EFFECTS OF A CHANGE IN THE PATTERN OF INSULIN DELIVERY ON CARBOHYDRATE-TOLERANCE IN DIABETIC AND NONDIABETIC HUMANS IN THE PRESENCE OF DIFFERING DEGREES OF INSULIN-RESISTANCE

While it is well established that people with non-insulin dependent di abetes mellitus have defects in both insulin secretion and action, the relative contribution of each to glucose intolerance is not known, Th erefore, nondiabetic (lean and obese) and non-insulin dependent diabet es mellitus subjects were studied on two occasions. On each occasion, insulin secretion was inhibited with somatostatin and glucose was infu sed in a pattern and amount that mimicked the systemic delivery rate n ormally observed after ingestion of 50 g of glucose, Insulin also was infused so as to mimic postprandial insulin profiles observed in separ ate groups of diabetic and nondiabetic subjects after food ingestion. Glucose turnover was measured using the isotope dilution method. A del ayed pattern of insulin delivery (i.e., a ''diabetic'' insulin profile ) led to higher (P < 0.05) glucose concentrations in all groups; howev er, the effects were transient, resulting in only a modest increase in the integrated glycemic responses. An isolated defect in insulin acti on had little effect on peak glucose concentration; however, it prolon ged the duration of hyperglycemia, leading to a 2.5-4.2-fold increase (P < 0.05) in the integrated glycemic response, A combined defect in t he pattern of insulin secretion and action was additive rather than sy nergistic. Both defects caused hyperglycemia by altering suppression o f endogenous glucose release and stimulation of glucose disposal, Wher eas obese diabetic and nondiabetic subjects had comparable defects in glucose clearance, non-insulin dependent diabetes mellitus subjects al so had defects in hepatic insulin action. Thus, abnormalities in the p attern of insulin secretion and action alone or in combination impair glucose tolerance. An isolated defect in insulin action has a more pro nounced and prolonged effect than does an isolated change in the patte rn of insulin secretion, Hepatic and extrahepatic insulin resistance r esults in marked and sustained hyperglycemia. (J. Clin. Invest. 1996. 97:2351-2361.)