Intrahepatic Mechanisms Underlying the Effect of Metformin in Decreasing Basal Glucose Production in Rats Fed a High-Fat Diet

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

Metformin Prevents the Development of Acute Lipid-Induced Insulin Resistance in the Rat Through Altered Hepatic Signaling Mechanisms

“…Lipid infusion significantly raised both plasma lipids and liver TAGs, but previous metformin administration had no effect on these parameters (Table 2). There was a trend for metformin to raise plasma lactate (P ϭ 0.082), in the absence of any effect of lipid infusion (Table 2), consistent with previously published findings in highfat-fed rats (11). Basal liver signaling.…”

“…Hyperlipidemia is an important component of this syndrome; in particular, elevation of circulating free fatty acid (FFA) concentrations has been associated with insulin resistance in many clinical studies (2,3). Furthermore, artificial elevation of systemic FFA in normal humans or animals by means of triacylglycerol-heparin infusion (4 -10) or increasing dietary fat content (11,12) results in insulin resistance, usually involving a substantial impairment in the ability of insulin to suppress hepatic glucose output (HGO) (4,7,9). Several groups have identified changes in expression or activation of molecules linked to the insulinsignaling cascade as a result of increased supply of FFAs to the liver.…”

Metformin improves hepatic IRS2/PI3K/Akt signaling in insulin-resistant rats of NASH and cirrhosis

“…Available data also demonstrated that metformin impaired glycogen synthesis in isolated rat hepatocytes (Otto et al 2003). However, increased hepatic glycogen content in response to metformin was detected in high-fat-fed insulin-resistant rat model and in hepatoma cells (Purrello et al 1988, Mithieux et al 2002. These conflicting results may be attributable to the differences in research models and methodology.…”

“…Increased hepatic glycogen content in response to metformin was detected in high-fat-fed, insulin-resistant rat model and in hepatoma cells. Also it has been reported that metformin impaired glycogen synthesis in isolated rat hepatocytes (Purrello et al 1988, Mithieux et al 2002, Otto et al 2003. No in vivo data on the influence of metformin on IRS2/PI3K/Akt signaling pathway is available.…”

Targeted deletion of liver glucose-6 phosphatase mimics glycogen storage disease type 1a including development of multiple adenomas

“…Plasma glucose, triglycerides, total cholesterol, uric acid and lactate concentrations were determined with Biomérieux colorimetric kits. Glucose-6 phosphate and glycogen determinations were carried out on frozen tissue homogenates as previously described [26,27].…”