Insulin resistance and non-insulin-dependent diabetes mellitus: cellular and molecular mechanisms.
Non-insulin-dependent diabetes mellitus is a complex metabolic disorder that involves numerous biochemical abnormalities, a heterogenous clinical picture, and a polygenic hereditary component. The pathophysiologic state involves increased basal hepatic glucose production, decreased insulin-mediated glucose utilization in target tissues, and altered pancreatic function with decreased beta cell function and enhanced glucagon secretion. Prospective studies indicate that insulin resistance and hyperinsulinemia exist in the prediabetic state at a time when glucose tolerance is normal. When hyperglycemia supervenes, both insulin secretion and insulin-mediated glucose utilization are further compromised, mediated in part by sustained hyperglycemia itself. Insulin resistance may occur at any level in the biologic action of insulin, from initial binding to cell surface receptors to the phosphorylation cascade that is initiated by autophosphorylation of the insulin receptor. Receptors isolated from patients with non-insulin-dependent diabetes mellitus have compromised autophosphorylation-kinase activity when isolated from adipocytes, liver, erythrocytes, and skeletal muscle. The magnitude of the decrease in insulin receptor kinase activity is correlated with the degree of fasting hyperglycemia. However, the defect in insulin receptor kinase activity is normalized after weight reduction or other measures that reduce hyperglycemia, indicating the secondary nature of the defect. Clarification of the mechanisms underlying insulin resistance in non-insulin-dependent diabetes mellitus will lead to new treatment modalities for this disease.
Olefsky
J M
JM
Department of Medicine, University of California, San Diego, La Jolla 92093.
Nolan
J J
JJ
D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000503:physiopathology; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007333:Insulin Resistance; D000078790:Insulin Secretion
D001786:Blood Glucose; D007328:Insulin