Article

Developmental changes in ovine myocardial glucose transporters and insulin signaling following hyperthermia-induced intrauterine fetal growth restriction.

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.
Experimental Biology and Medicine (Impact Factor: 2.23). 06/2006; 231(5):566-75.
Source: PubMed

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.

0 Bookmarks
 · 
62 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: GAPDH is a 146 kDa tetramer composed of four 30-40 kDa subunits. Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH) is a metabolic enzyme responsible for catalyzing one step in the glycolytic pathway, the reversible oxidative phosphorylation of glyceraldehyde 3-phosphate. Because GAPDH as a protein expressed in large amounts and which is required at all times for an important house keeping functions, levels of GAPDH mRNA are often used as standards in studies of mRNA expression. Increasingly, scientists are making use of specific antibodies to GAPDH as loading controls for western blotting experiments. Apart from a role in glycolysis, GAPDH may have other roles such as in the activation of transcription (1). GAPDH is reported to bind to a variety of other proteins, including the amyloid precursor protein, mutations in which cause some forms of Alzheimer's disease, and the polyglutamine tracts of Huntingtin, the protein product aberrant forms of which are causative of Huntington's disease (2,3). Associations with actin and tubulin have also be reported. The protein may also have a role in the regulation of apoptosis, and interestingly migrates from the cytoplasm into the nucleus when cells become apoptotic (4). Alternate Names: anti-GAPDH antibody, anti-glyceraldehyde-3-phosphate dehydrogenase antibody, anti-HGNC:4141 antibody, anti-G3PD antibody, anti-GAPD antibody, anti-MGC88685 antibody
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: The mechanisms by which maternal nutrient restriction (MNR) causes reduced fetal growth are poorly understood. We hypothesized that MNR inhibits placental mechanistic target of rapamycin (mTOR) and insulin/IGF-I signaling, down-regulates placental nutrient transporters, and decreases fetal amino acid levels. Pregnant baboons were fed control (ad libitum, n=11) or an MNR diet (70% of controls, n=11) from gestational day (GD) 30. Placenta and umbilical blood were collected at GD 165. Western blot was used to determine the phosphorylation of proteins in the mTOR, insulin/IGF-I, ERK1/2, and GSK-3 signaling pathways in placental homogenates and expression of glucose transporter 1 (GLUT-1), taurine transporter (TAUT), sodium-dependent neutral amino acid transporter (SNAT), and large neutral amino acid transporter (LAT) isoforms in syncytiotrophoblast microvillous membranes (MVMs). MNR reduced fetal weights by 13%, lowered fetal plasma concentrations of essential amino acids, and decreased the phosphorylation of placental S6K, S6 ribosomal protein, 4E-BP1, IRS-1, Akt, ERK-1/2, and GSK-3. MVM protein expression of GLUT-1, TAUT, SNAT-2 and LAT-1/2 was reduced in MNR. This is the first study in primates exploring placental responses to maternal undernutrition. Inhibition of placental mTOR and insulin/IGF-I signaling resulting in down-regulation of placental nutrient transporters may link maternal undernutrition to restricted fetal growth.-Kavitha, J. V., Rosario, F. J., Nijland, M. J., McDonald, T. J., Wu, G., Kanai, Y., Powell, T. L., Nathanielsz, P. W., Jansson, T. Down-regulation of placental mTOR, insulin/IGF-I signaling, and nutrient transporters in response to maternal nutrient restriction in the baboon.
    The FASEB Journal 12/2013; 28(3). DOI:10.1096/fj.13-242271 · 5.48 Impact Factor

Full-text (2 Sources)

Download
55 Downloads
Available from
May 16, 2014