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  • Title: Mechanism of fat-induced hepatic gluconeogenesis: effect of metformin.
    Author: Song S, Andrikopoulos S, Filippis C, Thorburn AW, Khan D, Proietto J.
    Journal: Am J Physiol Endocrinol Metab; 2001 Aug; 281(2):E275-82. PubMed ID: 11440903.
    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)H]glucose and [U-(14)C]alanine, 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 micromol x kg(-1) x min(-1), P < 0.05) and alanine gluconeogenesis (4.5 +/- 0.9 vs. 9.6 +/- 1.9 micromol x kg(-1) x min(-1), P < 0.05). Metformin reduced both endogenous glucose production (32.2 +/- 4.8 vs. 16.1 +/- 2.1 micromol x kg(-1) x min(-1), P < 0.05) and alanine gluconeogenesis (9.6 +/- 1.9 vs. 4.7 +/- 0.8 micromol x kg(-1) x 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.
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