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 β protein (IRβ) 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 IRβ protein concentrations. The increased myocardial Glut-4 PM and IRβ 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.
BarkerDJ. Early growth and cardiovascular disease. Arch Dis Child80: 305–307, 1999.
2.
BarkerDJ. Fetal origins of cardiovascular disease. Ann Med31: 3–6, 1999.
3.
BarkerDJ. In utero programming of cardiovascular disease. Theriogenology53: 555–574, 2000.
4.
GodfreyKM, BarkerDJ. Fetal nutrition and adult disease. Am J Clin Nutr71: 1344S–1352S, 2000.
5.
GopalakrishnanGS, GardnerDS, RhindSM, RaeMT, KyleCE, BrooksAN, WalkerRM, RamsayMM, KeislerDH, StephensonT, SymondsME. Programming of adult cardiovascular function after early maternal undernutrition in sheep. Am J Physiol Regul Integr Comp Physiol287: R12–R20, 2004.
6.
JaquetD, GaboriauA, CzernichowP, Levy-MarchalC. Insulin resistance early in adulthood in subjects born with intrauterine growth retardation. J Clin Endocrinol Metab85: 1401–1406, 2000.
7.
DesroisM, SidellRJ, GauguierD, KingLM, RaddaGK, ClarkeK. Initial steps of insulin signaling and glucose transport are defective in the type 2 diabetic rat heart. Cardiovasc Res61: 288–296, 2004.
8.
EckelJ, TillM, UphuesI. Cardiac insulin resistance is associated with an impaired recruitment of phosphatidylinositol 3-kinase to GLUT4 vesicles. Int J Obes Relat Metab Disord24(Suppl 2):S120–S121, 2000.
9.
ZorzanoA, SevillaL, CampsM, BeckerC, MeyerJ, KammermeierH, MunozP, GumaA, TestarX, PalacinM, BlasiJ, FischerY. Regulation of glucose transport, and glucose transporters expression and trafficking in the heart: studies in cardiac myocytes. Am J Cardiol80: 65A–76A, 1997.
10.
KesslerA, UphuesI, OuwensDM, TillM, EckelJ. Diversification of cardiac insulin signaling involves the p85 alpha/beta subunits of phosphatidylinositol 3-kinase. Am J Physiol Endocrinol Metab280: E65–E74, 2001.
11.
CheathamB, KahnCR. Insulin action and the insulin signaling network. Endocr Rev16: 117–142, 1995.
12.
BurgeringBM, CofferPJ. Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature376: 599–602, 1995.
de VrijerB, RegnaultTR, WilkeningRB, MeschiaG, BattagliaFC. Placental uptake and transport of ACP, a neutral nonmetabolizable amino acid, in an ovine model of fetal growth restriction. Am J Physiol Endocrinol Metab287: E1114–E1124, 2004.
15.
NicoliniU, HubinontC, SantolayaJ, FiskNM, RodeckCH. Effects of fetal intravenous glucose challenge in normal and growth retarded fetuses. Horm Metab Res22: 426–430, 1990.
16.
RegnaultTR, GalanHL, ParkerTA, AnthonyRV. Placental development in normal and compromised pregnancies—a review. Placenta23: S119–S129, 2002.
17.
ThureenPJ, TremblerKA, MeschiaG, MakowskiEL, WilkeningRB. Placental glucose transport in heat-induced fetal growth retardation. Am J Physiol263: R578–R585, 1992.
18.
AldorettaPW, CarverTD, HayWWJr.. Ovine uteroplacental glucose and oxygen metabolism in relation to chronic changes in maternal and fetal glucose concentrations. Placenta15: 753–764, 1994.
19.
AldorettaPW, HayWWJr.. Effect of glucose supply on ovine uteroplacental glucose metabolism. Am J Physiol277(4 Pt 2):R947–R958, 1999.
20.
CarverTD, HayWWJr.. Uteroplacental carbon substrate metabolism and O2 consumption after long-term hypoglycemia in pregnant sheep. Am J Physiol269(2 Pt 1): E299–E308, 1995.
21.
HalesCN, DesaiM, OzanneSE, CrowtherNJ. Fishing in the stream of diabetes: from measuring insulin to the control of fetal organogenesisBiochem Soc Trans24: 341–350, 1996.
22.
PhillipsDI, HirstS, ClarkPM, HalesCN, OsmondC. Fetal growth and insulin secretion in adult life. Diabetologia37: 592–596, 1994.
23.
EhrhardtRA, BellAW. Growth and metabolism of the ovine placenta during mid-gestation. Placenta16: 727–741, 1995.
24.
AlexanderGWD. Heat stress and development of the conceptus in the domestic sheep. J Agric Sci76: 53–72, 1971.
25.
BellAW, WilkeningRB, MeschiaG. Some aspects of placental function in chronically heat-stressed ewes. J Dev Physiol9: 17–29, 1987.
26.
RegnaultTR, OrbusRJ, BattagliaFC, WilkeningRB, AnthonyRV. Altered arterial concentrations of placental hormones during maximal placental growth in a model of placental insufficiency. J Endocrinol162: 433–442, 1999.
27.
MellorDJ, MathesonIC. Daily changes in the curved crown-rump length of individual sheep fetuses during the last 60 days of pregnancy and effects of different levels of maternal nutrition. Q J Exp Physiol Cogn Med Sci64: 119–131, 1979.
28.
GalanHL, HusseyMJ, ChungM, ChyuJK, HobbinsJC, BattagliaFC. Doppler velocimetry of growth-restricted fetuses in an ovine model of placental insufficiency. Am J Obstet Gynecol178: 451–456, 1998.
29.
GalanHL, AnthonyRV, RiganoS, ParkerTA, de VrijerB, FerrazziE, WilkeningRB, RegnaultTR. Fetal hypertension and abnormal Doppler velocimetry in an ovine model of intrauterine growth restriction. Am J Obstet Gynecol192: 272–279, 2005.
30.
RegnaultTR, OrbusRJ, de VrijerB, DavidsenML, GalanHL, WilkeningRB, AnthonyRV. Placental expression of VEGF, P1GF and their receptors in a model of placental insufficiency-intrauterine growth restriction (PI-IUGR). Placenta23: 132–144, 2002.
31.
KappesSM, WarrenWC, PrattSL, LiangR, AnthonyRV. Quantification and cellular localization of ovine placental lactogen messenger ribonucleic acid expression during mid- and late gestation. Endocrinology131: 2829–2838, 1992.
32.
GelardiNL, RapozaRE, RenzulliJF, CowettRM. Insulin resistance and glucose transporter expression during the euglycemic hyper-insulinemic clamp in the lamb. Am J Physiol277(6 Pt 1): E1142–E1149, 1999.
33.
LimesandSW, RegnaultTR, HayWWJr.. Characterization of glucose transporter 8 (GLUT8) in the ovine placenta of normal and growth restricted fetuses. Placenta25: 70–77, 2004.
34.
ThorensB, SarkarHK, KabackHR, LodishHF. Cloning and functional expression in bacteria of a novel glucose transporter present in liver, intestine, kidney, and beta-pancreatic islet cells. Cell55: 281–290, 1988.
35.
ChanTM, YoungKM, HutsonNJ, BrumleyFT, ExtonJH. Hepatic metabolism of genetically diabetic (db/db) mice. I. Carbohydrate metabolism. Am J Physiol229: 1702–1712, 1975.
36.
RossJC, FennesseyPV, WilkeningRB, BattagliaFC, MeschiaG. Placental transport and fetal utilization of leucine in a model of fetal growth retardation. Am J Physiol270(3 Pt 1): E491–E503, 1996.
37.
FischerY, ThomasJ, SevillaL, MunozP, BeckerC, HolmanG, KozkaIJ, PalacinM, TestarX, KammermeierH, ZorzanoA. Insulin-induced recruitment of glucose transporter 4 (GLUT4) and GLUT1 in isolated rat cardiac myocytes. Evidence of the existence of different intracellular GLUT4 vesicle populations. J Biol Chem272: 7085–7092, 1997.
38.
DevaskarSU, MuecklerMM. The mammalian glucose transporters. Pediatr Res31: 1–13, 1992.
39.
ZorzanoA, SevillaL, TomasE, GumaA, PalacinM, FischerY. GLUT4 trafficking in cardiac and skeletal muscle: isolation and characterization of distinct intracellular GLUT4-containing vesicle populations. Biochem Soc Trans25: 968–974, 1997.
40.
TianR, AbelED. Responses of GLUT4-deficient hearts to ischemia underscore the importance of glycolysis. Circulation103: 2961–2966, 2001.
41.
BelkeDD, LarsenTS, GibbsEM, SeversonDL. Glucose metabolism in perfused mouse hearts overexpressing human GLUT-4 glucose transporter. Am J Physiol Endocrinol Metab280: E420–E427, 2001.
42.
WallaceJM, BourkeDA, AitkenRP, LeitchN, HayWWJr.. Blood flows and nutrient uptakes in growth-restricted pregnancies induced by overnourishing adolescent sheep. Am J Physiol Regul Integr Comp Physiol282: R1027–R1036, 2002.
43.
WallaceJM, RegnaultTR, LimesandSW, HayWWJr., AnthonyRV. Investigating the causes of low birth weight in contrasting ovine paradigms. J Physiol565(Pt 1):19–26, 2005.
44.
OwensJA, FalconerJ, RobinsonJS. Glucose metabolism in pregnant sheep when placental growth is restricted. Am J Physiol257(2 Pt 2): R350–R357, 1989.
45.
WidnellCC, BaldwinSA, DaviesA, MartinS, PasternakCA. Cellular stress induces a redistribution of the glucose transporter. FASEB J4: 1634–1637, 1990.
46.
RussellRRIII, BergeronR, ShulmanGI, YoungLH. Translocation of myocardial GLUT-4 and increased glucose uptake through activation of AMPK by AICAR. Am J Physiol277: t-9, 1999.
47.
TillM, KolterT, EckelJ. Molecular mechanisms of contraction-induced translocation of GLUT4 in isolated cardiomyocytes. Am J Cardiol80: 85A–89A, 1997.
BehroozA, Ismail-BeigiF. Stimulation of glucose transport by hypoxia: signals and mechanisms. News Physiol Sci14: 105–110, 1999.
50.
RalpheJC, NauPN, MascioCE, SegarJL, ScholzTD. Regulation of myocardial glucose transporters GLUT1 and GLUT4 in chronically anemic fetal lambs. Pediatr Res58: 713–718, 2005.
51.
FowdenAL, LiJ, ForheadAJ. Glucocorticoids and the preparation for life after birth: are there long-term consequences of the life insurance?Proc Nutr Soc57: 113–122, 1998.
52.
OzanneSE, HalesCN. Early programming of glucose-insulin metabolism. Trends Endocrinol Metab13: 368–373, 2002.
CheungCY, JohnsonDD, ReyesV. Ontogeny of insulin-like growth factor-I and -II gene expression in ovine fetal heart. J Soc Gynecol Investig3: 309–315, 1996.
58.
DengXF, RokoshDG, SimpsonPC. Autonomous and growth factor-induced hypertrophy in cultured neonatal mouse cardiac myocytes. Comparison with rat. Circ Res87: 781–788, 2000.
59.
LemboG, HunterJJ, ChienKR. Signaling pathways for cardiac growth and hypertrophy. Recent advances and prospects for growth factor therapy. Ann NY Acad Sci752: 115–127, 1995.
60.
PellieuxC, SauthierT, AubertJF, BrunnerHR, PedrazziniT. Angiotensin II-induced cardiac hypertrophy is associated with different mitogen-activated protein kinase activation in normotensive and hypertensive mice. J Hypertens18: 1307–1317, 2000.
61.
van KesterenCA, van HeugtenHA, LamersJM, SaxenaPR, SchalekampMA, DanserAH. Angiotensin II-mediated growth and antigrowth effects in cultured neonatal rat cardiac myocytes and fibroblasts. J Mol Cell Cardiol29: 2147–2157, 1997.
62.
GluckmanPD, PinalCS. Regulation of fetal growth by the somatotrophic axis. J Nutr133(5 Suppl 2): 1741S–1746S, 2003.
63.
HoltRI. Fetal programming of the growth hormone-insulin-like growth factor axis. Trends Endocrinol Metab13: 392–397, 2002.
64.
ShioiT, McMullenJR, KangPM, DouglasPS, ObataT, FrankeTF, CantleyLC, IzumoS. Akt/protein kinase B promotes organ growth in transgenic mice. Mol Cell Biol22: 2799–2809, 2002.
65.
ShiojimaI, YefremashviliM, LuoZ, KureishiY, TakahashiA, TaoJ, RosenzweigA, KahnCR, AbelED, WalshK. Akt signaling mediates postnatal heart growth in response to insulin and nutritional status. J Biol Chem277: 37670–37677, 2002.
66.
DawesG, MottJ, ShelleyH. The importance of cardiac glycogen for the maintenance of life in foetal lambs and newborn animals during anoxia. J Physiol146: 516–538, 1959.
67.
ShelleyH. Glycogen reserves and their changes at birth. Br Med Bull17: 37–49, 1961.
68.
BarteldsB, KnoesterH, Beaufort-KrolGC, SmidGB, TakensJ, ZijlstraWG, HeymansHS, KuipersJr.. Myocardial lactate metabolism in fetal and newborn lambs. Circulation99: 1892–1897, 1999.
69.
GoodwinGW, AhmadF, DoenstT, TaegtmeyerH. Energy provision from glycogen, glucose, and fatty acids on adrenergic stimulation of isolated working rat hearts. Am J Physiol274: t-47, 1998.
70.
SchneiderCA, NguyenVT, TaegtmeyerH. Feeding and fasting determine postischemic glucose utilization in isolated working rat hearts. Am J Physiol260: t-8, 1991.
