Skeletal muscle glucose transporter protein responses to antenatal glucocorticoids in the ovine fetus

Abstract

We investigated the effects of maternal antenatal dexamethasone (Dex) treatment given as a single course (4 doses) or multiple courses (20 doses) on fetal skeletal muscle glucose transporter (GLUT) protein concentrations at 70% of gestation (106 to 107 days with term being 145 to 150 days) in the ovine fetus. Antenatal corticosteroid administration was associated with a decrease in endogenous fetal plasma cortisol concentrations (P<0·05), fetal hyperglycemia (P<0·02) and hyperinsulinemia (P<0·05). These metabolic/hormonal changes were associated with a decrease in fetal body weight (P<0·05) in the multiple course Dex group compared with the multiple course placebo group. These perturbations were associated with an increase in fetal skeletal muscle GLUT 1 concentrations that mediate basal glucose transport in the extensor digitorum lateralis and extensor digitorum longus muscles (P<0·05) 18 h after the last dose of Dex was given in the single course group.However, in the multiple course Dex group, a small increase in GLUT 1 was observed only in the biceps femoris. In contrast, both single and multiple courses of antenatal Dex were associated with an increase in the extensor digitorum lateralis and biceps femoris muscle GLUT 4 (insulin-responsive) concentrations (P<0·05). We conclude that antenatal corticosteroids perturb fetal glucose/insulin homeostasis, which is associated with increases in fetal skeletal muscle glucose transporters to compensate for and attenuate the associated catabolic fetal state. These changes consist of an increase in proteins that mediate basal glucose transport (GLUT 1) to meet immediate energy requirements of the fetal skeletal muscle with an increase in basal insulin sensitivity (GLUT 4) to compensate for the Dex-induced catabolic state after exposure to multiple courses of Dex.

Will the original glucose transporter isoform please stand up!

“…In the late-gestation ovine fetus, insulin and glucocorticoids regulate skeletal muscle GLUT1 expression by increasing the concentrations (39,47). After weaning during the postsuckling phase and beyond into adult stages, there is a decline in GLUT1 expression in most tissues except the brain (30,67,108,112).…”

The Effects of Glucocorticoids on Fetal and Placental Development

“…Besides placenta, GCs affect glucose transport in a variety of peripheral tissues, such as skeletal muscle, adipocytes, and endothelial cells [149][150][151][152][153][154][155][156][157][158][159][160]. High affinity low capacity GRs have been identified in the placenta of various species, including man, rat, and mouse [17,35,161,162].…”

“…Prenatal corticosteroid exposure of mice resulted in programming of the fetus such that the adult progeny exhibited glucose intolerance [170,171]. In addition, repeated courses of maternal corticosteroid administration have been shown to alter fetal glucose homeostasis and hepatic enzyme activity in rats [157,173]. In summary, the effects of glucocorticoids in placental glucose transport mechanisms in not fully understood.…”

Antenatal corticosteroids alter insulin signaling pathways in fetal baboon skeletal muscle

“…We found a decrease in Akt-1 in preterm animals after exposure to GCs suggesting the major effect of GCs is on growth, whereas Akt-2 did not change after GC exposure. It is possible that transient changes in insulin-signaling protein content in the muscle of preterm baboons could be due to concurrent variations in fetal insulin and/or glucose concentrations after GC exposure (Jellyman et al 2005, Grey et al 2006). However, birth weights were similar within gestational groups and published plasma glucose and insulin levels measured at birth were similar in preterm and term control animals (Blanco et al 2010).…”

“…Previous studies have shown decreased levels of GLUT1 and GLUT4 in skeletal muscle of fetal preterm baboons (Blanco et al 2010); these differences might be developmental as glucose homeostasis is controlled by passive diffusion through the placenta during fetal life and insulin stimulated glucose disposal is decreased in-utero. Others have shown perturbations in fetal skeletal muscle glucose transporters in sheep after a single dose of GCs, along with fetal hyperglycemia and hyperinsulinemia (Gray et al 2006). Therefore, information is needed on the precise change in insulin function and signaling at the muscle cell level resulting from fetal exposure to concentrations of corticosteroids in excess of those appropriate for the current stage of maturation.…”