HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (17) Citing Articles via Google Scholar Google Scholar Articles by Peterside, I. E. Articles by Simmons, R. A. Search for Related Content PubMed PubMed Citation Articles by Peterside, I. E. Articles by Simmons, R. A.

Impaired oxidative phosphorylation in hepatic mitochondria in growth-retarded rats

Department of Pediatrics, Children's Hospital and University of Pennsylvania, Philadelphia, Pennsylvania 19104

Submitted 7 October 2002 ; accepted in final form 7 August 2003

Intrauterine growth retardation (IUGR) has been linked to the development of type 2 diabetes in adulthood. We have developed an IUGR model in the rat whereby the animals develop diabetes between 3 and 6 mo of age that is associated with insulin resistance. Alterations in hepatic glucose metabolism are known to contribute to the hyperglycemia of diabetes; however, the mechanisms underlying this phenomenon have not been fully explained. To address this issue, intact liver mitochondria were isolated from IUGR and control offspring at different ages to examine the nature and time course of possible defects in oxidative metabolism. Phosphoenolpyruvate carboxykinase (PEPCK) expression was also measured in livers of IUGR and control offspring. Rates of ADP-stimulated (state 3) oxygen consumption were increased for succinate in the fetus and for -ketoglutarate and glutamate at day 1, reflecting possible compensatory metabolic adaptations to acute hypoxia and acidosis in IUGR rats. By day 14, oxidation of glutamate and -ketoglutarate had returned to normal, and by day 28, oxidation rates of pyruvate, glutamate, succinate, and -ketoglutarate were significantly lower than those of controls. Rotenone-sensitive NADH-O₂ oxidoreductase activity was similar in control and IUGR mitochondria at all ages, showing that the defect responsible for decreased pyruvate, glutamate, and -ketoglutarate oxidation in IUGR liver precedes the electron transport chain and involves pyruvate and -ketoglutarate dehydrogenases. Increased levels of manganese superoxide dismutase suggest that an antioxidant response has been mounted, and hydroxynonenal (HNE) modification of pyruvate dehydrogenase E2-(catalytic) and E3-binding protein subunits suggests that HNE-induced inactivation of this key enzyme may play a role in the mechanism of injury. The level of PEPCK mRNA was increased 250% in day 28 IUGR liver, indicating altered gene expression of the gluconeogenic enzyme that precedes overt hyperglycemia. These results indicate that uteroplacental insufficiency impairs mitochondrial oxidative phosphorylation in the liver and that this derangement predisposes the IUGR rat to increased hepatic glucose production by suppressing pyruvate oxidation and increasing gluconeogenesis.

liver; growth retardation; diabetes; gluconeogenesis

This article has been cited by other articles:

				P. J. Rozance, S. W. Limesand, J. S. Barry, L. D. Brown, S. R. Thorn, D. LoTurco, T. R. H. Regnault, J. E. Friedman, and W. W. Hay Jr. Chronic late-gestation hypoglycemia upregulates hepatic PEPCK associated with increased PGC1{alpha} mRNA and phosphorylated CREB in fetal sheep Am J Physiol Endocrinol Metab, February 1, 2008; 294(2): E365 - E370. [Abstract] [Full Text] [PDF]

				J. Wang, L. Chen, D. Li, Y. Yin, X. Wang, P. Li, L. J. Dangott, W. Hu, and G. Wu Intrauterine Growth Restriction Affects the Proteomes of the Small Intestine, Liver, and Skeletal Muscle in Newborn Pigs J. Nutr., January 1, 2008; 138(1): 60 - 66. [Abstract] [Full Text] [PDF]

				K. Dembele, X.-H. Yao, L. Chen, and B. L. G. Nyomba Intrauterine ethanol exposure results in hypothalamic oxidative stress and neuroendocrine alterations in adult rat offspring Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2006; 291(3): R796 - R802. [Abstract] [Full Text] [PDF]

				X.-H. Yao, L. Chen, and B. L. G. Nyomba Adult rats prenatally exposed to ethanol have increased gluconeogenesis and impaired insulin response of hepatic gluconeogenic genes J Appl Physiol, February 1, 2006; 100(2): 642 - 648. [Abstract] [Full Text] [PDF]

				M. Thamotharan, B.-C. Shin, D. T. Suddirikku, S. Thamotharan, M. Garg, and S. U. Devaskar GLUT4 expression and subcellular localization in the intrauterine growth-restricted adult rat female offspring Am J Physiol Endocrinol Metab, May 1, 2005; 288(5): E935 - E947. [Abstract] [Full Text] [PDF]