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

Abstract

Maternal undernutrition during pregnancy and placental insufficiency are characterized by impaired development of fetal pancreatic β-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 β-cell defects. Therefore, we measured fetal insulin secretion and β-cell mass following prolonged reduced fetal glucose supply in sheep. We also tested whether restoring physiological insulin concentrations would correct any β-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. β-Cell, pancreatic, and fetal mass were 50%, 37%, and 40% lower in HG compared with CON fetuses, respectively (P < 0.05). Insulin secretion and β-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 β-cell mass, and is not correctable with insulin.

Fig. 1.

Maternal arterial plasma glucose concentrations. Maternal arterial plasma glucose concentrations were measured throughout the 8-wk infusion period. Solid squares, control (CON); open squares, hypoglycemic (HG). *P < 0.0001 between CON and HG (mixed models ANOVA). Values are means ± SE.

Fig. 2.

Fetal glucose and insulin concentrations for the final week of study. Fetal arterial plasma glucose (A) and insulin (B) concentrations were measured throughout the final experimental week (while fetal vascular access was available). Solid squares, CON; open squares, HG. **Fetal arterial plasma glucose concentrations were significantly lower in HG fetuses compared with CON (P < 0.0001). *Fetal arterial plasma insulin concentrations were significantly lower in HG compared with CON fetuses (P < 0.05) throughout the final week. All statistics by mixed models ANOVA. Values are means ± SE.

Fig. 3.

Fetal glucose and insulin concentrations during glucose-stimulated insulin secretion (GSIS). Fetal arterial plasma glucose (A) and insulin (B) concentrations were measured during the square wave hyperglycemic clamp, which began at time 0. Solid squares, CON; open squares, HG. *P < 0.05 between CON and HG. Values are means ± SE.

Fig. 4.

Fetal arterial norepinephrine concentrations. Fetal arterial plasma norepinephrine concentrations plotted as a function of fetal arterial O₂ content. Soild squares, CON; open squares, HG, shaded squares, HG+I. r² = 0.46, P < 0.01, for all fetuses.