Abstract High-fat feeding has been shown to cause hepatic insulin resistance. The aims of this study were to investigate the biochemical steps responsible for enhanced gluconeogenesis as a result of increased dietary fat intake and the site or sites at which the antihyperglycemic agent metformin acts to inhibit this process. Male Hooded Wistar rats were fed either a standard chow diet (5% fat by weight) or a high-fat diet (60% fat by weight) for 14 days with or without metformin. Total endogenous glucose production and gluconeogenesis were determined using 6- 3 Hglucose and U- 14 Calanine, respectively. Gluconeogenic enzyme activity and, where appropriate, protein and mRNA levels were measured in liver tissues. The high-fat diet increased endogenous glucose production (21.9 ± 4.4 vs. 32.2 ± 4.8 μmol · kg −1 · min −1 , P < 0.05) and alanine gluconeogenesis (4.5 ± 0.9 vs. 9.6 ± 1.9 μmol · kg −1 · min −1 , P < 0.05). Metformin reduced both endogenous glucose production (32.2 ± 4.8 vs. 16.1 ± 2.1 μmol · kg −1 · min −1 , P < 0.05) and alanine gluconeogenesis (9.6 ± 1.9 vs. 4.7 ± 0.8 μmol · kg −1 · min −1 , P < 0.05) after high-fat feeding. These changes were reflected in liver fructose-1,6-bisphosphatase protein levels (4.5 ± 0.9 vs. 9.6 ± 1.9 arbitrary units, P < 0.05 chow vs. high-fat feeding; 9.5 ± 1.9 vs. 4.7 ± 0.8 arbitrary units, P < 0.05 high fat fed in the absence vs. presence of metformin) but not in changes to the activity of other gluconeogenic enzymes. There was a significant positive correlation between alanine gluconeogenesis and fructose-1,6-bisphosphatase protein levels ( r = 0.56, P < 0.05). Therefore, excess supply of dietary fat stimulates alanine gluconeogenesis via an increase in fructose-1,6-bisphosphatase protein levels. Metformin predominantly inhibits alanine gluconeogenesis by preventing the fat-induced changes in fructose-1,6-bisphosphatase levels. endogenous glucose production fructose-1,6-bisphosphatase fat feeding hepatic insulin resistance Footnotes This study was supported by a grant from the Diabetes Australia Research Trust Fund. Address for reprint requests and other correspondence: S. Andrikopoulos, Univ. of Melbourne, Dept. of Medicine, Royal Melbourne Hospital, Parkville, Victoria 3050, Australia (E-mail: email@example.com ). The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “ advertisement ” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Copyright © 2001 the American Physiological Society
AJP - Endocrinology and Metabolism – The American Physiological Society
Published: Aug 1, 2001
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