Maturation of glucose-stimulated insulin secretion in fetal sheep

To determine the gestational maturation of fetal insulin response to glucose and arginine and the effects of sustained hyperglycemia on these processes, we measured insulin secretion in different groups of fetal sheep at 75, 100, 122, and 137 days of gestation (50, 67, 81, and 91% of term gestation, respectively). The basal glucose concentration decreased progressively from 1.36 +/- 0.16 mM at 75 days to 1.00 +/- 0.07 mM at 137 days (p < 0.05). The fetal plasma insulin concentration did not change (54 +/- 11 pM at 75 days, 68 +/- 8 pM at 137 days), but there was a significant increase in the increment in plasma insulin concentration in response to a hyperglycemic clamp over this same period (deltaI pM/deltaG mM) from 20 +/- 3 at 75 days to 105 +/- 8 at 137 days (p < 0.001). The deltaI (pM) in response to arginine also increased from 129 +/- 17 pM at 75 days to 635 +/- 103 pM at 137 days (p < 0.001). Sustained hyperglycemia from 90 to 100 days reduced the deltaI (pM)/deltaG (mM) to glucose (13 +/- 2, p < 0.01) and the deltaI pM to arginine (369 +/- 86, p < 0.05) to values less than those found in euglycemic animals (deltaI/deltaG = 58 +/- 4 to glucose, deltaI = 525 +/- 71 to arginine). Thus, glucose and arginine stimulate insulin secretion at midgestation at 20% of the rate near term, and there is a consistently positive developmental pattern of insulin secretion to these secretagogues over the second half of gestation. Furthermore, chronic, high, relatively constant hyperglycemia blunts insulin secretion to glucose and arginine close to midgestation, similar to the effect seen near term. Such developmental and adaptive capacities may account for an important part of the variability in fetal glucose metabolism observed in animal models and human cases of diabetes during pregnancy.