Effect of insulin on growth hormone-induced metabolic derangements in diabetes

Abstract

To investigate the mechanism of growth hormone-induced hyperglycemia in diabetes, two studies were done in insulin-dependent diabetic patients receiving intensive insulin therapy with the insulin pump. First, the metabolic response to a standard breakfast following a subcutaneous insulin bolus was examined before and after 20 hourly boluses of intravenous growth hormone in eight patients. Despite unchanged insulin therapy, growth hormone administration produced a marked rise in fasting glucose concentrations (197 ± 21 v 96 ± 11 mg/dL), as well as increases in fasting levels of free fatty acids and branched chain amino acids. Nevertheless, postprandial blood glucose increments were only slightly greater after growth hormone (36 ± 14 v 20 ± 12 mgdL). Moreover, the increased levels of other insulin-sensitive fuels induced by growth hormone fell to normal following the meal. In a second study, six patients received a low-dose insulin clamp (designed to reproduce the mean postprandial concentrations of glucose and insulin observed in the meal study) before and after growth hormone administration. Despite endogenous glucose overproduction after growth hormone, modest elevations in free insulin (40 to 50 μU/mL) were sufficient to suppress glucose production to an extent comparable to the control day (from 2.8 ± 0.2 to 0.6 ± 0.3 mg/kg min after growth hormone v 1.6 ± 0.1 to 0.4 ± 0.2 mg/kg min on the control day). However, the normal stimulation of glucose uptake by insulin was abolished by growth hormone. We conclude that in diabetic patients growth hormone-stimulated hepatic glucose overproduction (and the increases in other insulin-sensitive fuels) can be relatively easily overcome with extra insulin. This may explain why, despite impairing insulin-stimulated peripheral glucose uptake, growth hormone had only a small effect on postprandial hyperglycemia following a mixed meal. Our data suggest that under clinical conditions growth hormone induces hyperglycemia in diabetes by a dual mechanism: stimulation of hepatic glucose production, which is largely responsible for fasting hyperglycemia; and impaired peripheral glucose uptake, which perpetuates the hyperglycemia postprandially in spite of suppression of endogenous glucose release.