Chronic anemic hypoxemia attenuates glucose-stimulated insulin secretion in fetal sheep

Abstract

Fetal insulin secretion is inhibited by acute hypoxemia. The relationship between prolonged hypoxemia and insulin secretion, however, is less well defined. To test the hypothesis that prolonged fetal hypoxemia impairs insulin secretion, studies were performed in sheep fetuses that were bled to anemic conditions for 9 ± 0 days (anemic, n = 19) and compared with control fetuses (n = 15). Arterial hematocrit and oxygen content were 34% and 52% lower, respectively, in anemic vs. control fetuses (P < 0.0001). Plasma glucose concentrations were 21% higher in the anemic group (P < 0.05). Plasma norepinephrine and cortisol concentrations increased 70% in the anemic group (P < 0.05). Glucose-, arginine-, and leucine-stimulated insulin secretion all were lower (P < 0.05) in anemic fetuses. No differences in pancreatic islet size or β-cell mass were found. In vitro, isolated islets from anemic fetuses secreted insulin in response to glucose and leucine as well as control fetal islets. These findings indicate a functional islet defect in anemic fetuses, which likely involves direct effects of low oxygen and/or increased norepinephrine on insulin release. In pregnancies complicated by chronic fetal hypoxemia, increasing fetal oxygen concentrations may improve insulin secretion.

Keywords: fetus; islet; oxygen; pancreas; β-cell.

Fig. 1.

Arterial hematocrit and oxygen are decreased in anemic fetuses. Fetal arterial hematocrit (A), oxygen content (B), Po₂ (C), and hemoglobin-oxygen saturation (D) were significantly lower in anemic fetuses (□, n = 19) compared with controls (●, n = 15), *P < 0.05, **P < 0.0001. Values are expressed as means ± SE; statistical analysis was performed by mixed-model ANOVA.

Fig. 2.

Norepinephrine is inversely associated with fetal oxygen concentrations. Fetal arterial plasma norepinephrine concentrations are inversely associated with fetal arterial blood oxygen content in anemic (□, n = 19) and control (●, n = 15) animals by linear regression analysis.

Fig. 3.

In vivo glucose stimulated insulin secretion is attenuated in anemic fetuses. Values are expressed as means ± SE. Fetal arterial plasma insulin (A) and glucose (B) concentrations are plotted relative to the start of a primed continuous variable-rate fetal hyperglycemia clamp (time = 0 min) in anemic (□, n = 11) and control (●, n = 7) animals. *Significantly lower insulin concentrations (A) and higher glucose concentrations (B) in anemic fetuses compared with controls by mixed models ANOVA, P < 0.05).

Fig. 4.

Lower glucose-stimulated insulin secretion is associated with lower oxygen and higher norepinephrine concentrations in anemic and control fetal sheep. Lower fetal arterial oxygen (A) and higher fetal norepinephrine (B) concentrations are associated with impaired fetal glucose-stimulated insulin secretion. Cortisol (C) concentrations are not associated with fetal insulin secretion. Insulin secretion is defined as the difference between insulin concentrations during the hyperglycemic clamp and at baseline and is compared with oxygen, norepinephrine, and cortisol by linear regression in anemic (□, n = 11) and control (●, n = 7) fetuses. Norepinephrine concentrations are log transformed.

Fig. 5.

In vitro glucose- and leucine-stimulated insulin secretion is equivalent in isolated anemic and control fetal islets. Pancreatic islets were isolated from anemic (open bars; n = 8) and control (solid bars; n = 8) fetuses. In vitro insulin secretion was assayed in 1-h static incubations with Krebs-Ringer bicarbonate buffer and additional glucose and leucine as indicated. Although glucose and leucine stimulated insulin secretion, there were no differences between anemic and control islets. Data are presented as means ± SE, and statistics were obtained through mixed-model ANOVA. Incubations with different letters were significantly different from each other (P < 0.0005).