Intrahepatic mechanisms underlying the effect of metformin in decreasing basal glucose production in rats fed a high-fat diet.
The aim of this study was to understand by which intrahepatic mechanism metformin (Met) may inhibit basal hepatic glucose production (HGP) in type 2 diabetes. We studied rats that were fed for 6 weeks a high-fat (HF) diet, supplemented (HF-Met) or not (HF) with Met (50 mg x kg(-1) x day(-1)). Basal HGP, assessed by 3-[(3)H]glucose tracer dilution, was lower by 20% in HF-Met rats compared with HF-rats: 41.6 +/- 0.7 vs. 52 +/- 1.5 micromol x kg(-1) x min(-1) (means +/- SE, n = 5; P < 0.01). Glucose-6 phosphatase (Glc6Pase) activity, assayed in a liver lobe freeze-clamped in situ, was lower by 25% in HF-Met rats compared with HF-rats (7.9 +/- 0.4 vs. 10.3 +/- 0.9 micromol x min(-1) x g(-1) wet liver; P < 0.05). Glucose-6 phosphate and glycogen contents, e.g., 42 +/- 5 nmol/g and 3.9 +/- 2.4 mg/g, respectively, in HF-rats were dramatically increased by three to five times in HF-Met rats, e.g., 118 +/- 12 nmol/g and 19.6 +/- 4.6 mg/g (P < 0.05 and P < 0.01, respectively). Glucose-6 phosphate dehydrogenase activity was increased in HF-Met compared with HF rats (1.51 +/- 0.1 vs. 1.06 +/- 0.08 micromol x min(-1) x g(-1); P < 0.01). Intrahepatic lactate concentration tended to be lower in the Met-group (-30%; NS), whereas plasma lactate concentration was higher in HF-Met rats (1.59 +/- 0.15 mmol/l) than in HF rats (1.06 +/- 0.06 mmol/l; P < 0.05). We concluded that Met decreases HGP in insulin-resistant HF-fed rats mainly by an inhibition of hepatic Glc6Pase activity, promoting glycogen sparing. Additional mechanisms might involve the diversion of glucose-6 phosphate into the pentose phosphate pathway and an inhibition of hepatic lactate uptake.
Mithieux
Gilles
G
Institut National de la Santé et de la Recherche Médicale, Units 449, Faculté de Médecine Laennec, Lyon, France. Merck-Lipha, Lyon, France. mithieux@laennec.univ-lyon1.fr
Guignot
Ludovic
L
Bordet
Jean-Claude
JC
Wiernsperger
Nicolas
N
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D004041:Dietary Fats / Q000494:pharmacology*; D005943:Gluconeogenesis / Q000187:drug effects*; D005952:Glucose-6-Phosphatase / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007773:Lactates / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D010762:Phosphorylase a / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
D001786:Blood Glucose; D004041:Dietary Fats; D007004:Hypoglycemic Agents; D007773:Lactates; D008687:Metformin; D010762:Phosphorylase a; D005952:Glucose-6-Phosphatase