Mechanism by Which Metformin Reduces Glucose Production in Type 2 Diabetes

摘要

To examine the mechanism by which metformin lowers endogenous glucose production in type 2 diabetic patients, we studied seven type 2 diabetic subjects, with fasting hyperglycemia (15.5 ± 1.3 mmol/l), before and after 3 months of metformin treatment. Seven healthy subjects, matched for sex, age, and BMI, served as control subjects. Rates of net hepatic glycogenolysis, estimated by ¹³C nuclear magnetic resonance spectroscopy, were combined with estimates of contributions to glucose production of gluconeogenesis and glycogenolysis, measured by labeling of blood glucose by ²H from ingested ²H2O. Glucose production was measured using [6,6-²H2]glucose. The rate of glucose production was twice as high in the diabetic subjects as in control subjects (0.70 ± 0.05 vs. 0.36 ± 0.03 mmol · m⁻² · min⁻¹, P < 0.0001). Metformin reduced that rate by 24% (to 0.53 ± 0.03 mmol · m⁻² · min⁻¹, P = 0.0009) and fasting plasma glucose concentration by 30% (to 10.8 ± 0.9 mmol/l, P = 0.0002). The rate of gluconeogenesis was three times higher in the diabetic subjects than in the control subjects (0.59 ± 0.03 vs. 0.18 ± 0.03 mmol · m⁻² · min⁻¹) and metformin reduced that rate by 36% (to 0.38 ± 0.03 mmol · m⁻² · min⁻¹, P = 0.01). By the ²H2O method, there was a twofold increase in rates of gluconeogenesis in diabetic subjects (0.42 ± 0.04 mmol · m⁻² · min⁻¹), which decreased by 33% after metformin treatment (0.28 ± 0.03 mmol · m⁻² · min⁻¹, P = 0.0002). There was no glycogen cycling in the control subjects, but in the diabetic subjects, glycogen cycling contributed to 25% of glucose production and explains the differences between the two methods used. In conclusion, patients with poorly controlled type 2 diabetes have increased rates of endogenous glucose production, which can be attributed to increased rates of gluconeogenesis. Metformin lowered the rate of glucose production in these patients through a reduction in gluconeogenesis.