Recent observations on the regulation of fetal metabolism by glucose

Abstract

Glucose is the principal energy substrate for the the fetus and is essential for normal fetal metabolism and growth. Fetal glucose metabolism is directly dependent on the fetal plasma glucose concentration. Fetal glucose utilization is augmented by insulin produced by the developing fetal pancreas in increasing amounts as gestation proceeds, which enhances glucose utilization among the insulin-sensitive tissues (skeletal muscle, liver, heart, adipose tissue) that increase in mass and thus glucose need during late gestation. Glucose-stimulated insulin secretion increases over gestation. Both insulin secretion and insulin action are affected by prevailing glucose concentrations and the amount and activity of tissue glucose transporters. In cases of intrauterine growth restriction (IUGR), fetal weight-specific tissue glucose uptake rates and glucose transporters are maintained or increased, while synthesis of amino acids into protein and corresponding insulin-IGF signal transduction proteins are decreased. These observations demonstrate the mixed phenotype of the IUGR fetus that includes enhanced glucose utilization capacity, but diminished protein synthesis and growth. Thus, the fetus has considerable capacity to adapt to changes in glucose supply by relatively common and understandable mechanisms that regulate fetal metabolism and growth and could underlie certain later life metabolic disorders such as insulin resistance, obesity and diabetes mellitus.

Figures

Figure 1. Simultaneous effect of fetal plasma glucose and insulin concentrations on fetal glucose oxidation rate

A, three-dimensional plot of individual values of CO2 production from glucose carbon oxidation at different fetal plasma concentrations of glucose and insulin. B, predicted three-dimensional glucose by insulin surface. Data obtained in near-term fetal sheep (Hay et al. 1989).

Figure 2. Schematic representation of regulation of translation initiation by amino acids, growth factors and hypoxia

Insulin, and to a lesser extent the IGFs, activate protein synthesis via a PI3 kinase → Akt → mTOR → p70S6k → 4EBP-1 → eIF4E signal transduction pathway, which can be inhibited at certain points by reduced molecular oxygen supply.

Figure 3. Effect of acute hyperinsulinaemia on signalling protein phosphorylation in fetal skeletal muscle in utero

The results show a robust insulin response to stimulate IR, IRS-1, p85-PI 3-Kinase, Akt and p70S6 kinase in fetal skeletal muscle in utero during a hyperinsulinaemic–euglycaemic clamp. Repeated muscle biopsies were taken in control (saline-infused) fetuses and in twin fetuses clamped over 240-min period (n = 3 animals/group). From Anderson et al. (2005), with permission.

Figure 4. Glucose-stimulated insulin secretion as a function of sustained normal, increased or decreased plasma glucose concentrations in fetal sheep (Hay et al. 1989; Carver et al. 1996)

Four groups of fetal sheep were studied by hyperglycaemic glucose clamp technique after each group had been maintained at a unqiue plasma glucose concentration for 12 days: ▿, control fetuses; ○, fetuses that were markedly and consistently hyperglycaemic (about twice normal); •, fetuses that were mildly hyperglycaemic but had 3 pulses of marked hyperglycaemia lasting 60 min each during a 24-h period; □, hypoglycaemic fetuses that had a plasma glucose about 50% of normal. A, fetal arterial blood glucose concentrations in 4 groups of fetal sheep during a 120 min hyperglycaemic glucose clamp. Values from 30 to 120 min are significantly different (P < 0.01) among all groups. B, fetal arterial plasma insulin concentrations in the same 4 groups of animals during the 120 min hyperglycaemic glucose clamps. Values are means ± s.e.m. From Carver et al. (1996), with permission.