Glucose replacement to euglycemia causes hypoxia, acidosis, and decreased insulin secretion in fetal sheep with intrauterine growth restriction

Abstract

Nutritional interventions for intrauterine growth restriction (IUGR) have raised concerns for fetal toxicity, the mechanisms of which are unknown. Most of these attempts did not aim to normalize fetal metabolic conditions. Therefore, we used a model of IUGR to determine whether normalization of fetal hypoglycemia for 2 wks would be tolerated and increase insulin concentrations and pancreatic beta-cell mass. IUGR fetuses received either a direct saline infusion (Sal, the control group) or a 30% dextrose infusion (Glu) to normalize glucose concentrations. Neither insulin concentrations (0.11 +/- 0.01 Glu vs. 0.10 +/- 0.01 ng/mL Sal) nor beta-cell mass (65.2 +/- 10.3 Glu vs. 74.7 +/- 18.4 mg Sal) changed. Glucose stimulated insulin secretion (GSIS) was lower in the Glu group. Glu fetuses became progressively more hypoxic: O2 content 1.4 +/- 0.5 Glu vs. 2.7 +/- 0.4 mM Sal, p < 0.05. Partial pressure of carbon dioxide (Paco2) (53.6 +/- 0.8 Glu vs. 51.6 +/- 0.8 Sal, p < 0.05) and lactate (7.74 +/- 3.82 Glu vs. 2.47 +/- 0.55 mM Sal, p < 0.0001) were greater and pH lower (7.275 +/- 0.071 Glu vs. 7.354 +/- 0.003 Sal, p < 0.01) in the Glu group. We conclude that correction of fetal hypoglycemia is not well tolerated and fails to increase insulin concentrations or beta-cell mass in IUGR fetuses.

Figure 1. Fetal glucose infusion rates and glucose concentrations

A) Glucose infusion rate in the Glu group. B) Fetal arterial plasma glucose concentrations. □ = Glu, ● = Sal, * = significant difference between Glu and Sal, p<0.05 by mixed models ANOVA. Values are mean ± SEM.

Figure 2. Fetal blood gas and acid-base status

Fetal arterial pO₂ (A), O₂ saturation (B), O₂ content (C), pCO₂ (D), lactate (E), and pH (F) are shown with SEM bars. □ = Glu, ● = Sal, * = significant difference between Glu and Sal, § = significant difference compared to day 0 in Glu only, p<0.05 by mixed models ANOVA.

Figure 3. Fetal arterial plasma insulin concentrations

Fetal arterial plasma insulin concentrations with SEM bars. □ = Glu, ● = Sal.

Figure 4. Fetal arterial plasma cortisol and norepinephrine concentrations

A) Fetal arterial plasma cortisol concentrations are plotted as a function of fetal arterial O₂ content at the end of the treatment period. r²=0.46, p<0.025. B) Natural log of fetal arterial plasma norepinephrine concentrations are plotted as a function of fetal arterial O₂ content at the end of the treatment period. r²=0.86, p<0.0001. C) Fetal arterial plasma cortisol and the natural log of norepinephrine concentrations are plotted for each animal. r²=0.34, p<0.05. For all graphs □ = Glu, ● = Sal.

Figure 5. Fetal insulin and glucagon secretion at the end of the treatment period

A) Fetal arterial plasma glucose concentrations ± SEM during the square wave hyperglycemic clamp started at time = 0 min. B) Glucose stimulated fetal plasma arterial insulin concentrations ± SEM. C) GSIS, defined as the difference between the average glucose stimulated insulin concentrations (time = 60, 75, and 90 min) and baseline insulin concentrations (time = −25, −15, and −5 min), plotted as a function of fetal arterial O₂ content measured before the hyperglycemic clamp, r²=0.35, p<0.05. D) Arginine stimulated fetal plasma arterial insulin concentrations ± SEM measured at the end of the hyperglycemic clamp following bolus administration of arginine at time = 0 min. E) Arginine stimulated fetal plasma arterial glucagon concentrations ± SEM were measured at the end of the hyperglycemic clamp following bolus administration of arginine at time = 0 min. For all graphs □ = Glu, ● = Sal; * = significant difference between Glu and Sal, § = significant difference compared to baseline for both groups, p<0.05 by mixed models ANOVA.