Increased fetal insulin concentrations for one week fail to improve insulin secretion or β-cell mass in fetal sheep with chronically reduced glucose supply.

Lavezzi JR, Thorn SR, O'Meara MC, LoTurco D, Brown LD, Hay WW Jr, Rozance PJ. Increased fetal insulin concentrations for one week fail to improve insulin secretion or beta-cell mass in fetal sheep with chronically reduced glucose supply. Am J Physiol Regul Integr Comp Physiol 304: R50-R58, 2013. First published November 7, 2012; doi:10.1152/ajpregu.00413.2012.-Maternal undernutrition during pregnancy and placental insufficiency are characterized by impaired development of fetal pancreatic beta-cells. Prolonged reduced glucose supply to the fetus is a feature of both. It is unknown if reduced glucose supply, independent of other complications of maternal undernutrition and placental insufficiency, would cause similar beta-cell defects. Therefore, we measured fetal insulin secretion and beta-cell mass following prolonged reduced fetal glucose supply in sheep. We also tested whether restoring physiological insulin concentrations would correct any beta-cell defects. Pregnant sheep received either a direct saline infusion (CON = control, n = 5) or an insulin infusion (HG = hypoglycemic, n = 5) for 8 wk in late gestation (75 to 134 days) to decrease maternal glucose concentrations and reduce fetal glucose supply. A separate group of HG fetuses also received a direct fetal insulin infusion for the final week of the study with a dextrose infusion to prevent a further fall in glucose concentration [hypoglycemic + insulin (HG + I), n = 4]. Maximum glucose-stimulated insulin concentrations were 45% lower in HG fetuses compared with CON fetuses. beta-Cell, pancreatic, and fetal mass were 50%, 37%, and 40% lower in HG compared with CON fetuses, respectively (P < 0.05). Insulin secretion and beta-cell mass did not improve in the HG + I fetuses. These results indicate that chronically reduced fetal glucose supply is sufficient to reduce pancreatic insulin secretion in response to glucose, primarily due to reduced pancreatic and beta-cell mass, and is not correctable with insulin.