Glucose Suppression of Insulin Secretion in Chronically Hyperglycemic Fetal Sheep

Abstract

Previous observations in fetal sheep indicate that glucose may inhibit as well as enhance insulin secretion. To study conditions involved in inhibition of insulin secretion, we compared changes in plasma insulin concentration in response to acute increases in glucose and arginine concentrations in a group of normal, late gestation fetal sheep (euglycemic controls, EC) and a comparable group made chronically hyperglycemic by constant maternal glucose infusion (hyperglycemics, HG). After 7-10 d of maternal and fetal hyperglycemia, fetal glucose concentrations (G) were significantly increased in the HG group (0.98 +/- 0.07 mM EC, 2.00 +/- 0.11 mM HG, p < 0.001) but fetal plasma insulin concentrations (I) were not significantly different (57 +/- 7 pM EC, 71 +/- 9 pM HG, p = 0.2). Furthermore, the I/G ratio was significantly decreased in the HG group (60 +/- 9 EC, 40 +/- 4 HG, p = 0.03) and during a hyperglycemic glucose clamp (delta G approximately equal to 1.4 mM), glucose-stimulated increase in steady state I was less in the HG than in the EC fetuses (mean delta I/delta G = 106 +/- 15 EC, 61 +/- 10 HG, p = 0.01). An arginine infusion at the end of the clamp produced similar increases in I in the EC and HG groups (delta I = 824 +/- 116 pM EC, 906 +/- 131 pM HG, p = 0.45). There were no differences between groups for blood oxygen saturation and content, pH, or lactate concentration. After 14-17 d of hyperglycemia, glucose-stimulated increase in I was even more reduced in the HG fetuses than observed at 7-10 d. Decreased insulin response to arginine also was present, although pancreatic insulin concentration was not decreased. Glucose-stimulated increase in I returned to normal after 7 d of no glucose infusion and euglycemia. These data indicate that glucose-stimulated insulin secretion is reversibly decreased by marked, chronic hyperglycemia. Because pharmacologic inhibitors of insulin secretion (e.g. streptozotocin or alloxan) were not used, and oxygenation, pH, and lactate values were similar between the two groups, this decrease of insulin secretion appears to be glucose-specific, although mechanisms involved can include both glucose and amino acid (arginine) stimulation processes. Such decrease in fetal insulin secretion may limit the rate of fetal glucose utilization during chronic hyperglycemia and thereby modulate the rate of fetal growth.