No abstract

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 ⅐ kg ؊1 ⅐ day ؊1 ). Basal HGP, assessed by 3-[ 3 H]glucose tracer dilution, was lower by 20% in HFMet rats compared with HF-rats: 41.6 ؎ 0.7 vs. 52 ؎ 1.5 mol ⅐ kg ؊1 ⅐ 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 mol ⅐ min ؊1 ⅐ 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 mol ⅐ min ؊1 ⅐ 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. Diabetes 51:139 -143, 2002