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: 2.17). 06/2006; 231(5):566-75.
Source: PubMed


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.

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Available from: James Barry, Dec 14, 2013
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    • "An altered function of the glucose–insulin axis (Gardner et al. 2005, Husted et al. 2007) appears to be one of the key underlying factors for this adverse association between early life exposures and health outcomes later in life. IUGR has been proposed to induce foetal adaptations, such as asymmetric growth and alterations in peripheral insulin sensitivity favouring the growth of some organs such as the brain at the expense of others, for example the pancreas (Petrik et al. 1998, Kind et al. 2003, Limesand et al. 2005a, 2005b, Barry et al. 2006, Germani et al. 2008), which should increase the chance of survival in a nutrientdeprived environment after birth. However, exposure in post-natal life to a mismatching diet, high in energy and fat, may greatly enhance the risk of developing type 2 diabetes as shown in rodent studies (Vickers et al. 2000, Rueda-Clausen et al. 2011). "
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    ABSTRACT: Aim: Exposure to adverse intra-uterine conditions can predispose for metabolic disorders later in life. By using a sheep model, we studied (i) how programming of glucose-insulin homoeostasis during late gestation is manifested later in life depending on the early post-natal dietary exposure and (ii) whether dietary alteration in obese individuals can prevent adverse outcomes of early life programming. Methods: During late gestation, twin-pregnant sheep were fed 100% (NORM) or 50% (LOW) of energy and protein requirements. After birth, offspring were exposed to a moderate (CONV) or high-carbohydrate-high-fat (HCHF) diet until around puberty. Offspring remaining thereafter (exclusively females) were fed a moderate diet until young adulthood. Results: LOW lambs had increased insulin secretory responses during intravenous glucose tolerance tests indicative of reduced insulin sensitivity. HCHF lambs were hypertriglyceridaemic, 75% had mild pancreatic collagen infiltration, and their acute insulin secretory response and insulin clearance during intravenous glucose and insulin tolerance tests, respectively, were reduced. However, NORM-HCHF in contrast to LOW-HCHF lambs had normal glucose tolerance, indicating that later health outcomes are highly influenced by pre-natal nutrition. Dietary alteration normalized glucose-insulin homoeostasis in adult HCHF females, whereas late-gestation undernutrition (LOW) permanently depressed insulin sensitivity. Conclusion: Maintenance of glucose tolerance in sheep exposed to pre-natal undernutrition relied on pancreatic hypersecretion of insulin to compensate for reduced insulin sensitivity. A mismatching high-fat diet in early post-natal life interfered with this pancreatic hypersecretion resulting in reduced glucose tolerance. Early post-natal, but not late pre-natal, impacts on glucose-insulin homoeostasis could be reversed by dietary correction later in life.
    Full-text · Article · Mar 2013 · Acta Physiologica
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    • "In addition to being observed in PI-IUGR fetuses [31], elevated plasma lactate concentrations have also been observed during acute catecholamine and adenosine infusion into uncompromised ovine fetuses [52, 74], indicating a regulatory role for these compounds. During PI, lactate becomes a crucial substrate for glycogen synthesis in cardiac tissue [75] and, in a process known as the Cori cycle, serves as a precursor for hepatic gluconeogenesis, along with amino acids and other substrates (Figure 5). In normal, well-nourished fetuses, gluconeogenesis does not develop until the final days of gestation in anticipation of postnatal life [76–78]. "
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    ABSTRACT: Placental insufficiency (PI) prevents adequate delivery of nutrients to the developing fetus and creates a chronic state of hypoxemia and hypoglycemia. In response, the malnourished fetus develops a series of stress hormone-mediated metabolic adaptations to preserve glucose for vital tissues at the expense of somatic growth. Catecholamines suppress insulin secretion to promote glucose sparing for insulin-independent tissues (brain, nerves) over insulin-dependent tissues (skeletal muscle, liver, and adipose). Likewise, premature induction of hepatic gluconeogenesis helps maintain fetal glucose and appears to be stimulated by both norepinephrine and glucagon. Reduced glucose oxidation rate in PI fetuses creates a surplus of glycolysis-derived lactate that serves as substrate for hepatic gluconeogenesis. These adrenergically influenced adaptive responses promote in utero survival but also cause asymmetric intrauterine growth restriction and small-for-gestational-age infants that are at greater risk for serious metabolic disorders throughout postnatal life, including obesity and type II diabetes.
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