Results of a Placebo-Controlled Study of the Metabolic Effects of the Addition of Metformin to Sulfonylurea-Treated Patients: Evidence for a central role of adipose tissue

OBJECTIVE To define the metabolic effects of metformin in the treatment of NIDDM and to evaluate potential mechanisms for its ability to improve glycemic control. RESEARCH DESIGN AND METHODS Sulfonylurea-treated patients, with inadequate glycemic control, were treated with metformin in either a placebo-controlled or open fashion. Measurements were made of 1) fasting and postprandial plasma glucose, insulin, and free fatty acid (FFA) concentrations; 2) glucose appearance and disappearance rates measured overnight with 3-[ 3 H]glucose; and 3) plasma FFA concentrations during a 45-min infusion period at relatively low (∼ 60 pmol/l) insulin concentrations. RESULTS Mean ± SE hourly plasma glucose, insulin, and FFA concentrations were similar before and after treatment in the placebo group. In contrast, mean hourly plasma glucose concentrations were significantly lower ( P P P −2 · min −1 ) were significantly lower after metformin as compared with the placebo-treated group ( P CONCLUSIONS Metformin treatment was associated with significantly lower day-long plasma glucose and FFA concentrations. Although overnight hepatic glucose production was unchanged following treatment with metformin, the overnight glucose metabolic clearance rate significantly increased. Given these findings, it is suggested that at least part of the antihyperglycemic effect of metformin is due to an increase in glucose uptake, secondary to a decrease in release of FFA from adipose tissue, and lower circulating FFA concentrations.