Developmental Changes in Ovine Myocardial Glucose Transporters and Insulin Signaling Following Hyperthermia-Induced Intrauterine Fetal Growth Restriction

Abstract

Developmental changes in ovine myocardial glucose transporters and insulin signaling following hyperthermia-induced intrauterine fetal growth restriction (IUGR) were the focus of our study. Our objective was to test the hypothesis that the fetal ovine myocardium adapts during an IUGR gestation by increasing glucose transporter protein expression, plasma membrane-bound glucose transporter protein concentrations, and insulin signal transduction protein concentrations. Growth measurements and whole heart tissue were obtained at 55 days gestational age (dGA), 90 dGA, and 135 dGA (term = 145 dGA) in fetuses from control (C) and hyperthermic (HT) pregnant sheep. Additionally, in 135 dGA animals, arterial blood was obtained and Doppler ultrasound was used to determine umbilical artery systolic (S) and diastolic (D) flow velocity waveform profiles to calculate pulsatility (S - D/mean) and resistance (S - D/S) indices. Myocardial Glut-1, Glut-4, insulin signal transduction proteins involved in Glut-4 translocation, and glycogen content were measured. Compared to age-matched controls, HT 90-dGA fetal body weights and HT 135-dGA fetal weights and gross heart weights were lower. Heart weights as a percent of body weights were similar between C and HT sheep at 135 dGA. HT 135-dGA animals had (i) lower fetal arterial plasma glucose and insulin concentrations, (ii) lower arterial blood oxygen content and higher plasma lactate concentrations, (iii) higher myocardial Glut-4 plasma membrane (PM) protein and insulin receptor beta protein (IRbeta ) concentrations, (iv) higher myocardial glycogen content, and (v) higher umbilical artery Doppler pulsatility and resistance indices. The HT ovine fetal myocardium adapts to reduced circulating glucose and insulin concentrations by increasing plasma membrane Glut-4 and IRbeta protein concentrations. The increased myocardial Glut-4 PM and IRbeta protein concentrations likely contribute to or increase the intracellular delivery of glucose and, together with the increased lactate concentrations, enhance glycogen synthesis, which allows for maintained myocardial growth commensurate with fetal body growth.

Intrauterine growth restriction decreases pulmonary alveolar and vessel growth and causes pulmonary artery endothelial cell dysfunction in vitro in fetal sheep

“…However, the severity depends on the model species used as well as the type, timing, and degree of insult. The model of IUGR used in this study is severe with effects documented as early as 60% gestation (6,7,12,22,48,83). Another sheep model of IUGR resulting from restriction of placentation sites (carunclectomy) is also characterized by abnormal alveolar Fig.…”

Chronic late-gestation hypoglycemia upregulates hepatic PEPCK associated with increased PGC1α mRNA and phosphorylated CREB in fetal sheep

“…Hepatic glycogen content was determined as previously described, and results are expressed as milligrams of glycogen per gram liver (wet weight) (2).…”

Adult Sequelae of Intrauterine Growth Restriction

“…12 A large number of manipulations have been used to induce offspring IUGR in animal models, including maternal calorie 13 and protein 14 restriction, fetal hypoxia from uterine artery ligation 15 and passive maternal smoking, 16 and maternal alcohol administration 17 and hyperthermia. 18 The association of IUGR with adult disease has been demonstrated in many animal species (for review see 19 ). In our laboratory, we have developed a rat model of IUGR caused by 50% maternal food restriction (MFR) during the second half of pregnancy.…”