Hypothyroidism in utero\textit{in utero} stimulates pancreatic beta cell proliferation and hyperinsulinaemia in the ovine fetus during late gestation

Development of pancreatic beta cell mass before birth is essential for normal growth of the fetus and for long-term control of carbohydrate metabolism in postnatal life. Thyroid hormones are also important regulators of fetal growth, and the present study tested the hypotheses that thyroid hormones promote beta cell proliferation in the fetal ovine pancreatic islets, and that growth retardation in hypothyroid fetal sheep is associated with reductions in pancreatic beta cell mass and circulating insulin concentration $\textit{in utero}$. Organ growth and pancreatic islet cell proliferation and mass were examined in sheep fetuses following removal of the thyroid gland in utero. The effects of triiodothyronine (T$_{3}$), insulin and leptin on beta cell proliferation rates were determined in isolated fetal ovine pancreatic islets $\textit{in vitro}$. Hypothyroidism in the sheep fetus resulted in an asymmetric pattern of organ growth, pancreatic beta cell hyperplasia, and elevated plasma insulin and leptin concentrations. In pancreatic islets isolated from intact fetal sheep, beta cell proliferation $\textit{in vitro}$ was reduced by T$_{3}$ in a dose-dependent manner and increased by insulin at high concentrations only. Leptin induced a bimodal response whereby beta cell proliferation was suppressed at the lowest, and increased at the highest, concentrations. Therefore, proliferation of beta cells isolated from the ovine fetal pancreas is sensitive to physiological concentrations of T$_{3}$, insulin and leptin. Alterations in these hormones may be responsible for the increased beta cell proliferation and mass observed in the hypothyroid sheep fetus and may have consequences for pancreatic function in later life.The project was funded in part by the Biotechnology and Biological Sciences Research Council (BB/HO1697X/1). S.E.H. was supported by a Nigel Groome PhD Studentship at Oxford Brookes University. S.E.H. was awarded a practical skills grant from the Society for Endocrinology and a travel grant from the Physiological Society to fund work at the University of Arizona

Hypoglycemia and the Origin of Hypoxia-Induced Reduction in Human Fetal Growth

The most well known reproductive consequence of residence at high altitude (HA >2700 m) is reduction in fetal growth. Reduced fetoplacental oxygenation is an underlying cause of pregnancy pathologies, including intrauterine growth restriction and preeclampsia, which are more common at HA. Therefore, altitude is a natural experimental model to study the etiology of pregnancy pathophysiologies. We have shown that the proximate cause of decreased fetal growth is not reduced oxygen availability, delivery, or consumption. We therefore asked whether glucose, the primary substrate for fetal growth, might be decreased and/or whether altered fetoplacental glucose metabolism might account for reduced fetal growth at HA.Doppler and ultrasound were used to measure maternal uterine and fetal umbilical blood flows in 69 and 58 residents of 400 vs 3600 m. Arterial and venous blood samples from mother and fetus were collected at elective cesarean delivery and analyzed for glucose, lactate and insulin. Maternal delivery and fetal uptakes for oxygen and glucose were calculated.The maternal arterial – venous glucose concentration difference was greater at HA. However, umbilical venous and arterial glucose concentrations were markedly decreased, resulting in lower glucose delivery at 3600 m. Fetal glucose consumption was reduced by >28%, but strongly correlated with glucose delivery, highlighting the relevance of glucose concentration to fetal uptake. At altitude, fetal lactate levels were increased, insulin concentrations decreased, and the expression of GLUT1 glucose transporter protein in the placental basal membrane was reduced.Our results support that preferential anaerobic consumption of glucose by the placenta at high altitude spares oxygen for fetal use, but limits glucose availability for fetal growth. Thus reduced fetal growth at high altitude is associated with fetal hypoglycemia, hypoinsulinemia and a trend towards lactacidemia. Our data support that placentally-mediated reduction in glucose transport is an initiating factor for reduced fetal growth under conditions of chronic hypoxemia

Neonatal exendin-4 reduces growth, fat deposition and glucose tolerance during treatment in the intrauterine growth-restricted lamb

BACKGROUND IUGR increases the risk of type 2 diabetes mellitus (T2DM) in later life, due to reduced insulin sensitivity and impaired adaptation of insulin secretion. In IUGR rats, development of T2DM can be prevented by neonatal administration of the GLP-1 analogue exendin-4. We therefore investigated effects of neonatal exendin-4 administration on insulin action and β-cell mass and function in the IUGR neonate in the sheep, a species with a more developed pancreas at birth. METHODS Twin IUGR lambs were injected s.c. daily with vehicle (IUGR+Veh, n = 8) or exendin-4 (1 nmol.kg-1, IUGR+Ex-4, n = 8), and singleton control lambs were injected with vehicle (CON, n = 7), from d 1 to 16 of age. Glucose-stimulated insulin secretion and insulin sensitivity were measured in vivo during treatment (d 12–14). Body composition, β-cell mass and in vitro insulin secretion of isolated pancreatic islets were measured at d 16. PRINCIPLE FINDINGS IUGR+Veh did not alter in vivo insulin secretion or insulin sensitivity or β-cell mass, but increased glucose-stimulated insulin secretion in vitro. Exendin-4 treatment of the IUGR lamb impaired glucose tolerance in vivo, reflecting reduced insulin sensitivity, and normalised glucose-stimulated insulin secretion in vitro. Exendin-4 also reduced neonatal growth and visceral fat accumulation in IUGR lambs, known risk factors for later T2DM. CONCLUSIONS Neonatal exendin-4 induces changes in IUGR lambs that might improve later insulin action. Whether these effects of exendin-4 lead to improved insulin action in adult life after IUGR in the sheep, as in the PR rat, requires further investigation.Kathryn L. Gatford, Siti A. Sulaiman, Saidatul N. B. Mohammad, Miles J. De Blasio, M. Lyn Harland, Rebecca A. Simmons, Julie A. Owen

Effects of ovariectomy and anabolic steroid implantation on the somatotrophic axis in feedlot heifers

A 2 x 2 factorial experimental design was used to evaluate effects of ovariectomy and implantation (200 mg trenbolone acetate and 28 mg estradiol benzoate; Synovex-Plus) on the performance, serum urea nitrogen, serum insulin like growth factor -1 (IGF-1), and mRNA expression of hepatic IGF-1, growth hormone (GH) receptor and estrogen receptor-α as well as pituitary GH, estrogen receptor-α and GH releasing hormone receptor in feedlot heifers. Thirty-two British x Continental heifers were randomly assigned to either an ovariectomized (OVX) or intact group and then to either a control group or a Synovex-Plus implant group. Heifers were fed a 900 g/kg concentrate steam-flaked maize based diet for 42 d. Liver biopsies were taken before OVX for baseline expression of IGF-1, GH receptor and hepatic estrogen receptor-α, which did not differ between treatment groups. Blood and body weight (BW) were taken on d 0, 28, and 42 and one heifer/pen was slaughtered on d 42 for liver and pituitary tissue samples. Initial and final BW did not differ due to OVX or implant. No gender x treatment interaction was observed for average daily gain (ADG) or final BW. Neither OVX nor implant affected ADG for the final 14 d of the feeding period, but 28 and 42 d ADG were greater in implanted than in control heifers. No 2- or 3-way interactions with day were observed for serum urea nitrogen. Serum urea nitrogen was greater in control heifers than in implanted heifers, but gender had no effect. Both implant and OVX increased serum IGF-1 and a gender x treatment interaction was observed. Neither gender nor implant treatment affected hepatic estrogen receptor-α, hepatic IGF-1, hepatic GH receptor, GH releasing hormone receptor, GH, or pituitary estrogen receptor-α. Data indicate that implanting heifers with Synovex-plus increases serum IGF-1, but the reason for this increase cannot be explained by mRNA expression of key somatotropic genes in the present study.A 2 x 2 factorial experimental design was used to evaluate effects of ovariectomy and implantation (200 mg trenbolone acetate and 28 mg estradiol benzoate; Synovex-Plus) on the performance, serum urea nitrogen, serum insulin like growth factor -1 (IGF-1), and mRNA expression of hepatic IGF-1, growth hormone (GH) receptor and estrogen receptor-α as well as pituitary GH, estrogen receptor-α and GH releasing hormone receptor in feedlot heifers. Thirty-two British x Continental heifers were randomly assigned to either an ovariectomized (OVX) or intact group and then to either a control group or a Synovex-Plus implant group. Heifers were fed a 900 g/kg concentrate steam-flaked maize based diet for 42 d. Liver biopsies were taken before OVX for baseline expression of IGF-1, GH receptor and hepatic estrogen receptor-α, which did not differ between treatment groups. Blood and body weight (BW) were taken on d 0, 28, and 42 and one heifer/pen was slaughtered on d 42 for liver and pituitary tissue samples. Initial and final BW did not differ due to OVX or implant. No gender x treatment interaction was observed for average daily gain (ADG) or final BW. Neither OVX nor implant affected ADG for the final 14 d of the feeding period, but 28 and 42 d ADG were greater in implanted than in control heifers. No 2- or 3-way interactions with day were observed for serum urea nitrogen. Serum urea nitrogen was greater in control heifers than in implanted heifers, but gender had no effect. Both implant and OVX increased serum IGF-1 and a gender x treatment interaction was observed. Neither gender nor implant treatment affected hepatic estrogen receptor-α, hepatic IGF-1, hepatic GH receptor, GH releasing hormone receptor, GH, or pituitary estrogen receptor-α. Data indicate that implanting heifers with Synovex-plus increases serum IGF-1, but the reason for this increase cannot be explained by mRNA expression of key somatotropic genes in the present study. Keywords: Synovex-plus, mRNA, genderSouth African Journal of Animal Science Vol. 38 (3) 2008: pp. 207-21