Department of Medicine, Physiology, and Pharmacology, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642
Address all correspondence and requests for reprints to: Dr. John E. Gerich, Department of Medicine, Physiology, and Pharmacology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, New York 14642.
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Introduction |
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There is mounting evidence (7, 8, 9, 10, 11, 12, 13) suggesting that the fundamental pathological sequence of events that leads to classic type 2 diabetes in most instances is the superimposition of obesity-related insulin resistance upon a ß-cell with a genetically limited capacity to compensate. This view has recently received support from several studies (8, 13, 14, 15). In two of these (8, 13), it was found that when matched for obesity, normal glucose-tolerant, first degree relatives of patients with type 2 diabetes had impaired insulin secretion, but were not insulin resistant.
Similarly, in another study (14) it was shown that normal glucose-tolerant monozygotic twins of someone with type 2 diabetes had impaired ß-cell function, but normal insulin sensitivity; moreover, monozygotic twins who had developed impaired glucose tolerance had the same degree of impaired insulin secretion as those who had maintained normal glucose tolerance, but they had a greater body mass index and waist to hip ratio and were insulin resistant. Thus, one could infer that the addition of obesity-related insulin resistance caused deterioration of their glucose tolerance, and without this they might have maintained normal glucose tolerance. Accordingly, the acquired obesity-related insulin resistance could be viewed as essential in such individuals.
Consistent with this interpretation are the recent studies by Henriksen et al. (16). These investigators induced insulin resistance in offspring of type 2 diabetic patients by treatment with dexamethasone; those who were unable to mount a normal compensatory increase in insulin secretion had greater deterioration in their glucose tolerance than those with a normal compensatory increase in insulin secretion despite the induction of comparable insulin resistance.
These studies illustrate how an acquired form of insulin resistance, such as that due to obesity, could lead to the development of type 2 diabetes in individuals with an underlying, presumably genetic, defect in ß-cell function. Moreover, they provide an explanation for observations that weight loss can markedly improve and sometimes normalize insulin sensitivity in obese patients with type 2 diabetes (17, 18, 19).
However, what about the 1015% of patients with type 2 diabetes who are not obese? Is insulin resistance also an essential factor in these individuals? There are numerous mechanisms by which nonobese individuals may be insulin resistant before or after they develop diabetes. High fat diets (20), decreased physical fitness (21), increased visceral fat accumulation (5, 22), smoking (23), pregnancy (24), certain commonly used medications (25), and hyperglycemia itself [i.e. glucose toxicity (26)] all can cause insulin resistance. Some also believe that insulin resistance is present in type 2 diabetes on a genetic basis independent of obesity (27, 28, 29, 30), although this issue is controversial (7, 8, 9, 10, 11).
In nonobese individuals who have become insulin resistant for reasons other than obesity, whether they become diabetic would depend on the balance between the severity of the insulin resistance and the ability of the ß-cell to compensate for the insulin resistance, just as is the case for obese individuals. Theoretically, a spectrum could exist: at one extreme, insulin resistance initially might be absent, and the immediate cause would be impaired insulin secretion; at the other extreme, impaired insulin secretion might be absent, and insulin resistance would be the immediate cause. I am unaware of any well documented cases of the latter situation.
As evidenced by the fact that most obese individuals and most pregnant women (some of whom may be severely insulin resistant) do not develop type 2 diabetes (6, 24) and the studies cited earlier by Henriksen et al. (16), the normal ß-cell usually increases its insulin secretion to compensate for insulin resistance, so that persistent hyperglycemia does not occur. Although the exact mechanism for this is not well understood, this may be due at least in part to the fact that the plasma glucose concentration is the primary stimulus for insulin release. An increase in plasma glucose evokes additional insulin secretion to restore euglycemia (31). Thus, it would seem unlikely for insulin resistance to cause diabetes without an underlying impairment in ß-cell function.
On the other hand, there are well documented instances in which type 2 diabetes has developed in nonobese individuals in the absence of insulin resistance (7, 32, 33, 34, 35). Thus, at least in some individuals insulin resistance is not essential for the development of type 2 diabetes. Nevertheless, it should be pointed out that most of the above studies included small numbers of subjects who were not randomly selected from a defined population. Thus, it is not known in what proportion of nonobese type 2 diabetic patients the diabetes is the sole result of impaired insulin secretion. However, given the numerous lifestyle and otherwise acquired factors (1) that may adversely affect insulin sensitivity, this proportion might not represent the overwhelming majority of patients.
It is worth pointing out that in obese patients, although insulin resistance may be critical for developing diabetes, it may not be essential for persistence of diabetes. Several studies have demonstrated complete restoration of normal insulin sensitivity after weight reduction in obese individuals (17, 18, 19), but the diabetes has persisted. This implies an essential role for irreversibly impaired insulin secretion even in obese individuals. This view is consistent with the demonstration in the United Kingdom Prospective Diabetes Study of a progressive deterioration of ß-cell function over time in both obese and nonobese patients with type 2 diabetes (36).
Regardless of the controversy of whether impaired insulin secretion or insulin resistance is the essential or primary genetic defect in type 2 diabetes, available research data and clinical experience allow one to draw certain conclusions regarding therapy. Theoretically, treatment should be directed at the underlying pathological process even if one does not know its molecular basis. Efforts to improve insulin sensitivity deserve major emphasis in those patients in whom insulin resistance is the major problem, and conversely, efforts to improve ß-cell function or, when indicated, insulin administration should be of prime concern in those in whom impaired insulin secretion is the main problem.
Impaired insulin secretion can be considered to be universally present in all patients with type 2 diabetes, even those who are hyperinsulinemic. Similarly, insulin resistance can be considered to be universally present in all obese individuals with type 2 diabetes and probably many, if not most, nonobese patients. Practically speaking, therefore, in most patients the best therapeutic results will be obtained by efforts simultaneously directed at improving insulin secretion and reducing insulin resistance. Prevention of diabetes is another matter. Here one would expect that lessening the burden of insulin resistance on the ß-cell might be the most fruitful approach. A recent prospective trial (37) has shown diet and exercise to be effective measures. Whether other lifestyle changes and pharmacological approaches also work remains to be demonstrated.
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Acknowledgments |
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Footnotes |
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Received February 11, 2000.
Accepted March 10, 2000.
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References |
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