The acute effect of metformin on glucose production in the conscious dog is primarily attributable to inhibition of glycogenolysis

Although metformin has been used worldwide to treat type 2 diabetes for sev eral decades, its mechanism of action on glucose homeostasis remains contro versial. To further assess the effect of metformin on glucose metabolism, 1 0 42-hour-fasted conscious dogs were studied in the absence ([Con] n = 5) a nd presence ([Met] n = 5) of a portal infusion of metformin (0.15 mg . kg(- 1) . min(-1)) over 300 minutes. Hepatic glucose production was measured by both arteriovenous-difference and tracer methods. All dogs were maintained on a pancreatic clamp and in a euglycemic state to ensure that any changes in glucose metabolism would result directly from the effects of metformin. The arterial metformin level was 21 +/- 3 mug/mL during the test period. Ne t hepatic glucose output (NHGO) decreased in Met dogs from 1.9 +/- 0.2 to 0 .7 +/- 0.1 mg . kg(-1) . min(-1)(P < .05). NHGO remained unchanged in Con d ogs (1.7 +/- 0.3 to 1.5 +/- 0.3 mg . kg(-1)min(-1)). Tracer-determined gluc ose production paralleled NHGO. The net hepatic glycogenolytic rate decreas ed from 1.0 +/- 0.2 to -0.3 +/- 0.2 mg . kg(-1) . min(-1)(P < .05) in Met d ogs, but remained unchanged in Con dogs (0.8 +/- 0.2 to 0.8 +/- 0.3 mg kg-l min-l). No significant change in gluconeogenic flux was found in either th e Met group (1.2 +/- 0.3 to 1.3 +/- 0.3 mg . kg(-1) . min(-1)) or the Con g roup (1.3 +/- 0.4 to 1.0 +/- 0.3 mg . kg(-1) . min(-1)). No significant cha nges were observed in glucose utilization or glucose clearance in either gr oup. In conclusion, in the normal fasted dog, (1) the primary acute effect of metformin on glucose metabolism was an inhibition of hepatic glucose pro duction and not a stimulation of glucose utilization; and (2) the inhibitio n of glucose production was attributable to a decrease in hepatic glycogeno lysis and not to an alteration in gluconeogenic flux. Copyright (C) 2000 by W.B. Saunders Company.