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University of Rochester, School of Medicine and Dentistry, Departments of Medicine, Physiology, and Pharmacology, Rochester, New York 14642
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Abstract |
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 Top Abstract I. IntroductionII. StrategyIII. 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 ConclusionReferences |
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I. Introduction |
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TopAbstractI. IntroductionII. StrategyIII. 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 ConclusionReferences |
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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).
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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.
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II. Strategy |
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TopAbstractI. IntroductionII. StrategyIII. 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 ConclusionReferences |
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III. Studies in Genetically Predisposed Individuals with NGT |
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TopAbstractI. IntroductionII. StrategyIII. 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 ConclusionReferences |
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, 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.
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provides the observations of ß-cell function of NGT
first-degree type 2 diabetic relatives excluding those of monozygotic
twins. Of the 53 studies, 26 (49%) indicate impaired ß-cell
function, 20 (38%) indicate normal ß-cell function, and only 7
(
13%) indicate ß-cell hypersecretion. Thus, the preponderance of
experimental evidence favors impaired, rather than excessive, insulin
secretion being present in these individuals before the development of
IGT and thus provide support for the concept that the initial (?
genetic) lesion in type 2 diabetes may involve impaired insulin
secretion rather than insulin resistance. 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.
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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 HbA1C (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.
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IV. Prospective Studies of Individuals Before Development of Type 2 Diabetes |
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TopAbstractI. IntroductionII. StrategyIII. 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 ConclusionReferences |
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). 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).
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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.
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V. Studies of Normal Glucose-Tolerant Women with a History of Gestational Diabetes |
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TopAbstractI. IntroductionII. StrategyIII. 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 ConclusionReferences |
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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.
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VI. Reversibility of Insulin Resistance and Impaired Insulin Secretion by Therapeutic Interventions |
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TopAbstractI. IntroductionII. StrategyIII. 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 ConclusionReferences |
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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.
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VII. Are All Type 2 Diabetics Insulin Resistant? |
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TopAbstractI. IntroductionII. StrategyIII. 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 ConclusionReferences |
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VIII. Hypothesis for Pathogenesis of Type 2 Diabetes |
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TopAbstractI. IntroductionII. StrategyIII. 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 ConclusionReferences |
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). 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.
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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.
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IX. Summary and Conclusion |
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TopAbstractI. IntroductionII. StrategyIII. 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 ConclusionReferences |
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Footnotes |
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References |
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TopAbstractI. IntroductionII. StrategyIII. 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 ConclusionReferences |
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W. Wente, A. M. Efanov, M. Brenner, A. Kharitonenkov, A. Koster, G. E. Sandusky, S. Sewing, I. Treinies, H. Zitzer, and J. Gromada Fibroblast Growth Factor-21 Improves Pancreatic {beta}-Cell Function and Survival by Activation of Extracellular Signal-Regulated Kinase 1/2 and Akt Signaling Pathways Diabetes, September 1, 2006; 55(9): 2470 - 2478. [Abstract] [Full Text] [PDF]
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C.-G. Ostenson, H. Gaisano, L. Sheu, A. Tibell, and T. Bartfai Impaired Gene and Protein Expression of Exocytotic Soluble N-Ethylmaleimide Attachment Protein Receptor Complex Proteins in Pancreatic Islets of Type 2 Diabetic Patients Diabetes, February 1, 2006; 55(2): 435 - 440. [Abstract] [Full Text] [PDF]
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 S. Kralisch, J. Klein, U. Lossner, M. Bluher, R. Paschke, M. Stumvoll, and M. Fasshauer Hormonal regulation of the novel adipocytokine visfatin in 3T3-L1 adipocytes J. Endocrinol., June 1, 2005; 185(3): R1 - R8. [Abstract] [Full Text] [PDF]
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 J. Ek, C. S. Rose, D. P. Jensen, C. Glumer, K. Borch-Johnsen, T. Jorgensen, O. Pedersen, and T. Hansen The Functional Thr130Ile and Val255Met Polymorphisms of the Hepatocyte Nuclear Factor-4{alpha} (HNF4A): Gene Associations with Type 2 Diabetes or Altered {beta}-Cell Function among Danes J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 3054 - 3059. [Abstract] [Full Text] [PDF]
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Y.-F. Chiu, L.-M. Chuang, C.-F. Hsiao, Y.-J. Hung, M.-W. Lin, Y.-T. Chen, J. Grove, E. Jorgenson, T. Quertermous, N. Risch, et al. An Autosomal Genome-wide Scan for Loci Linked to Pre-Diabetic Phenotypes in Nondiabetic Chinese Subjects From the Stanford Asia-Pacific Program of Hypertension and Insulin Resistance Family Study Diabetes, April 1, 2005; 54(4): 1200 - 1206. [Abstract] [Full Text] [PDF]
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A. Mari, A. Gastaldelli, A. Natali, T. Ostergard, O. Schmitz, and E. Ferrannini Characterization of {beta}-cell function impairment in first-degree relatives of type 2 diabetic subjects: modeling analysis of 24-h triple-meal tests Am J Physiol Endocrinol Metab, March 1, 2005; 288(3): E541 - E546. [Abstract] [Full Text] [PDF]
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M. Fasshauer, J. Klein, S. Kralisch, M. Klier, U. Lossner, M. Bluher, and R. Paschke Serum amyloid A3 expression is stimulated by dexamethasone and interleukin-6 in 3T3-L1 adipocytes J. Endocrinol., December 1, 2004; 183(3): 561 - 567. [Abstract] [Full Text] [PDF]
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O. Laukkanen, J. Pihlajamaki, J. Lindstrom, J. Eriksson, T. T. Valle, H. Hamalainen, P. Ilanne-Parikka, S. Keinanen-Kiukaanniemi, J. Tuomilehto, M. Uusitupa, et al. Polymorphisms of the SUR1 (ABCC8) and Kir6.2 (KCNJ11) Genes Predict the Conversion from Impaired Glucose Tolerance to Type 2 Diabetes. The Finnish Diabetes Prevention Study J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 6286 - 6290. [Abstract] [Full Text] [PDF]
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J.-L. Chiasson and R. Rabasa-Lhoret Prevention of Type 2 Diabetes: Insulin Resistance and Beta-Cell Function Diabetes, December 1, 2004; 53(suppl_3): S34 - S38. [Abstract] [Full Text] [PDF]
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 M. Zang, A. Zuccollo, X. Hou, D. Nagata, K. Walsh, H. Herscovitz, P. Brecher, N. B. Ruderman, and R. A. Cohen AMP-activated Protein Kinase Is Required for the Lipid-lowering Effect of Metformin in Insulin-resistant Human HepG2 Cells J. Biol. Chem., November 12, 2004; 279(46): 47898 - 47905. [Abstract] [Full Text] [PDF]
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N. N. Rudovich, H. J. Rochlitz, and A. F.H. Pfeiffer Reduced Hepatic Insulin Extraction in Response to Gastric Inhibitory Polypeptide Compensates for Reduced Insulin Secretion in Normal-Weight and Normal Glucose Tolerant First-Degree Relatives of Type 2 Diabetic Patients Diabetes, September 1, 2004; 53(9): 2359 - 2365. [Abstract] [Full Text] [PDF]
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 B. Zethelius, C. N. Hales, H. O. Lithell, and C. Berne Insulin Resistance, Impaired Early Insulin Response, and Insulin Propeptides as Predictors of the Development of Type 2 Diabetes: A population-based, 7-year follow-up study in 70-year-old men Diabetes Care, June 1, 2004; 27(6): 1433 - 1438. [Abstract] [Full Text] [PDF]
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 F. Ashcroft and P. Rorsman Type 2 diabetes mellitus: not quite exciting enough? Hum. Mol. Genet., April 1, 2004; 13(suppl_1): R21 - R31. [Abstract] [Full Text] [PDF]
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M. C. Sugden and M. J. Holness Potential Role of Peroxisome Proliferator-Activated Receptor-{alpha} in the Modulation of Glucose-Stimulated Insulin Secretion Diabetes, February 1, 2004; 53(90001): S71 - 81. [Abstract] [Full Text]
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K. Xiang, Y. Wang, T. Zheng, W. Jia, J. Li, L. Chen, K. Shen, S. Wu, X. Lin, G. Zhang, et al. Genome-Wide Search for Type 2 Diabetes/Impaired Glucose Homeostasis Susceptibility Genes in the Chinese: Significant Linkage to Chromosome 6q21-q23 and Chromosome 1q21-q24 Diabetes, January 1, 2004; 53(1): 228 - 234. [Abstract] [Full Text] [PDF]
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 S. R. Weiss, S.-L. Cheng, I. A. Kourides, R. A. Gelfand, and W. H. Landschulz Inhaled Insulin Provides Improved Glycemic Control in Patients With Type 2 Diabetes Mellitus Inadequately Controlled With Oral Agents: A Randomized Controlled Trial Arch Intern Med, October 27, 2003; 163(19): 2277 - 2282. [Abstract] [Full Text] [PDF]
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E. Ferrannini, A. Gastaldelli, M. Matsuda, Y. Miyazaki, M. Pettiti, L. Glass, and R. A. DeFronzo Influence of Ethnicity and Familial Diabetes on Glucose Tolerance and Insulin Action: A Physiological Analysis J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3251 - 3257. [Abstract] [Full Text] [PDF]
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C. Thamer, M. Stumvoll, A. Niess, O. Tschritter, M. Haap, R. Becker, F. Shirkavand, O. Bachmann, K. Rett, A. Volk, et al. Reduced Skeletal Muscle Oxygen Uptake and Reduced {beta}-Cell Function: Two early abnormalities in normal glucose-tolerant offspring of patients with type 2 diabetes Diabetes Care, July 1, 2003; 26(7): 2126 - 2132. [Abstract] [Full Text] [PDF]
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J. E. Gerich Clinical Significance, Pathogenesis, and Management of Postprandial Hyperglycemia Arch Intern Med, June 9, 2003; 163(11): 1306 - 1316. [Abstract] [Full Text] [PDF]
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H. Suzuki, M. Fukushima, M. Usami, M. Ikeda, A. Taniguchi, Y. Nakai, T. Matsuura, A. Kuroe, K. Yasuda, T. Kurose, et al. Factors Responsible for Development From Normal Glucose Tolerance to Isolated Postchallenge Hyperglycemia Diabetes Care, April 1, 2003; 26(4): 1211 - 1215. [Abstract] [Full Text] [PDF]
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 J. E. Gerich Contributions of Insulin-Resistance and Insulin-Secretory Defects to the Pathogenesis of Type 2 Diabetes Mellitus Mayo Clin. Proc., April 1, 2003; 78(4): 447 - 456. [Abstract] [PDF]
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 T. M. Wolever and C. Mehling Long-term effect of varying the source or amount of dietary carbohydrate on postprandial plasma glucose, insulin, triacylglycerol, and free fatty acid concentrations in subjects with impaired glucose tolerance Am. J. Clinical Nutrition, March 1, 2003; 77(3): 612 - 621. [Abstract] [Full Text] [PDF]
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D. A. Stoffers, B. M. Desai, D. D. DeLeon, and R. A. Simmons Neonatal Exendin-4 Prevents the Development of Diabetes in the Intrauterine Growth Retarded Rat Diabetes, March 1, 2003; 52(3): 734 - 740. [Abstract] [Full Text] [PDF]
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R. C. Bonadonna, M. Stumvoll, A. Fritsche, M. Muggeo, H. Haring, E. Bonora, and T. W. van Haeften Altered Homeostatic Adaptation of First- and Second-Phase {beta}-Cell Secretion in the Offspring of Patients With Type 2 Diabetes: Studies With a Minimal Model to Assess {beta}-Cell Function Diabetes, February 1, 2003; 52(2): 470 - 480. [Abstract] [Full Text] [PDF]
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P. D. Borge, J. Moibi, S. R. Greene, M. Trucco, R. A. Young, Z. Gao, and B. A. Wolf Insulin Receptor Signaling and Sarco/Endoplasmic Reticulum Calcium ATPase in {beta}-Cells Diabetes, December 1, 2002; 51(90003): S427 - 433. [Abstract] [Full Text] [PDF]
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 H. E Lebovitz Review: Type 2 diabetes: how far have we come? The British Journal of Diabetes & Vascular Disease, November 1, 2002; 2(6): 446 - 449. [Abstract] [PDF]
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 H. Y. Gaisano, C.-G. Ostenson, L. Sheu, M. B. Wheeler, and S. Efendic Abnormal Expression of Pancreatic Islet Exocytotic Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein Receptors in Goto-Kakizaki Rats Is Partially Restored by Phlorizin Treatment and Accentuated by High Glucose Treatment Endocrinology, November 1, 2002; 143(11): 4218 - 4226. [Abstract] [Full Text] [PDF]
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Z. T. Bloomgarden Treatment of Type 2 Diabetes: The American Association of Clinical Endocrinologists Meeting, May 2002 Diabetes Care, September 1, 2002; 25(9): 1644 - 1649. [Full Text] [PDF]
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 F. BERNASSOLA, M. FEDERICI, M. CORAZZARI, A. TERRINONI, M. L. HRIBAL, V. DE LAURENZI, M. RANALLI, O. MASSA, G. SESTI, W.H. IRWIN MCLEAN, et al. Role of transglutaminase 2 in glucose tolerance: knockout mice studies and a putative mutation in a MODY patient FASEB J, September 1, 2002; 16(11): 1371 - 1378. [Abstract] [Full Text] [PDF]
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O. Tschritter, M. Stumvoll, F. Machicao, M. Holzwarth, M. Weisser, E. Maerker, A. Teigeler, H. Haring, and A. Fritsche The Prevalent Glu23Lys Polymorphism in the Potassium Inward Rectifier 6.2 (KIR6.2) Gene Is Associated With Impaired Glucagon Suppression in Response to Hyperglycemia Diabetes, September 1, 2002; 51(9): 2854 - 2860. [Abstract] [Full Text] [PDF]
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A. J.G. Hanley, R. D'Agostino Jr., L. E. Wagenknecht, M. F. Saad, P. J. Savage, R. Bergman, and S. M. Haffner Increased Proinsulin Levels and Decreased Acute Insulin Response Independently Predict the Incidence of Type 2 Diabetes in the Insulin Resistance Atherosclerosis Study Diabetes, April 1, 2002; 51(4): 1263 - 1270. [Abstract] [Full Text] [PDF]
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 R. Sinha, G. Fisch, B. Teague, W. V. Tamborlane, B. Banyas, K. Allen, M. Savoye, V. Rieger, S. Taksali, G. Barbetta, et al. Prevalence of Impaired Glucose Tolerance among Children and Adolescents with Marked Obesity N. Engl. J. Med., March 14, 2002; 346(11): 802 - 810. [Abstract] [Full Text] [PDF]
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A. J. G. Hanley, G. McKeown-Eyssen, S. B. Harris, R. A. Hegele, T. M. S. Wolever, J. Kwan, and B. Zinman Cross-Sectional and Prospective Associations between Abdominal Adiposity and Proinsulin Concentration J. Clin. Endocrinol. Metab., January 1, 2002; 87(1): 77 - 83. [Abstract] [Full Text] [PDF]
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 M. Stumvoll, H. G. Wahl, S. Jacob, A. Rettig, F. Machicao, and H. Haring Two novel prevalent polymorphisms in the hormone-sensitive lipase gene have no effect on insulin sensitivity of lipolysis and glucose disposal J. Lipid Res., November 1, 2001; 42(11): 1782 - 1788. [Abstract] [Full Text] [PDF]
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 V. Vuksan, J. L. Sievenpiper, Z. Xu, E. Y. Y. Wong, A. L. Jenkins, U. Beljan-Zdravkovic, L. A. Leiter, R. G. Josse, and M. P. Stavro Konjac-Mannan and American Ginsing: Emerging Alternative Therapies for Type 2 Diabetes Mellitus J. Am. Coll. Nutr., October 1, 2001; 20(90005): 370S - 380. [Abstract] [Full Text]
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 J. van Tilburg, T. W van Haeften, P. Pearson, and C. Wijmenga Defining the genetic contribution of type 2 diabetes mellitus J. Med. Genet., September 1, 2001; 38(9): 569 - 578. [Abstract] [Full Text] [PDF]
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M. Federici, M. Hribal, L. Perego, M. Ranalli, Z. Caradonna, C. Perego, L. Usellini, R. Nano, P. Bonini, F. Bertuzzi, et al. High Glucose Causes Apoptosis in Cultured Human Pancreatic Islets of Langerhans: A Potential Role for Regulation of Specific Bcl Family Genes Toward an Apoptotic Cell Death Program Diabetes, June 1, 2001; 50(6): 1290 - 1301. [Abstract] [Full Text]
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A. Taniguchi, Y. Nakai, M. Sakai, S. Yoshii, M. Hayashi, K. Nishitani, D. Hamanaka, S. Nakaishi, T. Kamamoto, I. Nagata, et al. Relationship of Regional Adiposity to Insulin Resistance in Nonobese Japanese Type 2 Diabetic Patients Diabetes Care, May 1, 2001; 24(5): 966 - 968. [Full Text]
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K. C. Chiu, L.-M. Chuang, and C. Yoon Comparison of Measured and Estimated Indices of Insulin Sensitivity and {beta} Cell Function: Impact of Ethnicity on Insulin Sensitivity and {beta} Cell Function in Glucose-Tolerant and Normotensive Subjects J. Clin. Endocrinol. Metab., April 1, 2001; 86(4): 1620 - 1625. [Abstract] [Full Text]
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L. J. Bischof, C. C. Martin, C. A. Svitek, B. T. Stadelmaier, L. A. Hornbuckle, J. K. Goldman, J. K. Oeser, J. C. Hutton, and R. M. O’Brien Characterization of the Mouse Islet-Specific Glucose-6-Phosphatase Catalytic Subunit-Related Protein Gene Promoter by In Situ Footprinting: Correlation With Fusion Gene Expression in the Islet-Derived {beta}TC-3 and Hamster Insulinoma Tumor Cell Lines Diabetes, March 1, 2001; 50(3): 502 - 514. [Abstract] [Full Text]
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C. Weyer, P. A. Tataranni, C. Bogardus, and R. E. Pratley Insulin Resistance and Insulin Secretory Dysfunction Are Independent Predictors of Worsening of Glucose Tolerance During Each Stage of Type 2 Diabetes Development Diabetes Care, January 1, 2001; 24(1): 89 - 94. [Abstract] [Full Text]
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S. Matthaei, M. Stumvoll, M. Kellerer, and H.-U. Häring Pathophysiology and Pharmacological Treatment of Insulin Resistance Endocr. Rev., December 1, 2000; 21(6): 585 - 618. [Abstract] [Full Text]
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 A. Mezzetti, F. Cipollone, and F. Cuccurullo Oxidative stress and cardiovascular complications in diabetes: isoprostanes as new markers on an old paradigm Cardiovasc Res, August 18, 2000; 47(3): 475 - 488. [Abstract] [Full Text] [PDF]
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 S. M. Grundy, I. J. Benjamin, G. L. Burke, A. Chait, R. H. Eckel, B. V. Howard, W. Mitch, S. C. Smith Jr, and J. R. Sowers Diabetes and Cardiovascular Disease : A Statement for Healthcare Professionals From the American Heart Association Circulation, September 7, 1999; 100(10): 1134 - 1146. [Full Text] [PDF]
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 H. E. Lebovitz Type 2 Diabetes: An Overview Clin. Chem., August 1, 1999; 45(8): 1339 - 1345. [Abstract] [Full Text] [PDF]
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W. W. Winder and D. G. Hardie AMP-activated protein kinase, a metabolic master switch: possible roles in Type 2 diabetes Am J Physiol Endocrinol Metab, July 1, 1999; 277(1): E1 - E10. [Abstract] [Full Text] [PDF]
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B. Ahren, P. Sauerberg, and C. Thomsen Increased insulin secretion and normalization of glucose tolerance by cholinergic agonism in high fat-fed mice Am J Physiol Endocrinol Metab, July 1, 1999; 277(1): E93 - E102. [Abstract] [Full Text] [PDF]
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R. J. Mahler and M. L. Adler Type 2 Diabetes Mellitus: Update on Diagnosis, Pathophysiology, and Treatment J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1165 - 1171. [Full Text]
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E. Ferrannini Insulin Resistance versus Insulin Deficiency in Non-Insulin-Dependent Diabetes Mellitus: Problems and Prospects Endocr. Rev., August 1, 1998; 19(4): 477 - 490. [Abstract] [Full Text] [PDF]
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