Dose Response to Insulin in Man: Differential Effects on Glucose and Ketone Body Regulation

Abstract

This prospective study was undertaken to elucidate the relationship between progressive log increments in plasma free insulin concentration and the resultant changes in the concentrations of plasma glucose, potassium, ketones, and free fatty acids in man. We attempted to define both the maximal and minimal threshold for substrate response relative to circulating concentrations of plasma insulin. Hyperglycemia and hyperketonemia were experimentally induced with dexamethasone in six diabetic subjects. Circulating plasma insulin concentration was acutely elevated by the continuous iv infusion of insulin in order to attain ten-fold increments in circulating plasma insulin concentration. Specifically, following a progressive elevation above basal concentration, maximal increments in circulating plasma insulin of 7 μU/ml, 90μU/ml, and 1, 621 μU/ml were obtained. The differential effects of these acute alterations in plasma insulin concentration on plasma substrate concentrations were compared to a controlsaline infusion study. The maximal rate of reduction in the plasma concentration of glucose and potassium was observed during pharmacological circulating concentrations of insulin (< 1, 000 μU/ml). This response contrasted to that observed for plasma ketone body and free fatty acid concentration. For these substrates, the maximal rate of reduction was observed during physiological increments in plasma insulin concentration (less than 90 μU/ml). While this dissociation of response in terms of plasma glucose, fatty acids, and ketones to insulin characterizes steroid-induced hyperglycemia and hyperketonemia, it is probable that a comparable dissociation may apply to other pathological stressinduced states.