EFFECT OF METFORMIN ON GLUCOSE-METABOLISM IN THE SPLANCHNIC BED

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 glu cose and lactate were measured in the inferior vena cava (IVC), hepati c portal vein (HPV), hepatic vein (HV) and aorta (A) after intrajejuna l administration of metformin (50 and 250 mg kg-1) without and with gl ucose (2 g kg-1). 3 Metformin 250 mg kg-1 reduced the hyperglycaemic r esponse 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 lact ate concentrations in the glucose-loaded state: the highest concentrat ion (2.5 fold increase) was recorded in the HPV 60 min after administr ation of 250 mg kg-1 metformin, with a high lactate concentration pers isting in the HV at 120 min. Metformin 250 mg kg-1 also increased lact ate concentrations in the basal state, with highest concentrations (2 fold increase) in the HPV. 5 Two hours after intrajejunal administrati on of metformin, 50 mg kg-1, rings of tissue from the small intestine showed an average 22% decrease in glucose oxidation ([C-14]-glucose co nversion to (CO2)-C-14) and a 10% increase in lactate production. Sinc e glucose metabolism in the gut is predominantly anaerobic, metformin caused an overall 9.5% increase of intestinal glucose utilization. 6 M etformin, 10(-6) and 10(-4) mol l-1, did not significantly alter gluco se oxidation or lactate production by isolated hepatocytes, but a very high concentration of metformin (10(-2) mol l-1) increased lactate pr oduction by 60%. 7 The results support the view that metformin increas ed intestinal glucose utilization and lactate production by the intest ine. Under basal conditions there was net extraction of lactate by the liver but not after an enteral glucose load.