Insulin receptors and action in clinical disorders of carbohydrate tolerance

The basic postbinding biochemical events associated with insulin action include receptor autophosphorylation, the generation of chemical mediators of insulin action, and the translocation of glucose transporters to the cell membrane. These events yield increased glucose transport and changes in the degree of phosphorylation of several of the key enzymes of intermediary metabolism, resulting in the stimulation of glycogen synthesis, glucose oxidation, and lipid synthesis, and in the inhibition of glycogenolysis, lipolysis, and gluconeogenesis. At the clinical level in man, the rate-limiting step for insulin-stimulated disposal of oral glucose in vivo is glucose transport into peripheral tissues, chiefly muscle, whereas the contributions of insulin suppression of hepatic glucose output and stimulation of glucose oxidation are quite limited. Impaired glucose tolerance, noninsulin-dependent diabetes mellitus, and obesity are common clinical disorders associated with significant insulin resistance. For those patients with mild insulin resistance and absolute hyperinsulinemia, the resistance appears to be largely secondary to downregulation of the number of insulin receptors. For those patients with more severe insulin resistance, additional postreceptor defects of insulin action contribute significantly to the clinical disorder. The detailed characterization of these postreceptor defects remains to be determined.