METABOLIC EFFECTS OF METFORMIN IN NON-INSULIN-DEPENDENT DIABETES-MELLITUS

Background. The metabolic effects and mechanism of action of metformin are still poorly understood, despite the fact that it has been used t o treat patients with non-insulin-dependent diabetes mellitus (NIDDM) for more than 30 years. Methods. In 10 obese patients with NIDDM, we u sed a combination of isotope dilution, indirect calorimetry, bioimpeda nce, and tissue-balance techniques to assess the effects of metformin on systemic lactate, glucose, and free-fatty-acid turnover, lactate ox idation and the conversion of lactate to glucose; skeletal-muscle gluc ose and lactate metabolism; body composition; and energy expenditure b efore and after four months of treatment. Results. Metformin treatment decreased the mean (+/-SD) glycosylated hemoglobin value from 13.2+/- 2.2 percent to 10.5+/-1.6 percent (P<0.001) and reduced fasting plasma glucose concentrations from 220+/-41 to 155+/-28 mg per deciliter (12 .2+/-0.7 to 8.6+/-0.5 mmol per liter) (P<0.001). Although resting ener gy expenditure did not change, the patients lost 2.7+/-1.3 kg of weigh t (P<0.001:), 88 percent of which was adipose tissue. The mean (+/-SE) rate of plasma glucose turnover (hepatic glucose output and systemic glucose disposal) decreased from 2.8+/-0.2 to 2.0+/-0.2 mg per kilogra m of body weight per minute (15.3+/-0.9 to 10.8+/-0.9 mu mol per kilog ram per minute) (P<0.001), as a result of a decrease in hepatic glucos e output; systemic glucose clearance did not change. The rate of conve rsion of lactate to glucose (gluconeogenesis) decreased by 37 percent (P<0.001), whereas lactate oxidation increased by 25 percent (P<0.001) . There were no changes in the plasma lactate concentration, plasma la ctate turnover, muscle lactate release, plasma free-fatty-acid turnove r or uptake of glucose by muscle. Conclusions. Metformin acts primaril y by decreasing hepatic glucose output, largely by inhibiting gluconeo genesis, It also seems to induce weight toss, preferentially involving adipose tissue.