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The Genetic Basis of Type 2 Diabetes Mellitus: Impaired Insulin Secretion versus Impaired Insulin Sensitivity

University of Rochester, School of Medicine and Dentistry, Departments of Medicine, Physiology, and Pharmacology, Rochester, New York 14642

	Abstract

Top Abstract I. Introduction II. Strategy III. Studies in Genetically... IV. Prospective Studies of... V. Studies of Normal... VI. Reversibility of Insulin... VII. Are All Type... VIII. Hypothesis for... IX. Summary and Conclusion References

 

I. Introduction

A. General considerations

B. Diabetogenic vs. diabetes-related genes

C. Secondary impairment of insulin secretion and insulin sensitivity

D. Insulin deficiency vs. impaired insulin secretion

E. Misinterpretation of the Oral Glucose Tolerance Test (OGTT)

II. Strategy

III. Studies in Genetically Predisposed Individuals with NGT

A. First-degree relatives (excluding twins)

B. Identical twins discordant for type 2 diabetes

IV. Prospective Studies of Individuals Before Development of Type 2 Diabetes

V. Studies of Normal Glucose-Tolerant Women with a History of Gestational Diabetes

VI. Reversibility of Insulin Resistance and Impaired Insulin Secretion by Therapeutic Interventions

VII. Are all Type 2 Diabetics Insulin Resistant?

VIII. Hypothesis for Pathogenesis of Type 2 Diabetes

IX. Summary and Conclusion

	I. Introduction

Top Abstract I. Introduction II. Strategy III. Studies in Genetically... IV. Prospective Studies of... V. Studies of Normal... VI. Reversibility of Insulin... VII. Are All Type... VIII. Hypothesis for... IX. Summary and Conclusion References

 
A. General considerations
TYPE 2 diabetes mellitus accounts for 80–90% of all diabetes in most countries (1). It is, however, an extremely heterogeneous disorder: 5–10% of patients may have maturity-onset diabetes of youth (MODY) (2); another 5–10% may have latent adult-onset autoimmune diabetes (3); and another 5–10% may have diabetes secondary to rare genetic disorders (4, 5, 6). The etiology of diabetes in the remaining 70–85% of patients, the typical patient, remains poorly defined and a matter of great controversy. Ethnic and geographic differences in the incidence of this "garden-variety type" type 2 diabetes indicate that it too is heterogeneous (1). Indeed, two diabetes susceptibility genes for type 2 diabetes have recently been identified: the one found in Mexican Americans [NIDDM 1 (7)] is different from the one found in Finnish families (NIDDM 2) (8).

Although the pathogenesis of "garden-variety type" type 2 diabetes is controversial, it is generally agreed that: 1) the disease has strong genetic and environmental (acquired) components (9, 10, 11, 12, 13); 2) its inheritance is polygenic (14, 15, 16, 17), meaning that the simultaneous presence of several abnormal genes or polymorphisms is necessary for development of the disease; 3) impairment of insulin sensitivity and insulin secretion, each of which is under genetic control (18, 19, 20), are both important elements in its pathogenesis (12, 16, 21, 22, 23); 4) most patients are obese; and 5) obesity, especially intraabdominal obesity (24, 25, 26, 27), causes insulin resistance and is under genetic control (11).

What is disputed are: 1) the quantitative contribution of insulin resistance and impaired insulin secretion; 2) their role as genetic factors; 3) the major sites of insulin resistance (liver vs. muscle vs. adipose tissue vs. kidney); and 4) the steps that lead to the development of type 2 diabetes (28, 29, 30, 31, 32, 33, 34).

The focus of this debate is whether the primary genetic determinants for type 2 diabetes are abnormal genes or polymorphisms related to insulin resistance or impaired insulin secretion, not whether insulin resistance or impaired insulin secretion is more important in the pathogenesis of type 2 diabetes. Clearly, both are important and whether or not their basis is genetic does not diminish their importance.

The overwhelmingly predominant view at the present time, as reflected in textbooks and review articles (35, 36, 37), is that genes affecting insulin sensitivity are the primary genetic factors. Consequently, a substantial effort is underway to determine its molecular basis. As will become apparent, however, there is also a considerable body of evidence suggesting that genes affecting insulin secretion may be the primary genetic factors. Because insulin resistance almost universally is regarded as the primary genetic factor in type 2 diabetes, I have taken pains to point out potential shortcomings in studies supporting this point of view. Clearly, many of the studies supporting a genetic defect in the ß-cell have similar shortcomings. Although not pointing these out with equal emphasis may be viewed as a bias on my part, this approach was taken to demonstrate that the evidence supporting insulin resistance as the primary genetic defect is not as strong as is generally perceived. It is not expected that this debate will resolve the question of whether impaired insulin secretion or insulin resistance is the primary genetically determined factor for development of type 2 diabetes, but rather it is hoped that this debate will lead to a reassessment of current dogma and perhaps a more equitable reallocation of efforts to determine the molecular basis for the genetic components of type 2 diabetes consistent with available evidence.

B. Diabetogenic vs. diabetes-related genes
A major problem limiting our understanding of the genetic basis of type 2 diabetes is that many environmental and genetically based factors influence insulin sensitivity and insulin secretion: these include age, gender, ethnicity, physical fitness, diet, smoking (38), obesity, and fat distribution (12). Although many of these may be under genetic control (11), it is important to emphasize that the genes may not necessarily represent specific diabetes genes. For example, let us suppose that the insulin resistance in type 2 diabetics was mainly due to intraabdominal fat accumulation and that this were mainly under genetic control. One could conclude that the insulin resistance found in type 2 diabetics was genetic, but it would not represent a specific diabetes gene since most insulin-resistant obese people do not develop diabetes (39). On the other hand, a mutation in the insulin receptor gene causing insulin resistance could be considered a diabetes-specific gene since, if severe enough, most people with the genetic defect would develop diabetes and most people without diabetes would not have this gene.

It is important, therefore, to distinguish between diabetogenic genes, with which this article is concerned, and diabetes-related genes (e.g., those regulating appetite, energy expenditure, and intraabdominal fat accumulation) (10). The latter class of genes may be defined as not being specific (i.e., not being mainly limited to people with diabetes), as by themselves not being sufficient to cause diabetes and not necessarily being essential. These genes are best considered as genetically determined risk factors. An example might be a gene or group of genes causing obesity. These genes would not be limited to individuals destined to become diabetic (e.g., not specific), would not be sufficient since most obese individuals do not become diabetic, and would not be essential since, depending on the population, a considerable number of lean individuals develop type 2 diabetes. A diabetogenic gene may be defined as being essential and relatively specific but, given the polygenic nature of type 2 diabetes, may not be sufficient in itself to cause diabetes. For example, a mild alteration in the activity of glucokinase, such as is found in some MODY patients (32), which reduces insulin secretion, is relatively specific, being mainly limited to families with this type of diabetes; it may not be sufficient to cause diabetes in most individuals unless there are increased requirements for insulin such as that due to superimposition of acquired insulin resistance (e.g., obesity, physical inactivity, or pregnancy) but it may be considered to be essential since without this defect, diabetes would not other- wise occur.

Thus, depending on the severity of the expression of the genes in a given individual and on the accompanying environmental (acquired) factors, a combination of several diabetes-related genes and several diabetic genes may be necessary to cause diabetes. Indeed, in the GK rat there appears to be at least six genetic loci involved (40), and in humans two different susceptibility genes have been recently identified, one in Mexican-Americans (NIDDM 1) (7) and one in Finnish families (NIDDM 2) (8).

C. Secondary impairment of insulin secretion and insulin sensitivity
Another confounding factor is that hyperglycemia and hyperinsulinemia in themselves can impair insulin secretion and insulin sensitivity (41, 42, 43). Thus, people with impaired glucose tolerance (IGT) and overt type 2 diabetes can be expected to have insulin resistance and impaired insulin secretion independent of genetic causes merely because they are hyperglycemic. Because of this, cross-sectional studies including individuals with IGT and type 2 diabetes have not proven to be particularly informative in delineating between genetic and acquired alterations in insulin secretion and action.

D. Insulin deficiency vs. impaired insulin secretion
Another factor that has led to confusion regarding our understanding of the genetic basis of type 2 diabetes is that the literature has been obfuscated by establishment of a dichotomy of insulin deficiency vs. insulin resistance. For example, it has been argued that individuals with type 2 diabetes or IGT are hyperinsulinemic, and therefore the main problem must be insulin resistance rather than insulin deficiency (21, 28, 29). Although this may be true, it is a misleading analysis. It assumes that hyperinsulinemia, even if inappropriate for the prevailing hyperglycemia, indicates normal pancreatic ß-cell function. In other words, insulin deficiency, rather than impaired ß-cell function, has been contrasted with insulin resistance.

Strictly speaking, absolute insulin deficiency rarely occurs except in patients with insulin-dependent type 1 diabetes of several years duration. Many type 1 diabetic patients in ketoacidosis have been reported to have plasma insulin levels in the normal range (44). These insulin levels are of course grossly inappropriate for the degree of hyperglycemia.

The dichotomy established between insulin deficiency and insulin resistance has led to a general underemphasis of the issue of the appropriateness of ß-cell function. According to the dichotomy, a person having a plasma glucose level of 200 mg/dl and a plasma insulin of 20 µU/ml would be hyperinsulinemic compared with a person with a plasma glucose of 100 mg/dl with a plasma insulin of 10 µU/ml. Such a person would be considered not to have impaired ß-cell function, but to be insulin resistant because of the hyperinsulinemia. However, a person with normal glucose tolerance whose plasma glucose level is raised 200 mg/dl would secrete 2–4 times more insulin than a type 2 diabetic patient with a plasma glucose of 200 mg/dl (45, 46).

Thus, although hyperinsulinemia may signify the presence of insulin resistance, this may not necessarily be the case, and increased plasma insulin levels do not necessarily indicate normal ß-cell function. It is important to recognize that another determinant of insulin secretion, in addition to the ambient plasma glucose levels, is insulin sensitivity. Obese insulin-resistant individuals secrete more insulin than lean insulin-sensitive individuals at comparable plasma glucose levels (45). Few studies have analyzed insulin secretion in relation to insulin sensitivity (47).

As recently pointed out by Reaven (48), because of the feedback between plasma glucose concentration (the major stimulus for insulin release) and ß-cell insulin secretion, it is virtually impossible to develop diabetes due to the severity of insulin resistance found in most type 2 diabetic patients unless the capacity to secrete additional amounts of insulin to compensate for the insulin resistance is impaired. Thus, hyperglycemia may be considered prima facia evidence for impaired insulin secretion. The question of course is whether this inability to compensate for insulin resistance is the result of an underlying genetic defect or merely secondary to ß-cell exhaustion.

E. Misinterpretation of the Oral Glucose Tolerance Test (OGTT)
The misleading dichotomy between insulin deficiency (vs. impaired insulin release) and insulin resistance has been reinforced by questionable interpretation of cross-sectional studies examining plasma insulin responses during OGTTs (21, 49).

Virtually all studies examining the relationship between the 2-h plasma glucose level (a generally recognized index of glucose tolerance) and the 2-h plasma insulin level have found an inverted U relationship (Fig. 1) with plasma insulin levels increasing to a peak around 200 mg/dl followed by a progressive decrease. This pattern has been interpreted to indicate that early on, as glucose tolerance decreases, there is increased insulin secretion and, therefore, that insulin resistance, rather than insulin deficiency, is responsible for the development of IGT; later on, diabetes develops when the ß-cell can no longer compensate for this insulin resistance (21, 49, 50).

View larger version (17K): [in this window] [in a new window]   Figure 1. Relationship between 2 h plasma glucose, 30 min plasma insulin, and 2 h plasma insulin levels during OGTTs.

Second, it does not take into consideration the importance of the kinetics of insulin release and the dependence of insulin secretion upon the prevailing plasma glucose concentration. As shown in Fig. 1, if one examines the early (30 min) plasma insulin response during the OGTT, one finds that there is a progressive decrease in this early plasma insulin response as glucose tolerance deteriorates. This decrease is clearly evident before the diagnosis of IGT would be made (e.g., 2 h plasma glucose exceeding 140 mg/dl). Moreover, experimental reduction in early insulin release in normal human volunteers has been shown to produce glucose intolerance and late (2 h) hyperinsulinemia (63). These observations provide evidence that there is impaired pancreatic ß-cell function before the onset of IGT and that late hyperinsulinemia may actually be the result of an inadequate ß-cell response to the hyperglycemia due to impaired early insulin release and may not necessarily indicate the presence of insulin resistance.

	II. Strategy

Top Abstract I. Introduction II. Strategy III. Studies in Genetically... IV. Prospective Studies of... V. Studies of Normal... VI. Reversibility of Insulin... VII. Are All Type... VIII. Hypothesis for... IX. Summary and Conclusion References

 
Because IGT and type 2 diabetes can be associated secondarily with impaired insulin secretion and insulin resistance due to glucose toxicity, this review will rely primarily on the analysis of data derived from study of individuals with normal glucose tolerance (NGT) who are at high risk to develop type 2 diabetes, presumably on a genetic basis. These individuals include 1) NGT first-degree relatives of people with type 2 diabetes; 2) NGT women with a history of gestational diabetes; and 3) NGT individuals who subsequently developed IGT or type 2 diabetes. In addition, the reversibility of defects in insulin sensitivity and insulin secretion by weight loss will be examined. The rationale for this is that if insulin resistance or impaired insulin secretion were purely genetic in origin, these abnormalities should not be completely reversed by such an intervention. On the other hand, it is possible that genetic factors may cause a given degree of obesity to have exaggerated effects on insulin sensitivity and ß-cell function. This possibility will be considered in detail later. Although, as indicated earlier, it is generally agreed that development of type 2 diabetes cannot occur without impaired insulin secretion, evidence will be presented that type 2 diabetes can occur without insulin resistance. Finally, based on this review of the literature, a schema will be proposed for the pathogenesis of type 2 diabetes incorporating the concept of interactions between diabetes-related genes, diabetogenic genes, and environmental factors.

	III. Studies in Genetically Predisposed Individuals with NGT

Top Abstract I. Introduction II. Strategy III. Studies in Genetically... IV. Prospective Studies of... V. Studies of Normal... VI. Reversibility of Insulin... VII. Are All Type... VIII. Hypothesis for... IX. Summary and Conclusion References

 
A. First-degree relatives (excluding twins)
1. Insulin secretion. Over the past 30 yr, there have been more than 60 studies of insulin secretion and/or insulin sensitivity in normal glucose-tolerant individuals who were the first-degree relative of someone with type 2 diabetes (30, 31, 39, 47, 53, 56, 60, 61, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119) (Tables 1, 2, and 3). Unfortunately, in most of these studies insulin secretion and insulin resistance were not simultaneously assessed. Furthermore, in most of the early studies, the methods used to evaluate insulin secretion or insulin sensitivity would not be considered to be state of the art by present standards. Finally and most importantly, in many studies subjects were usually not well matched for acquired factors such as age, gender, and obesity that are known to influence insulin secretion and insulin sensitivity.

It is important to point out that the studies using more sophisticated techniques or more rigorous tests to evaluate ß-cell function (e.g., hyperglycemic clamps and standardized glucose infusion tests) were more likely to detect abnormalities. For example, Pimenta et al. (30) and Van Haeften et al. (119) found absolutely normal plasma insulin responses to OGTTs in first-degree relatives with NGT but during hyperglycemic clamp studies found reduced responses. These results suggest that, in some individuals with NGT, the OGTT may not be a sufficient stress to elicit subtle defects in ß-cell function.

Certain widely cited reports deserve additional comment. In one of the earliest studies, Rojas et al. (73) examined plasma insulin responses to intravenous glucose in control volunteers and NGT offspring of two diabetic parents who were carefully matched for age, gender, and obesity. It was found that glucose-stimulated insulin release was decreased in the NGT offspring. Warram et al. (39) subsequently analyzed the data of these and additional offspring of two diabetic parents using the minimal model approach of Bergman et al. (120, 121). Initial results of those who subsequently either had or had not developed diabetes were compared. In this population, already demonstrated to have reduced ß-cell function, presumably on a genetic basis, it was found that those who subsequently developed diabetes had been insulin resistant when they were still NGT, whereas those who did not develop diabetes had not been insulin resistant. It was concluded that insulin resistance was a risk factor for development of type 2 diabetes.

This study is often cited in the literature as providing evidence that insulin resistance is the main genetic factor for type 2 diabetes. However, since the group who subsequently developed diabetes were markedly obese compared with the group that did not develop diabetes (i.e., 140 vs. 106% ideal body weight), it is possible that the insulin resistance was simply the result of obesity. Indeed, comparison of the minimal model parameters of insulin secretion and insulin sensitivity in this group with those of similarly obese individuals having no family history of diabetes reported by Bergman et al. (120, 121) (Table 4) provides evidence that the subjects studied by Warram et al. (39) were no more insulin resistant than these individuals but had reduced first-phase insulin release. Thus, the study of Warram et al. (39) can be interpreted as showing that people with a genetic predisposition to impaired insulin secretion develop diabetes when acquired insulin resistance (due to obesity) is superimposed and exceeds the ability of the ß-cell to compensate for it.

The study of Eriksson et al. (56) is also cited frequently as demonstrating increased insulin release in offspring of people with type 2 diabetes. However, in this study relatives of type 2 diabetic and control subjects were not well matched for gender and obesity. Furthermore, during the hyperglycemic clamps, plasma glucose levels were increased by a certain increment so that the groups were not necessarily studied at identical plasma glucose levels. These limitations make the results of the study difficult to interpret. Indeed, in a subsequent study (102), which probably included some of the same subjects but with better matching, insulin responses during hyperglycemic clamps were similar in the control group and first-degree NGT relatives of type 2 diabetics.

In summary, contrary to the current prevalent view, the preponderance of the data from studies examining ß-cell function of individuals with NGT and a presumed genetic predisposition to develop type 2 diabetes, because they had a first-degree type 2 diabetic relative, provides evidence for an underlying impairment in insulin secretion.

2. Insulin sensitivity. Twenty-eight studies have examined the appropriateness of insulin action in NGT individuals with a first-degree type 2 diabetic relative (Table 2). Of these, 15 (54%) found normal insulin sensitivity while 13 (46%) found reduced insulin sensitivity. If one excludes studies that probably included some people with IGT or where there was obvious poor matching of groups for factors known to affect insulin sensitivity (e.g., age, gender, obesity, VO₂ max), or where it is not clear whether groups were well matched (39, 56, 60, 88, 89, 91, 95, 108, 110, 112, 105, 117), we are left with 16 studies of which 14 (88%) indicate normal insulin sensitivity and 3 (12%) indicate reduced insulin sensitivity. Granted that these exclusions may represent a certain bias, it is safe to say, nevertheless, that the preponderance of data do not provide strong support for the concept that NGT first-degree relatives of type 2 diabetic patients are insulin resistant independent of factors such as age, gender, obesity, physical fitness, and body fat distribution. Indeed, Nyholm et al. (104) recently reported that apparent differences in insulin sensitivity between NGT subjects with and without a family history of diabetes were no longer statistically significant when data were corrected for differences in VO₂ max, an index of physical fitness.

B. Identical twins discordant for type 2 diabetes
Studies of discordant identical twins (Table 3) have provided a more definitive picture of ß-cell function and insulin sensitivity before development of diabetes than those of first-degree relatives of type 2 diabetic patients. Of the five studies, all (61, 113, 115, 116) except that of Gottlieb et al. (114) have indicated that the NGT discordant twin had reduced insulin secretion. Gottlieb et al. (114) studied children and thus probably included twins discordant for type 1 diabetes. As shown in Table 3, the only study examining both insulin sensitivity and beta cell function (61) found impaired insulin secretion without insulin resistance. This latter study deserves more comment.

Although the small number of subjects studied presents the possibility of type 1 and type 2 statistical errors, certain observations are of interest. Discordant twins with NGT and IGT both had impaired insulin release. The degree of impairment was comparable but those with IGT also had reduced insulin sensitivity. This was associated with an increased waist/hip ratio (1.04 ± 0.03 vs. 0.93 ± 0.02 in NGT twins and 0.90 ± 0.03 in normal controls), and an increased Hb_A1C (9.1 ± 0.05% vs. 6.8 ± 0.3% in NGT twins and 5.7 ± 0.37% in normal controls). Thus, one could postulate from these data that glucose toxicity (41, 42) and excess intraabdominal fat in the IGT twins were responsible for the decreased insulin sensitivity. The twins with type 2 diabetes were more obese than those with IGT [body mass index (BMI) 30.1 ± 1.5 kg/m² vs. 27.6 ± 2.0 kg/m²] and had moderately worse insulin sensitivity (M value 5.2 ± 0.7 vs. 8.1 ± 0.6 mg/kg/min) and markedly worse first-phase insulin secretion (-67 ± 16 vs. 151 ± 22 µU/ml/min). Note that the value for insulin secretion in the type 2 diabetic twin is negative.

The observations of this study suggest that the major factor responsible for transition from NGT to IGT is superimposition of insulin resistance upon impaired ß-cell function and that the major factor responsible for transition from IGT to type 2 diabetes is worsening of the already impaired insulin secretion. The latter could represent progression of a genetic ß-cell deficit and/or toxic effects of hyperglycemia. The appearance in insulin resistance could be readily explained by a combination of obesity and glucose toxicity (i.e., not necessarily a diabetogenic gene).

In summary, the data from twin studies are consistent with the consensus of the data from other family studies discussed above indicating that impaired ß-cell function precedes insulin resistance in the pathogenesis of type 2 diabetes when confounding factors such as age, gender, and obesity are taken into consideration.

	IV. Prospective Studies of Individuals Before Development of Type 2 Diabetes

Top Abstract I. Introduction II. Strategy III. Studies in Genetically... IV. Prospective Studies of... V. Studies of Normal... VI. Reversibility of Insulin... VII. Are All Type... VIII. Hypothesis for... IX. Summary and Conclusion References

 
There have been numerous studies reporting baseline data on NGT individuals who subsequently developed type 2 diabetes (Table 5). Many of these have been epidemiological in that they compared, within a certain population, the baseline characteristics of individuals who did or did not subsequently become diabetic. These studies have provided evidence that both impaired insulin secretion and insulin resistance are risk factors for development of type 2 diabetes (22, 23, 122, 123, 124). However, they do not directly address the issue of which of these factors precedes the other and which is genetic because often those who subsequently developed diabetes were more obese or less physically active than those who did not develop diabetes (22, 122, 124). Moreover, in many cases insulin sensitivity was not directly measured, and surrogate determinations such as fasting or 2 h OGTT plasma insulin levels were used. Recall that an increased 2 h plasma insulin level may be the result of impaired early insulin release because this leads to greater hyperglycemia and a greater stimulus for insulin release and therefore may not necessarily indicate insulin resistance. Finally, individuals with IGT and potentially secondary changes due to glucose toxicity were often included (122, 125).

In the other study of the Pima Indians (49), longitudinal data were given for 24 individuals who developed IGT. Although not analyzed, the baseline acute insulin response of these individuals (IVGTT) was less (190 vs. 220) than that of a control group while their glucose infusion rate (3.3 mg/kg/min) during a hyperinsulinemic clamp was comparable to that of the control group (3.8 mg/kg/min). Since the subjects that became diabetic were more obese (BMI 38 vs. 32 Kg/M²), the small reduction in their glucose infusion rates could be attributable to their greater obesity. Moreover the fact that their acute insulin responses were not greater than that of the control group, despite their greater obesity, suggests that their ß-cell function may have been impaired. These two studies (49, 126) are widely cited as supporting genetically determined insulin resistance as the initial factor predisposing to type 2 diabetes but the evidence is equivocal.

The report of Martin et al. (127) represents the same data reported by Warram et al. (39), which has already been commented on in detail. As explained earlier, the observations of this study actually are consistent with the concept that superimposition of the insulin resistance of obesity upon a genetically impaired capacity to secretion insulin is a common sequence leading to type 2 diabetes.

Chen et al. (125) reported baseline data on 23 individuals who developed type 2 diabetes and compared them to 144 individuals who remained nondiabetic. Those who developed type 2 diabetes initially had impaired early insulin release during an OGTT. Unfortunately, about half of each group had IGT at baseline. Thus, it is difficult to use these data to distinguish between a genetic cause and one due to glucose toxicity in explaining the reduced insulin secretion.

Taken together, these prospective studies indicate that both impaired insulin release and insulin resistance are risk factors for development of type 2 diabetes and that each can, and usually does, precede type 2 diabetes. However, they do not provide unassailable evidence that either the impaired insulin secretion or the insulin resistance necessarily has a genetic basis.

	V. Studies of Normal Glucose-Tolerant Women with a History of Gestational Diabetes

Top Abstract I. Introduction II. Strategy III. Studies in Genetically... IV. Prospective Studies of... V. Studies of Normal... VI. Reversibility of Insulin... VII. Are All Type... VIII. Hypothesis for... IX. Summary and Conclusion References

 
Women who have experienced transient diabetes during a pregnancy (gestational diabetes) are at high risk to subsequently develop type 2 diabetes (128), and it has been suggested that gestational diabetes and type 2 diabetes are the same disorder (129). Current evidence suggests that gestational diabetes occurs in women who cannot secrete sufficient insulin to compensate adequately for the reduction in insulin sensitivity that normally occurs during the third trimester of pregnancy (128, 130). This would be analogous to the situation wherein a person with a genetically reduced capacity to augment insulin secretion develops type 2 diabetes after becoming obese.

Several studies summarized in Table 6 have examined insulin secretion and insulin sensitivity in women with prior gestational diabetes after their glucose tolerance had returned to normal. Of the eight studies (131, 132, 133, 134, 135, 136, 137, 138, 139) examining insulin secretion, all but one (136) found evidence for reduced insulin secretion. On the other hand, of the five studies (132, 135, 137, 138, 139) examining insulin sensitivity, only one (135) found it to be reduced, and in that study there was also evidence of reduced insulin secretion. Thus, if gestational diabetes represents the forerunner of type 2 diabetes, the results of these studies support the view that a defect (possibly genetic) in insulin secretion precedes insulin resistance in the pathogenesis of type 2 diabetes. It should be pointed out, however, that gestational diabetes represents a heterogeneous disorder that may include those destined to develop type 2 diabetes as well as those with type 1 diabetes, latent adult-onset autoimmune diabetes, and MODY.

	VI. Reversibility of Insulin Resistance and Impaired Insulin Secretion by Therapeutic Interventions

Top Abstract I. Introduction II. Strategy III. Studies in Genetically... IV. Prospective Studies of... V. Studies of Normal... VI. Reversibility of Insulin... VII. Are All Type... VIII. Hypothesis for... IX. Summary and Conclusion References

Three studies have unequivocally demonstrated complete reversal of insulin resistance with dietary intervention in type 2 diabetic patients (140, 141, 142). Reversal to normal (143) or near normal (144) insulin sensitivity had also been observed after insulin therapy in lean and obese type 2 diabetic patients. In contrast, no study has unequivocally demonstrated restitution of normal islet ß-function with therapeutic interventions.

Beck-Nielsen et al. (141) studied obese type 2 diabetic subjects before and after a year’s treatment on a weight-reducing diet and compared the results to a control group of nondiabetic subjects. Although the type 2 diabetic subjects did not attain a normal weight, insulin sensitivity (assessed by the percent decrease in plasma glucose after intravenous insulin) improved to the point where it was indistinguishable from that of the normal controls. In contrast, insulin secretion (evaluated as the acute response to intravenous glucose) remained markedly impaired. Bak et al. (140) and Freidenberg et al. (142) found similar resolution of insulin resistance using the euglycemic hyperinsulinemic clamp technique.

These studies demonstrating the reversibility of insulin resistance but not impaired insulin release therefore provide evidence that, in type 2 diabetes, insulin resistance may be an acquired defect and that impaired insulin secretion is the genetic factor.

	VII. Are All Type 2 Diabetics Insulin Resistant?

Top Abstract I. Introduction II. Strategy III. Studies in Genetically... IV. Prospective Studies of... V. Studies of Normal... VI. Reversibility of Insulin... VII. Are All Type... VIII. Hypothesis for... IX. Summary and Conclusion References

 
Although one would expect that all people with type 2 diabetes should be insulin resistant simply because of glucose toxicity (41, 42), such is actually not the case. Several studies have failed to find people with type 2 diabetes to be insulin resistant (27, 145, 146, 147, 148, 149, 150, 151). Arner et al. (145), for example, have reported that newly diagnosed lean Swedish type 2 diabetics are not insulin resistant but merely have impaired insulin secretion. Banerji et al. (27) have reported that a similar situation exists among nonobese blacks. Byrne et al. (47) found normal insulin sensitivity in a mixed population. Furthermore, it appears that insulin resistance, when present in this population (26, 27), may be largely explained on the basis of body fat distribution. Finally, two other studies have found that British and Japanese people with IGT have impaired insulin secretion without being insulin resistant (58, 60). Although there are no population-based studies indicating what percentage of people with type 2 diabetes or IGT are insulin resistant, one can nevertheless conclude that not all people with type 2 diabetes are insulin resistant. Thus, insulin resistance is not a requirement for development of type 2 diabetes.

	VIII. Hypothesis for Pathogenesis of Type 2 Diabetes

Top Abstract I. Introduction II. Strategy III. Studies in Genetically... IV. Prospective Studies of... V. Studies of Normal... VI. Reversibility of Insulin... VII. Are All Type... VIII. Hypothesis for... IX. Summary and Conclusion References

 
Based on the reviewed evidence, the following working hypothesis is proposed as an explanation for the interaction between genetic and environmental factors in the pathogenesis of most cases of type 2 diabetes, realizing, of course, that type 2 diabetes is genetically and environmentally heterogeneous (Fig. 2). This hypothesis is based on the premise that a threshold exists which, if exceeded by the cumulative adverse effects of genetic and acquired factors on insulin secretion and insulin sensitivity, will lead to either IGT or type 2 diabetes. Another premise of this hypothesis, supported by the literature reviewed, is that defects in ß-cell function are likely to be the most important genetic predisposing factors.

View larger version (42K): [in this window] [in a new window]   Figure 2. Hypothesis for interaction of genetic and environmental factors in the pathogenesis of type 2 diabetes. Four possible combinations are depicted. Length of segments in each bar reflects severity of the adverse influence of the factor on glucose tolerance.

In most individuals, however, multiple genetic defects in insulin secretion may be necessary but not sufficient to cause diabetes without acquired factors such as superimposition of insulin resistance (e.g., pregnancy, weight gain, glucose toxicity, physical inactivity, etc.) or without the simultaneous presence of diabetes-related or diabetogenic genes causing or predisposing to insulin resistance. An experimental example of such a situation comes from the results of recent knockout studies in mice (152): mice with a homozygous knockout of insulin receptor substrate 1 (IRS 1) had insulin resistance and hyperinsulinemia but maintained NGT with aging. Mice heterozygous for knockout of the ß-cell glucokinase (GK) gene developed glucose intolerance with aging due to reduced insulin secretion. Double knockout mice (IRS 1 plus GK) developed overt diabetes with aging.

In different individuals, different combinations of genetic defects of insulin secretion and insulin action and of environmental factors are expected. This could readily provide an explanation of the heterogeneity of type 2 diabetes. For simplicity, if one assumes 1) that two defective ß-cell genes are required and four exist; and 2) that, in addition, one environmental factor is needed and four exist (e.g., overeating, reduced physical activity, toxins, glucose toxicity); and 3) that one genetic polymorphism in either appetite or energy expenditure or body fat distribution is needed, the unique combination of these elements leading to diabetes would exceed 4000.

	IX. Summary and Conclusion

Top Abstract I. Introduction II. Strategy III. Studies in Genetically... IV. Prospective Studies of... V. Studies of Normal... VI. Reversibility of Insulin... VII. Are All Type... VIII. Hypothesis for... IX. Summary and Conclusion References

 
Despite the fact that it is the prevalent view that insulin resistance is the main genetic factor predisposing to development of type 2 diabetes, review of several lines of evidence in the literature indicates a lack of overwhelming support for this concept. In fact, the literature better supports the case of impaired insulin secretion being the initial and main genetic factor predisposing to type 2 diabetes, especially 1) the studies in people at high risk to subsequently develop type 2 diabetes (discordant monozygotic twins and women with previous gestational diabetes), 2) the studies demonstrating compete alleviation of insulin resistance with weight loss, and 3) the studies finding that people with type 2 diabetes or IGT can have impaired insulin secretion and no insulin resistance compared with well matched NGT subjects. The fact that insulin resistance may be largely an acquired problem in no way lessens its importance in the pathogenesis of type 2 diabetes. Life style changes (exercise, weight reduction) and pharmacological agents (e.g., biguanides and thiazolidendiones) that reduce insulin resistance or increase insulin sensitivity clearly have major beneficial effects (122, 144, 145, 146, 153, 154, 155).

	Footnotes

 
Address reprint requests to: John E. Gerich, M.D., Department of Medicine, Physiology, and Pharmacology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642 USA.

	References

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1. McCarty D, Zimmet P 1994 Diabetes 1994 to 2010: global estimates and projections. Bayer Pubs ISBN 0646202448
2. Fajans S 1989 Maturity-onset diabetes of the young (MODY). Diabetes Metab Rev 5:579–606[Medline]
3. Niskanen L, Tuomi T, Karjalainen J, Groop L, Uusitupa M 1995 GAD antibodies in NIDDM: ten-year follow-up from the diagnosis. Diabetes Care 18:1557–1565[Abstract]
4. Gerbitz K, Gempel K, Brdiczka D 1996 Mitochondria and diabetes: genetic, biochemical, and clinical implications of the cellular energy circuit. Diabetes 45:113–126[Abstract]
5. Moller D, Flier J 1991 Insulin resistance—mechanisms, syndromes, and implications. N Engl J Med 325:938–948[Medline]
6. Taylor SI 1992 Molecular mechanisms of insulin resistance. Lessons from patients with mutations in the insulin-receptor gene. Diabetes 41:1473–1490[Abstract]
7. Hanis C, Boerwinkle E, Chakraborty R, Ellsworth D, Concannon P, Stirling B, Morrison V, Wopelhorst B, Spielman R, Gogolin-Ewens K, Shephard J, Williams S, Risch N, Hinids D, Iwasaki N, Ogata M, Omori Y, Petzold C, Rietzsch H, Schroder H, Schulze J, Cox N, Menzel S, Bouraj V, Chen X, Lim L, Lindner T, Meren L, Wang Y, Xiang K, Yamagota K, Bell G 1996 A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nat Genet 13:161–166[CrossRef][Medline]
8. Mahtani M, Widen E, Lehto M, Thomas J, McCarthy M, Brayer J, Bryant B, Chan G, Daly M, Forsblom C, Kanninen T, Kirby A, Kruglyak L, Munnelly K, Parkkonen M, Reev-Daly M, Weaver A, Brettin T, Duyk G, Lander E, Groop L 1996 Mapping of a gene for type 2 diabetes associated with an insulin secretion defect by a genome scan in Finnish families. Nat Genet 14:90–94[CrossRef][Medline]
9. Hamman R 1992 Genetic and environmental determinants of noninsulin dependent diabetes mellitus (NIDDM). Diabetes Metab Rev 8:287–338[Medline]
10. Kahn C 1994 Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes 43:1066–1084[Medline]
11. Bouchard C 1995 Genetics and the metabolic syndrome. Int J Obesity 19[Suppl]:S52–S59
12. Yki-Järvinen H 1995 Role of insulin resistance in the pathogenesis of NIDDM. Diabetologia 38:1378–1388[CrossRef][Medline]
13. Hales C, Barker D 1992 Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 35:595–601[CrossRef][Medline]
14. Hitman G, Metcalfe K 1993 The genetics of diabetes—an update. Diabetes Annu 7:1–17
15. Turner R, Hattersley A, Shaw J, Levy J 1995 Type II diabetes: clinical aspects of molecular biological studies. Diabetes 44:1–10[Abstract]
16. Granner D, O’Brien R 1992 Molecular physiology and genetics of NIDDM. Diabetes Care 15:369–395[Abstract]
17. Aitman T, Todd J 1995 Molecular genetics of diabetes mellitus. Baillieres Clin Endocrinol Metab 9:631–656[CrossRef][Medline]
18. Iselius L, Lindsten J, Morton N, Efendic S, Cerasi E, Haegermark A, Luft R 1985 Genetic regulation of the kinetics of glucose-induced insulin release in man. Clin Genet 28:8–15[Medline]
19. Bogardus C, Lillioja S, Nyomba B, Zurlo F, Swinburn B, Esposito-DelPuente A, Knowler W, Ravussin E, Bennett P 1989 Distribution of in vivo insulin action in Pima Indians as a mixture of three normal distributions. Diabetes 38:1423–1432[Abstract]
20. Martin B, Warram J, Rosner B, Rich S, Soeldner J, Krolewski A 1992 Familial clustering of insulin sensitivity. Diabetes 41:850–854[Abstract]
21. DeFronzo R, Bonadonna R, Ferrannini E 1992 Pathogenesis of NIDDM—a balanced overview. Diabetes Care 15:318–368[Abstract]
22. Lillioja S, Mott D, Spraul M, Ferraro R, Foley J, Ravussin E, Knowler W, Bennett P, Bogardus C 1993 Insulin resistance and insulin secretory dysfunction as precursors of non-insulin-dependent diabetes mellitus: prospective studies of Pima Indians. N Engl J Med 329:1988–1992[Abstract/Free Full Text]
23. Haffner S, Miettinen H, Gaskill S, Stern M 1995 Decreased insulin secretion and increased insulin resistance are independently related to the 7-year risk of NIDDM in Mexican-Americans. Diabetes 44:1386–1391[Abstract]
24. Bjorntorp P 1988 Abdominal obesity and the development of non-insulin-dependent diabetes mellitus. Diabetes Metab Rev 4:615–622[Medline]
25. Kissebah A, Freedman D, Peiris A 1989 Health risk of obesity. Med Clin North Am 73:111–138[Medline]
26. Carey D, Jenkins A, Campbell L, Freund J, Chisholm D 1996 Abdominal fat and insulin resistance in normal and overweight women: direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM. Diabetes 45:633–638[Abstract]
27. Banerji M, Chaiken R, Gordon D, Kral J, Lebovitz H 1995 Does intra-abdominal adipose tissue in black men determine whether NIDDM is insulin-resistant or insulin-sensitive? Diabetes 44:141–146[Abstract]
28. Olefsky J, Nolan J 1995 Insulin resistance and non-insulin-dependent diabetes mellitus: cellular and molecular mechanisms. Am J Clin Nutr 61:980S–986S
29. Beck-Nielsen H, Groop L 1994 Metabolic and genetic characterization of prediabetic states. Sequence of events leading to non-insulin-dependent diabetes mellitus. J Clin Invest 94:1714–1721
30. Pimenta W, Kortytkowski M, Mitrakou A, Jenssen T, Yki-Jarvinen H, Evron W, Dailey G, Gerich J 1995 Pancreatic beta-cell dysfunction as the primary genetic lesion in NIDDM. JAMA 273:1855–1861[Abstract]
31. Cerasi E 1995 Insulin deficiency and insulin resistance in the pathogenesis of NIDDM: is a divorce possible. Diabetologia 38:992–997[Medline]
32. Polonsky K, Sturis J, Bell G 1996 Noninsulin-dependent diabetes mellitus—a genetically programmed failure of the beta cell to compensate for insulin resistance. N Engl J Med 334:777–783[Free Full Text]
33. Taylor SI, Accili D, Imai Y 1994 Insulin resistance or insulin deficiency. Which is the primary cause of NIDDM? Diabetes 43:735–740[Medline]
34. Cerasi E, Luft R 1967 "What is inherited—what is added" hypothesis for the pathogenesis of diabetes mellitus. Diabetes 16:615–627[Medline]
35. DeFronzo R, Bonadonna R, Ferrannini E 1997 Pathogenesis of NIDDM. In: Alberti K, Zimmet P, DeFronzo R (eds) International Textbook of Diabetes Mellitus. Wiley and Sons, New York, pp 635–712
36. Olefsky J 1995 Diabetes mellitus (type II): etiology and pathogenesis. In: DeGroot L, Besser M, Burger H, Jameson J, Loriaux D, Marshall J, O’Dell W, Potts J, Rubenstein A (eds) Endocrinology. W. B. Saunders, Philadelphia, pp 1436–1463
37. Garber A 1994 Diabetes mellitus. In: Stein J, Hutton J, Kohler P, O’Rourke R, Reynolds H, Samuels M, Sande M, Trier J, Zvarfler N (eds) Internal Medicine. C.V. Mosby, Boston, pp 1391–1424
38. Targher G, Alberiche M, Zenere M, Bonadonna R, Muggeo M, Bonora E 1997 Cigarette smoking and insulin resistance in patients with noninsulin-dependent diabetes mellitus. J Clin Endocrinol Metab 82:3619–3624[Abstract/Free Full Text]
39. Warram J, Martin B, Krolewski A, Soeldener S, Kahn C 1990 Slow glucose removal rate and hyperinsulinemia precede the development of type II diabetes in the offspring of diabetic parents. Ann Intern Med 113:909–915
40. Gauguier D, Froguel P, Parent V, Bernard C, Bihoreau M, Portha B, James M, Penicaud L, Lathrop M, Ktorza A 1996 Chromosomal mapping of genetic loci associated with non-insulin dependent diabetes in the GK rat. Nat Genet 12:38–43[CrossRef][Medline]
41. Rossetti L, Giaccari A, DeFronzo R 1990 Glucose toxicity. Diabetes Care 13:610–630[Abstract]
42. Yki-Järvinen H 1992 Glucose toxicity. Endocr Rev 13:415–431[CrossRef][Medline]
43. Mandarino L, Baker B, Rizza R, Genest J, Gerich J 1984 Infusion of insulin impairs human adipocyte, glucose metabolism in vitro without decreasing adipocyte insulin receptor binding. Diabetologia 27:358–363[CrossRef][Medline]
44. Gerich J, Martin M, Recant L 1971 Clinical and metabolic characteristics of hyperosmolar nonketotic coma. Diabetes 20:228–238[Medline]
45. Perley J, Kipnis D 1967 Plasma insulin responses to oral and intravenous glucose: studies in normal and diabetic subjects. J Clin Invest 46:1954–1962
46. Porte D 1991 ß-Cells in type II diabetes mellitus. Diabetes 40:166–180[Abstract]
47. Byrne M, Sturgis J, Sobel R, Polonsky K 1996 Elevated plasma glucose 2 h postchallenge predicts defects in B-cell function. Am J Physiol 270:E572–579
48. Reaven G 1995 Pathophysiology of insulin resistance in human disease. Physiol Rev 75:473–486[Abstract/Free Full Text]
49. Lillioja S, Mott D, Howard B, Bennet P, Yki-Jarvinen H, Freymond D, Nyomba B, Zurlo F, Swinburn B, Bogardus C 1988 Impaired glucose tolerance as a disorder of insulin action: longitudinal and cross-sectional studies in Pima Indians. N Engl J Med 318:1217–1225[Abstract]
50. Saad M, Knowler W, Pettitt D, Nelson R, Charles M, Bennett P 1991 A two-step model for development of noninsulin dependent diabetes. Am J Med 90:229–235[Medline]
51. Mitrakou A, Kelley D, Veneman T, Pangburn T, Reilly J, Gerich J 1992 Role of reduced suppression of hepatic glucose output and diminished early insulin release in impaired glucose tolerance. N Engl J Med 326:22–29[Abstract]
52. O’Meara N, Sturis J, VanCouter E, Polonsky K 1993 Lack of control by glucose of ultradian insulin secretory oscillations in impaired glucose tolerance and in non-insulin-dependent diabetes mellitus. J Clin Invest 92:262–271
53. O’Rahilly S, Turner R, Matthews D 1988 Impaired pulsatile secretion of insulin in relatives of patients with noninsulin-dependent diabetes. N Engl J Med 318:1225–1230[Abstract]
54. Larsson H, Berglund G, Ahren B 1995 Glucose modulation of insulin and glucagon secretion is altered in impaired glucose tolerance. J Clin Endocrinol Metab 80:1778–1782[Abstract]
55. Larsson H, Ahren B 1996 Islet dysfunction in obese women with impaired glucose tolerance. Metabolism 45:502–509[CrossRef][Medline]
56. Eriksson J, Franssila-Kallunki A, Ekstand A, Saloranta C, Widen E, Shalin C, Groop L 1989 Early metabolic defects in persons at increased risk for noninsulin-dependent diabetes mellitus. N Engl J Med 321:337–343[Abstract]
57. Berrish TS, Hetherington CS, Alberti KG, Walker M 1995 Peripheral and hepatic insulin sensitivity in subjects with impaired glucose tolerance. Diabetologia 38:699–704[Medline]
58. Taniguchi A, Nakai Y, Dor K, Fukuzawa H, Fukushima M, Kawamura H, Tokuyama K, Suzuki M, Fujitani J, Tanaka H, Nagata I 1995 Insulin sensitivity, insulin secretion, and glucose effectiveness in obese subjects: a minimal model analysis. Metabolism 44:1397–1400[Medline]
59. Kanatsuka A, Sakurada M, Hashimoto N, Iwaoka H, Yamaguchi T, Tairo M, Yoshida S, Yoshida A 1988 First-phase insulin response to glucose in nonobese and obese subjects with glucose intolerance: analysis by C-peptide secretion rate. Metabolism 37:878–884[Medline]
60. O’Rahilly S, Rudenski A, Burnett M, Nugent T, Hosker J, Darling P 1986 Beta cell dysfunction rather than insulin insensitivity is the primary defect in familial type II diabetes. Lancet 2:360–364[CrossRef][Medline]
61. Vaag A, Henriksen JE, Madsbad S, Holm N, Beck-Nielsen H 1995 Insulin secretion, insulin action, and hepatic glucose production in identical twins discordant for non-insulin-dependent diabetes mellitus. J Clin Invest 95:690–698
62. Kosaka K, Hogura R, Kuzuya T 1977 Insulin responses in equivocal and definite diabetes with special reference to subjects who had mild glucose intolerance but later developed definite diabetes. Diabetes 26:944–952[Medline]
63. Calles-escandon J, Robbins D 1987 Loss of early phase of insulin release in humans impairs glucose tolerance and blunts thermic effect of glucose. Diabetes 36:1167–1172[Abstract]
64. Grodsky G, Karam J, Pablatos F, Forsham P 1965 Serum insulin response to glucose in prediabetic subjects. Lancet 1:290–291
65. Welborn TA, Rubenstein AH, Haslam R, Fraser R 1966 Normal insulin response to glucose. Lancet 1:280–284[CrossRef][Medline]
66. Colwell J, Lein A 1967 Diminished insulin response to hyperglycemia in prediabetes and diabetes. Diabetes 16:560–565[Medline]
67. Siperstein M, Unger R, Madison L 1968 Studies of muscle capillary basement membranes in normal subjects, diabetic prediabetic patients. J Clin Invest 47:1973–1999
68. Simpson R, Benedetti A, Grodsky G, Karam J, Forsham P 1968 Early phase of insulin release. Diabetes 17:684–692[Medline]
69. Boden G, Soeldner JS, Gleason RE, Marble A 1968 Elevated serum human growth hormone and decreased serum insulin in prediabetic males after intravenous tolbutamide and glucose. J Clin Invest 47:729–731
70. Daweke H, Ruenauver R, Schilling W, Gruneklee D, Jahnke K, Oberdisse K, Liebermeister H, Gries F 1968 Untersuchungen des kohlenhydrat und fettstoffwechsels bei prädiabetes. Diabetologia 4:349–357[Medline]
71. Paulsen EP, Richenderfer L, Ginsberg-Fellner F 1968 Plasma glucose, free fatty acids and immunoreactive insulin in sixty-six obese children: studies in reference to a family history of diabetes mellitus. Diabetes 17:261–269[Medline]
72. Soeldner S, Geason E, Williams P, Garcia J, Beardwood M, Marble A 1968 Diminished serum insulin responses to glucose in genetic prediabetic males with normal glucose tolerance. Diabetes 17:17–26[Medline]
73. Rojas L, Soeldner JS, Gleason RE, Kahn CB, Marble A 1969 Offspring of two diabetic parents: differential serum insulin responses to intravenous glucose and tolbutamide. J Clin Endocrinol Metab 29:1569–1579[Medline]
74. Serrano-Rias M, Ramos F, Rodriguer-Minon JL, Viranco F 1970 Studies in prediabetes insulin response to oral glucose intravenous tolbutamide and rapid intravenous glucose infusion in genetic prediabetes. Diabetologia 6:392–398[Medline]
75. Rull J, Conn J, Floyd J, Fajans S 1970 Levels of plasma insulin during cortisone glucose tolerance tests in "nondiabetic" relatives of diabetic patients: implications of diminished insulin secretory reserve in subclinical diabetes. Diabetes 19:1–10[Medline]
76. Lowrie E, Soeldner J, Hampers C, Merill J 1970 Glucose metabolism and insulin secretion in uremic prediabetic and normal subjects. J Lab Clin Med 76:603–615[Medline]
77. Jackson W, Mieghem W, Keller P 1972 Insulin excess as the initial lesion in diabetes. Lancet 1:1040–1044[Medline]
78. Sonksen P, Soeldner J, Gleason R, Boden G 1973 Abnormal serum growth hormone responsive in genetically potential diabetic male patients with normal oral glucose tolerance: evidence for an insulin-like action of growth hormone in vivo. Diabetologia 9:426–437[Medline]