Pathogenesis of insulin resistance and hyperglycemia in non-insulin-dependent diabetes mellitus

Abstract

H uman diabetes is currently classified into two general categories [1]: type I, or insulin-dependent diabetes mellitus and type II, or non-insulin-dependent diabetes mellitus. Insulin-dependent diabetes mellitus is due to an absolute deficiency of insulin secondary to profound beta cell destruction. In non-insulin-dependent diabetes mellitus, the cause of the abnormal metabolic state is less well understood. A major factor that has clouded the etiologic picture is the heterogeneous constellation of disease syndromes represented by non-insulin-dependent diabetes mellitus [2,3], all leading to a final common pathway-hyperglycemia. Thus, non-insulin-dependen t diabetes mellitus may be considered a rather nonspecific diagnosis featuring hyperglycemia as the cardinal clinical finding, and diverse etiologic factors, either alone or in combination, are capable of causing hyperglycemia. Shortly after the discovery of insulin, most diabetoloo gists thought that insuli n deficiency was the single abnormality in all diabetic states. With this line of reasoning, it , was thought that insulin-dependent diabetes mellituS was due to absolute insulin deficiency, whereas non-insulindependent diabetes mellitus was due to partial insulin deficiency with a variable degree of residual insulin secretory capacity depending on the severity of the diabetic state. However, it is now recognized that the situation is not so simple and that three major metabolic abnormalities coexist and contribute to the hyperglycemic state in non-insulin-dependent diabetes mellitus [4-9] (Figure 1). These include (1) peripheral insulin resistance, (2) increased basal hepatic glucose production, and (3) impaired insulin secretion. Although the causal mechanisms may be heterogeneous in different groups of patients with non-insulin-dependent diabetes mellitus, the ultimate expression of the hyperglycemic disease state involves some combination of these three metabolic defects. In understanding this disease state, the pathogenesis of the underlying metabolic defects, the pathogenesis of the hyperglycemia, and, finally, the pathogenesis of non-insulin-dependent diabetes mellitus itself must be considered. Each of these topics will be considered throughout this symposium, and specific papers are presented dealing with each of these individual issues. By way of introduction to the material presented in the symposium, this paper will provide a brief overview of the Pathogenesis of insulin resistance, increased hepatic glucose production, and impaired insulin secretion, followed by a more detailed consideration of the causes of the hyperglycemia. Finally, a few Comments about the pathogenesis of the non-insulin-dependent diabetic state will be offered.