title: 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.
authors.affiliation: Department of Pediatrics, Section of Neonatology, University of Colorado School of Medicine, The Children's Hospital, 1056 East 19th Avenue, Box B070, Denver, CO 80218, USA. shara.knight@uchsc.edu
authors.forename: James S
authors.initials: JS
authors.lastname: Barry
authors.forename: Meredith L
authors.initials: ML
authors.lastname: Davidsen
authors.forename: Sean W
authors.initials: SW
authors.lastname: Limesand
authors.forename: Henry L
authors.initials: HL
authors.lastname: Galan
authors.forename: Jacob E
authors.initials: JE
authors.lastname: Friedman
authors.forename: Timothy R H
authors.initials: TR
authors.lastname: Regnault
authors.forename: William W
authors.initials: WW
authors.lastname: Hay
mesh_terms: D000818:Animals; D001835:Body Weight; D005260:Female; D005317:Fetal Growth Retardation; D005334:Fever; D005865:Gestational Age; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000235:genetics / Q000378:metabolism*; D006003:Glycogen / Q000032:analysis; D007328:Insulin / Q000378:metabolism*; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D009929:Organ Size; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D011247:Pregnancy; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D034561:Sheep, Domestic; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051272:Glucose Transporter Type 1; D051275:Glucose Transporter Type 4; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D006003:Glycogen; D019869:Phosphatidylinositol 3-Kinases; D011972:Receptor, Insulin; D051057:Proto-Oncogene Proteins c-akt; D005947:Glucose