Mechanism of Metf ormin Action in Obese and Lean Noninsulin-Dependent Diabetic Subjects*

The effect of metformin on glucose metabolism was examined in eight obese (percent ideal body weight, 151 ± 9%) and six lean (percent ideal body weight, 104 ± 4%) noninsulin-dependent diabetic (NIDD) subjects before and after 3 months of metformin treatment (2.5 g/day). Fasting plasma glucose (11.5-8.8 mmol/L), hemoglobin-Aic (9.8-7.7%), oral glucose tolerance test response (20.0-17.0 mmol/L; peak glucose), total cholesterol (5.67-4.71 mmol/L), and triglycerides (2.771.52 mmol/L) uniformly decreased (P < 0.05-0.001) after metformin treatment; fasting plasma lactate increased slightly from baseline (1.4 to 1.7 mmol/L; P NS). Body weight decreased by 5 kg in obese NIDD subjects, but remained constant in lean NIDD. Basal hepatic glucose production declined in all diabetics from 83 to 61 mg/m• min (P < 0.01), and the decrease correlated (r = 0.80; P < 0.01) closely with the fall in fasting glucose concentration. Fasting insulin (115 to 79 pmol/L) declined (P < 0.05) after metformin. During a 6.9 mmol/L hyperglycemic clamp, glucose uptake increased in every NIDD subject (113 ± 15 to 141 ± 12 mg/m-min; P < 0.001) without a change in the plasma insulin response. During a euglycemic insulin clamp, total glucose uptake rose in obese NIDD subjects (121 ± 10 to 146 ± 9 mmol/m-min; P < 0.05), but decreased slightly in lean NIDD (121 ± 10 to 146 ± 0.5; P = NS). Hepatic glucose production was suppressed by more than 80-90% in all insulin clamp studies before and after metformin treatment. In conclusion, metformin lowers the fasting plasma glucose and insulin concentrations, improves oral glucose tolerance, and decreases plasma lipid levels independent of changes in body weight. The improvement in fasting glucose results from a reduction in basal hepatic glucose production. Metformin per se does not enhance tissue sensitivity to insulin in NIDD subjects. The improvement in glucose metabolism under hyperglycemic, but not euglycemic, conditions suggests that metformin augments glucose-mediated glucose uptake. Metformin has no stimulatory effect on insulin secretion. (J Clin Endocrinol Metab 73: 1294-1301,1991) M is a biguanide which has gained widespread usage in the treatment of noninsulindependent diabetes mellitus (NIDDM) in Europe and Canada (1, 2). This drug, unlike phenformin, is rarely associated with lactic acidosis (3-5) and has been used both alone (1, 2, 6-10) and with sulfonylureas (11-13) to treat noninsulin-dependent diabetic (NIDD) patients. Although effective in lowering blood glucose levels in NIDDM, controversy exists concerning its mechanism of action. Multiple mechanisms of action have been suggested, including delayed gastrointestinal absorption of glucose (2, 14), improved peripheral tissue sensitivity to insulin (15-21), and suppression of hepatic glucose production (7,22) due to an inhibition of gluconeogenesis (23-25). It generally is agreed that biguanides do not alter insulin secretion (1, 7,18, 21, 26, 27). With respect to metformin's effect on peripheral tissues, both receptor Received October 9,1990. Address all correspondence and requests for reprints to: Dr. Ralph A. DeFronzo, Diabetes Division, University of Texas Health Science Center, 7703 Floyd Curl Drive, San Antonio, Texas 78284-7877. * This work was supported by a grant from Lipha Chemicals. f Current address: Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215. (10, 27, 28, 29) and postreceptor events have been implicated (10, 30-32). The modest improvement in insulin binding may result from a decline in circulating plasma insulin levels (27). Most recently, Purrello et al. (32, 33) and Fantus and Brosseau (34) have provided evidence for enhanced glucose transport after metformin therapy. In the present study we have employed the euglycemic insulin and hyperglycemic clamp techniques (35) in combination with tritiated glucose and indirect calorimetry (36) to provide quantitative information concerning insulin secretion, insulin sensitivity, and hepatic glucose production in NIDD patients before and after metformin treatment. Because the cellular mechanisms responsible for the defect in insulin action differ in obesity and type II diabetes mellitus (37, 38), both normal weight and obese NIDD subjects were studied. Materials and Methods