Effect of metformin on glucose metabolism in the splanchnic bed

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Abstract
1 Use of the antihyperglycaemic agent, metformin, is often associated with a small rise in circulating lactate. This study investigates the source of the lactate and examines the effect of metformin on glucose metabolism by the intestine and liver of rats. 2 Changes in plasma glucose and lactate were measured in the inferior vena cava (IVC), hepatic portal vein (HPV), hepatic vein (HV) and aorta (A) after intrajejunal administration of metformin (50 and 250 mg kg−1) without and with glucose (2 g kg−1). 3 Metformin 250 mg kg−1 reduced the hyperglycaemic response to a glucose challenge, associated with a greater reduction of glucose concentrations in the HPV (average decrease of 33% at 60 and 120 min) than at other sites. 4 Both doses of metformin increased lactate concentrations in the glucose-loaded state: the highest concentration (2.5 fold increase) was recorded in the HPV 60 min after administration of 250 mg kg−1 metformin, with a high lactate concentration persisting in the HV at 120 min. Metformin 250 mg kg−1 also increased lactate concentrations in the basal state, with highest concentrations (2 fold increase) in the HPV. 5 Two hours after intrajejunal administration of metformin, 50 mg kg−1, rings of tissue from the small intestine showed an average 22% decrease in glucose oxidation ([14C]-glucose conversion to 14CO2) and a 10% increase in lactate production. Since glucose metabolism in the gut is predominantly anaerobic, metformin caused an overall 9.5% increase of intestinal glucose utilization. 6 Metformin, 10−6 and 10−4 mol l−1, did not significantly alter glucose oxidation or lactate production by isolated hepatocytes, but a very high concentration of metformin (10−2 mol l−1) increased lactate production by 60%. 7 The results support the view that metformin increased intestinal glucose utilization and lactate production by the intestine. Under basal conditions there was net extraction of lactate by the liver but not after an enteral glucose load.