Mechanism of fat-induced hepatic gluconeogenesis: effect of metformin

High-fat feeding has been shown to cause hepatic insulin resistance. The ai ms of this study were to investigate the biochemical steps responsible for enhanced gluconeogenesis as a result of increased dietary fat intake and th e site or sites at which the antihyperglycemic agent metformin acts to inhi bit this process. Male Hooded Wistar rats were fed either a standard chow d iet (5% fat by weight) or a high-fat diet (60% fat by weight) for 14 days w ith or without metformin. Total endogenous glucose production and gluconeog enesis were determined using [6-H-3] glucose and [U-C-14] alanine, respecti vely. Gluconeogenic enzyme activity and, where appropriate, protein and mRN A levels were measured in liver tissues. The high-fat diet increased endoge nous glucose production (21.9 +/- 4.4 vs. 32.2 +/- 4.8 mu mol.kg(-1). min(- 1), P< 0.05) and alanine gluconeogenesis (4.5 +/- 0.9 vs. 9.6 +/- 1.9 <mu>m ol.kg(-1).min(-1), P< 0.05). Metformin reduced both endogenous glucose prod uction (32.2 +/- 4.8 vs. 16.1 +/- 2.1 <mu>mol.kg(-1).min(-1), P< 0.05) and alanine gluconeogenesis (9.6 +/- 1.9 vs. 4.7 +/- 0.8 <mu>mol.kg(-1).min(-1) , P< 0.05) after high-fat feeding. These changes were reflected in liver fr uctose-1,6-bisphosphatase protein levels (4.5 +/- 0.9 vs. 9.6 +/- 1.9 arbit rary 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 metfor min) but not in changes to the activity of other gluconeogenic enzymes. The re was a significant positive correlation between alanine gluconeogenesis a nd fructose-1,6-bisphosphatase protein levels (r = 0.56, P< 0.05). Therefor e, excess supply of dietary fat stimulates alanine gluconeogenesis via an i ncrease in fructose-1,6-bisphosphatase protein levels. Metformin predominan tly inhibits alanine gluconeogenesis by preventing the fat-induced changes in fructose-1,6-bisphosphatase levels.