Programming of Rat Muscle and Fat Metabolism by in Utero Overexposure to Glucocorticoids

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.

Section: Discussionmentioning

confidence: 70%

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

Gray¹,

Stonestreet²,

Thamotharan³

et al. 2006

“…To avoid litter effects, no more than three animals from a single litter were tested. After an overnight fast, serum concentrations of insulin and glucose were measured in saphenous vein samples, collected by repeated puncture, at baseline (0900 h), 30 and 120 min after rats were given 2 g/kg glucose (Sigma-Aldrich) in water by gavage as previously described (Cleasby et al 2003). Blood samples were allowed to clot at 4 8C, centrifuged, and stored at K80 8C until assayed.…”

Section: Oral Glucose Tolerancementioning

confidence: 99%

Fetal and neonatal nicotine exposure and postnatal glucose homeostasis: identifying critical windows of exposure

Bruin

Kellenberger

Gerstein³

et al. 2007

Fetal and lactational exposure to nicotine at concentrations comparable with those in women who smoke causes impaired glucose tolerance in male offspring in postnatal life. It remains unknown whether there are critical windows of susceptibility to nicotine exposure. Female nulliparous Wistar rats were given saline vehicle or nicotine bitartrate (1 mg/kg per day) prior to pregnancy, which was then: A) discontinued during pregnancy and lactation; B) continued until parturition; C) continued until weaning; and D) discontinued during pregnancy and restarted from lactation until weaning. At 26 weeks of age, offspring in each group were challenged with an oral glucose load. b-Cell mass, apoptosis, and proliferation were measured at birth, and at 4 and 26 weeks of age. The animals in group C (exposed to nicotine throughout pregnancy and lactation) had reduced b-cell mass from birth through 26 weeks of age and impaired glucose homeostasis at 26 weeks of age. b-Cell mass was also reduced at birth and at 4 weeks of age in animals exposed to nicotine during pregnancy alone (group B). However, enhanced proliferation following weaning led to recovery of this defect to 98% of control levels by week 26. The response to the glucose load in groups A, B, and D did not differ from controls. Continued exposure to nicotine from conception through lactation results in permanent b-cell loss and subsequent impaired glucose tolerance. This model of type 2 diabetes requires that nicotine exposure occurs both in utero and during lactation.

“…Disturbances in glycemic control are a feature of the programmed adult phenotype in several animal models; for example, fetal growth restriction induced by uterine artery ligation in rats produces glucose-intolerant offspring with impaired insulin signaling and altered hepatic gluconeogenesis (Vuguin et al 2004). Moreover, treatment of pregnant mothers with either dexamethasone (Dex) or carbenoxolone, an inhibitor of 11b-hydroxysteroid dehydrogenase, increases fetal glucocorticoid exposure and leads to offspring hyperglycemia, glucose intolerance, hyperinsulinemia, and insulin resistance (Nyirenda et al 1998, Cleasby et al 2003, O'Regan et al 2004. The similar effects of Dex and carbenoxolone suggest that fetal glucocorticoid exposure per se, rather than indirect effects of glucocorticoids on maternal physiology, is the primary stimulus for these programming outcomes.…”

Section: Introductionmentioning

confidence: 99%

Developmental programming of adult hyperinsulinemia, increased proinflammatory cytokine production, and altered skeletal muscle expression of SLC2A4 (GLUT4) and uncoupling protein 3

Wyrwoll¹,

Mark²,

Mori³

et al. 2008

Fetal glucocorticoid excess programs detrimental effects in the adult phenotype including hyperleptinemia and aberrant glycemic control. In this study, we determined the interactive effects of maternal dexamethasone (Dex) treatment and postnatal dietary u-3 (n-3) fatty acids on adult proinflammatory cytokine production and skeletal muscle expression of genes central to glucose handling and fatty acid metabolism. Dex acetate was administered to pregnant rats (0 . 75 mg/ml drinking water) from day 13 to term. Offspring of treated and control mothers were cross-fostered to mothers on either a standard (Std) or high n-3 (Hn3) diet, and remained on these diets postweaning. Adult offspring exposed to Dex in utero exhibited fasting hyperinsulinemia when raised on the Std diet but not when raised on the Hn3 diet. Dex also programmed increased plasma tumour necrosis factora and interleukin 1b (IL-1b), but the increase in IL-1b was also prevented by the Hn3 diet. In skeletal muscle, expression of insulin regulated Slc2a4 (formerly known as GLUT4) was elevated (up to 15-fold) after Dex in utero, and this resulted in elevated intracellular, but not membrane-associated, SLC2A4 protein. Fetal glucocorticoid excess also reduced adult skeletal muscle Ucp3 expression in all offspring, whereas skeletal muscle expression of both Ppard and Ppargc1a were increased in females but not males. In conclusion, our data show that fetal glucocorticoid excess programs adult hyperinsulinemia and increased proinflammatory cytokine production. Related changes in the skeletal muscle Slc2a4, Ucp3, and Ppard indicate that fetal glucocorticoid excess disturbs adult glucose/fatty acid transport and metabolism.