Insulin Resistance vs. Impaired Insulin Secretion
It was initially assumed that all diabetes was due to insulin deficiency. A genetic basis for this theory was supported by Cerasi and Luft, who reported in 1967 that insulin secretion was reduced in normoglycemic, nondiabetic first-degree relatives of individuals with type 2 diabetes. Further evidence for this finding was provided by Vaag et al. in 1995, when they demonstrated impaired insulin secretion in the nondiabetic twins of twin subjects discordant for type 2 diabetes. More recently, Weyer et al. illustrated the importance of insulin deficiency in the pathogenesis of type 2 diabetes in a prospective evaluation of Pima Indians. This ethnic group has the highest reported incidence of diabetes worldwide. Subjects were studied longitudinally over approximately 5 years as some maintained normal glucose tolerance while others progressed from normal, to impaired glucose tolerance, to diabetes. Insulin action was assessed by the euglycemic clamp technique, and insulin secretion was assessed by the intravenous glucose tolerance test. Characteristics of subjects who progressed to diabetes were compared with those of subjects who maintained normal glucose tolerance throughout the study period. While both groups exhibited a progressive but modest increase in insulin resistance, only the group that developed diabetes showed a progressive decline in insulin secretion.
Despite the evidence cited above, there are equally compelling data supporting the primacy of insulin resistance in the development and progression of type 2 diabetes. This concept was initially proposed in the early 1940s by Himsworth and Kerr, who noted variations in the responses of diabetic patients to exogenously administered insulin. They proposed that insulin resistance, rather than insulin deficiency, was the primary defect in many patients with type 2 diabetes. Their theory was largely ignored, however, until the early 1960s, when radioimmunoassay became available and permitted reliable measurements of endogenous insulin levels. Utilizing that methodology, Bernson and Yalow were the first to report higher-than-average insulin levels in subjects with type 2 diabetes.Subsequent data have demonstrated hyperinsulinemia and impaired insulin-stimulated glucose disposal in offspring of diabetic subjects; these same defects were present in patients with impaired glucose tolerance.
These data imply a genetic component of insulin resistance and illustrate its importance as an early pathophysiologic abnormality in the pathogenesis of type 2 diabetes. Moreover, specific molecular mechanisms resulting in insulin resistance have been elucidated. In vivo studies by Cline et al. have shown defects in insulin stimulated glucose transport.In vitro studies have accumulated evidence for insulin-signalling defects, including a reduction in the insulin receptor tyrosine kinase, insulin receptor substrate (IRS) protein phosphorylation, and phosphatidylinositol (PI) 3-kinase activation.
The general interpretation of the above data is that defects in both insulin action and insulin secretion are significant factors in the development and progression of most cases of type 2 diabetes and both warrant similar attention when attempting to pharmacologically treat this condition. The severity of insulin defects may vary markedly in individuals; it depends on the duration of diabetes, which may influence beta cell mass and insulin secretory capacity. The extent of insulin defects is also subject to exogenous factors such as obesity, visceral fat accumulation, high-fat diet, smoking, and decreased physical fitness; all of these have been shown to increase insulin resistance.
In practice, the dual metabolic defects in type 2 diabetes can be addressed simultaneously with combinations of therapies that have complementary mechanisms. An example is the combination of insulin secretagogues and insulin sensitizers. Such combination therapy has been documented to improve diabetic control to a greater extent than monotherapy.
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