslipidemia, and gestational diabetes in women) 13.3% had previously undetected diabetes and 17.3% had IGT. A total of 1.418 IGT subjects identified during the screening procedure were included in the study for a predictive median follow-up period of 3.9 yr. The results will be available by 2002, and it will be interesting to see whether treatment with acarbose is able to decrease the conversion rate of IGT to manifest type 2 diabetes mellitus in a higher proportion than nonpharmacological intervention protocols including dietary advice and exercise in the Da Qing study (215).

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 {alpha}-glucosidase inhibitors. {alpha}-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 {alpha}-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 {alpha}-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 {alpha}-glucosidase inhibitors decrease postprandial glycemia these patients are suitable candidates for treatment with {alpha}-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, {alpha}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, AGo and BGo) 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.


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Table 3A. Metabolic studies in humans with type 2 diabetes: effects of metformin

 

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Table 3B. Metabolic studies in humans without type 2 diabetes: effects of metformin

 
In the insulin-stimulated state during the clamp, peripheral glucose disposal is increased even in the absence of improved fasting glycemia, indicating a reduction in insulin resistance. This is thought to be mainly a result of enhanced glucose transport and storage in muscle. The effect on glucose transport is most likely due to a potentiation of insulin-stimulated translocation of glucose transporters and an increase in their intrinsic activity (287, 288). Glycogen synthesis is increased as a result of stimulatory effects of metformin on the signaling chain to activation of glycogen synthase. Moreover, the in vivo effect on muscle may, in part, be due to a reduction in FFA oxidation. Finally, in insulin-resistant subjects the effect on muscle appears to be more pronounced, suggesting a reversal of insulin resistance rather than a mere improvement in insulin sensitivity.

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{gamma} 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{gamma} are highest in adipocytes, intestinal cells, and macrophages but very low in most other tissues including muscle. PPAR{gamma} 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{gamma} 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{gamma} 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{gamma} expressed in muscle may be sufficient or alternatively might be induced during treatment with thiazolidinediones, leading to a direct PPAR{gamma}-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{gamma}-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{alpha} (337) and leptin (338, 339), both of which have been implicated in obesity-related insulin resistance. Although the definite role of the cytokine TNF{alpha} for human insulin resistance remains to be determined, TNF{alpha} 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{alpha} (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{gamma} 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 4Go). 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.


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Table 4. Comparison of troglitazone, rosiglitazone, and pioglitazone

 
b. Lipid profile.
Interestingly, other abnormalities commonly associated with insulin resistance, such as dyslipidemia and arterial hypertension, also appeared to be improved by thiazolidinediones (343, 345, 350). While none of the compounds reduced total cholesterol, differential effects on lipoproteins were noted. All three thiazolidinediones increased HDL cholesterol. However, while troglitazone and rosiglitazone increased LDL cholesterol, this was not the case with pioglitazone. No significant effect on triglyceride levels was reported for either of the compounds. In healthy volunteers, troglitazone, which, unlike other thiazolidinediones, carries an antioxidant vitamin E moiety, also reduced the amount of LDL lipid hydroperoxides (351), which are thought to be of particular atherogenic potential (352).

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 5Go). No such data are available for rosiglitazone or pioglitazone at the present time.


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Table 5. Metabolic studies in humans: effects of troglitazone

 
During oral glucose and meal tolerance tests, a 25% reduction of postchallenge blood glucose was observed in some studies after troglitazone treatment accompanied by a similar reduction in plasma insulin levels (363, 364). In addition, a slight but significant improvement of these parameters was observed in nondiabetic individuals (365, 366). Using the hyperinsulinemic-euglycemic clamp technique, a significant improvement in insulin-stimulated glucose uptake (by 41–97%) was shown not only in patients with type 2 diabetes (356, 363, 364) but also in normal glucose-tolerant, insulin-resistant subjects (by 10% with insulin given at a rate of 40 mU/kg·min and 27% with insulin given at a rate of 300 mU/kg·min) (365). In patients with type 2 diabetes treated with troglitazone 400 mg daily, endogenous glucose production, as determined by the isotope dilution technique, decreased by 30% in one study, approaching the mean normal rate (363). In another study, however, a significant reduction in glucose production was reported only for the group treated with the highest dose (600 mg daily) but not with 100, 200, or 400 mg (364). In insulin-resistant women with PCOS, troglitazone treatment resulted in improved insulin resistance (assessed by minimal model), which was associated with significant decreases in testosterone, dehydroepiandrosterone sulfate, estradiol, and estrone (367). It was concluded that treatment of insulin resistance and hyperinsulinemia in PCOS may reduce the accelerated steroidogenesis and release of LH characteristic for this disease.

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{gamma}-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{gamma}-activation causes fatty transformation of bone marrow stromal cells, which is considered to be a serious condition (379). Furthermore, PPAR{gamma}s were recently shown to be involved in differentiation and uptake of oxidized LDL by macrophages/monocytes, suggesting that endogenous PPAR{gamma} ligands are important regulators of gene expression during atherogenesis (380, 381, 382). Moreover, in mice, PPAR{gamma}-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 6Go. 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.


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Table 6. Effect of sulfonylureas on endogenous glucose production

 
b. Effect of sulfonylureas on glucose utilization.
Several studies have examined the effect of sulfonylureas on peripheral glucose utilization in type 1 as well as in type 2 diabetic subjects (Table 7Go). In type 1 diabetic subjects, the majority of the studies failed to demonstrate any effect of sulfonylureas on glucose utilization (439, 441, 442, 443), while one short-term study revealed an increased glucose utilization due to chlorpropamide as well as glipizide treatment (440).


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Table 7. Effect of sulfonylureas on glucose utilization in IGT- and type 2 diabetic subjects

 
The effect of sulfonylureas on glucose utilization in IGT- and type 2 diabetic subjects were examined in six studies (439, 444, 445, 446, 447, 448), which are summarized in Table 7Go. All of these studies revealed that sulfonylureas increase peripheral glucose utilization by an average of 29%, ranging from nonsignificant (10%) to significant (52%). This improved peripheral insulin sensitivity was associated with a mean increase of plasma insulin levels averaging 33% in these studies (range, 18–63%). Thus, the effect of sulfonylureas to increase peripheral glucose utilization is accompanied by an augmented insulin secretion of similar magnitude. Although this does not exclude an extrapancreatic effect of sulfonylureas to improve peripheral glucose utilization, the above mentioned studies were not designed to specifically answer the question of whether sulfonylureas have an intrinsic extrapancreatic mode of action to improve peripheral insulin action. Those studies would have to exclude interfering variables, such as nonstable concentrations of insulin, glucose, and FFA, as well as other metabolites and hormones, known to influence peripheral insulin action. Consequently, based on the existing data, the evidence of an extrapancreatic action of sulfonylureas is rather indirect and based on studies not vigorously designed to answer this question.

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 8Go. 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.


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Table 8. Effect of insulin therapy on peripheral glucose disposal and endogenous glucose production in subjects with type 2 diabetes mellitus

 

    IV. Perspectives
 Top
 Abstract
 I. Introduction
 II. Pathophysiology and...
 III. Pharmacological Treatment
 IV. Perspectives
 V. Summary and Conclusion
 References
 
Optimal treatment of patients with insulin-resistant type 2 diabetes mellitus includes normalization of weight, glycemia, lipidemia, and blood pressure (468, 482, 483). In addition, according to the American Diabetes Association guidelines, aspirin therapy should be considered as primary prevention strategy in high-risk patients with type 1 or type 2 diabetes. During the last years, antihyperglycemic agents have been expanded by the introduction of drugs known to ameliorate hyperglycemia without increasing insulin secretion, i.e., metformin, acarbose (US market), and thiazolidinediones (troglitazone, rosiglitazone, pioglitazone), as well as novel insulinotropic agents, i.e., glimepiride and meglitinides (repaglinide and nateglinide; insulin-secreting drugs with short duration of action suitable for meal-adapted dosage). Are there any other drugs for oral treatment of type 2 diabetics on the horizon?

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. 4Go. Agents that may eventually supplement our therapeutic potential are included.



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Figure 4. Antihyperglycemic agents. Summary of hyperglycemic agents currently available and potential new therapeutic targets and substances.

 
As proposed in Fig. 5Go the currently available antihyperglycemic agents should be selected for treatment of type 2 diabetic subjects, based on the dynamic pathophysiologically abnormalities of the disease, needless to say, keeping in mind the respective contraindications.



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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.

 
As the essential part of the nonpharmacological treatment basis, type 2 diabetic patients should participate in a structured diabetes education program. During this program, the patients learn everything important about diabetes, especially self-measurement of blood glucose, and the impact of nutrition and physical activity on the progression of the disease. The patient should be taught that he/she is suffering from a chronic and progressive disease probably requiring different modes of therapy including, eventually, insulin and, importantly, that the speed of disease progression is largely dependent upon exogenous effects such as body weight and level of physical activity. Thus, the patient should get the message that he/she can actively combat disease progression and in this regard the physician should empower the self-responsibility of the patient.

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., {alpha}-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). Back


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

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