Increased Adrenergic Signaling Is Responsible for Decreased Glucose-Stimulated Insulin Secretion in the Chronically Hyperinsulinemic Ovine Fetus

Insulin may stimulate its own insulin secretion and is a potent growth factor for the pancreatic beta- cell. Complications of pregnancy, such as diabetes and intrauterine growth restriction, are associated with changes in fetal insulin concentrations, secretion, and beta-cell mass. However, glucose concentrations are also abnormal in these conditions. The direct effect of chronic fetal hyperinsulinemia with euglycemia on fetal insulin secretion and beta-cell mass has not been tested. We hypothesized that chronic fetal hyperinsulinemia with euglycemia would increase glucose- stimulated insulin secretion ( GSIS) and beta-cell mass in the ovine fetus. Singleton ovine fetuses were infused with iv insulin to produce high physiological insulin concentrations, or saline for 7-10 days. The hyperinsulinemic animals also received a direct glucose infusion to maintain euglycemia. GSIS, measured at 133 +/- 1 days of gestation, was significantly attenuated in the hyperinsulinemic fetuses (P < .05). There was no change in beta-cell mass. The hyperinsulinemic fetuses also had decreased oxygen (P < .05) and higher norepinephrine (1160 +/- 438 vs 522 +/- 106 pg/mL; P < .005). Acute pharmacologic adrenergic blockade restored GSIS in the hyperinsulinemic-euglycemic fetuses, demonstrating that increased adrenergic signaling mediates decreased GSIS in these fetuses.