EFFECT OF SUSTAINED PHYSIOLOGICAL HYPERINSULINEMIA AND HYPERGLYCEMIA ON INSULIN-SECRETION AND INSULIN SENSITIVITY IN MAN

Two study protocols to examine the effects of chronic (72-96 h) physio logic euglycaemic hyperinsulinaemia (+ 72 pmol/l) and chronic hypergly caemic (+ 1.4 mmol/l) hyperinsulinaemia (+ 78 pmol/l) on insulin sensi tivity and insulin secretion were performed in 15 healthy young subjec ts. Subjects received a three-step euglycaemic insulin (insulin infusi on rates = 1.5, 3, and 6 nmol.kg(-1).min(-1)) clamp and a hyperglycaem ia (6.9 mmol/l) clamp before and after chronic insulin or glucose infu sion. Following 4 days of sustained euglycaemic hyperinsulinaemia whol e body glucose disposal decreased by 20-40%. During each insulin clamp step, the defect in insulin action was accounted for by impaired non- oxidative glucose disposal (p < 0.01). Chronic euglycaemic hyperinsuli naemia did not alter insulin-mediated suppression of hepatic glucose p roduction. Following insulin infusion the ability of hyperglycaemia to stimulate insulin secretion was significantly diminished. Following 7 2 h of chronic glucose infusion (combined hyperglycaemic hyperinsulina emia), there was no change in whole body glucose disposal. However, gl ucose oxidation during each insulin clamp step was significantly incre ased and there was a reciprocal decline in non-oxidative glucose dispo sal by 25-39% (p < 0.01); suppression of hepatic glucose production by insulin was unaltered by chronic hyperglycaemic hyperinsulinaemia. Ch ronic glucose infusion increased the plasma insulin response to acute hyperglycaemia more than twofold. These results demonstrate that chron ic, physiologic hyperinsulinaemia, whether created by exogenous insuli n infusion or by stimulation of endogenous insulin secretion, leads to the development of insulin resistance, which is characterized by a sp ecific defect in the non-oxidative (glycogen synthetic) pathway. These findings indicate that hyperinsulinaemia should be considered, not on ly as a compensatory response to insulin resistance, but also as a sel f-perpetuating cause of the defect in insulin action.