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

Abstract

Although metformin has been used worldwide to treat type 2 diabetes for several decades, its mechanism of action on glucose homeostasis remains controversial. To further assess the effect of metformin on glucose metabolism, 10 42-hour-fasted conscious dogs were studied in the absence ([Con] n = 5) and 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 μg/mL during the test period. Net 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 dogs (1.7 ± 0.3 to 1.5 ± 0.3 mg · kg −1min −1). Tracer-determined glucose production paralleled NHGO. The net hepatic glycogenolytic rate decreased from 1.0 ± 0.2 to −0.3 ± 0.2 mg · kg −1 · min −1 ( P < .05) in Met dogs, but remained unchanged in Con dogs (0.8 ± 0.2 to 0.8 ± 0.3 mg · kg −1 · min −1). No significant change in gluconeogenic flux was found in either the Met group (1.2 ± 0.3 to 1.3 ± 0.3 mg · kg −1 · min −1) or the Con group (1.3 ± 0.4 to 1.0 ± 0.3 mg · kg −1 · min −1). No significant changes were observed in glucose utilization or glucose clearance in either group. In conclusion, in the normal fasted dog, (1) the primary acute effect of metformin on glucose metabolism was an inhibition of hepatic glucose production and not a stimulation of glucose utilization; and (2) the inhibition of glucose production was attributable to a decrease in hepatic glycogenolysis and not to an alteration in gluconeogenic flux.