Effect of Metformin on Glucagon-Like Peptide 1 (GLP-1) and Leptin Levels in Obese Nondiabetic Subjects Edoardo Mannucci , MD 1 , Agostino Ognibene , MD 2 , Francesco Cremasco , MD 1 , Gianluca Bardini , MD 1 , Antonella Mencucci , MD 1 , Enrica Pierazzuoli , MD 1 , Silvia Ciani , BS 1 , Gianni Messeri , MS 2 and Carlo M. Rotella , MD 1 1 Section of Endocrinology, Department of Clinical Pathophysiology, University of Florence 2 Clinical Chemistry Laboratory, Careggi General Hospital, Florence, Italy Abstract OBJECTIVE —To evaluate the effects of metformin on glucagon-like peptide 1 (GLP-1) and leptin levels. RESEARCH DESIGN AND METHODS —A total of 10 obese nondiabetic male patients were studied before and after a 14-day treatment with 2,550 mg/day metformin and were compared with 10 untreated obese control subjects. On days 0 and 15, leptin and GLP-1(7–36)amide/(7–37) levels were assessed before and after an oral glucose load during a euglycemic hyperinsulinemic clamp to avoid the interference of variations of insulinemia and glycemia on GLP-1 and leptin secretion. The effects of metformin on GLP-1(7–36)amide degradation in human plasma and in a buffer solution containing dipeptidyl peptidase IV (DPP-IV) were also studied. RESULTS —Leptin levels were not affected by the oral glucose load, and they were not modified after metformin treatment. Metformin induced a significant ( P < 0.05) increase of GLP-1(7–36)amide/(7–37) at 30 and 60 min after the oral glucose load (63.8 ± 29.0 vs. 50.3 ± 15.6 pmol/l and 75.8 ± 35.4 vs. 46.9 ± 20.0 pmol/l, respectively), without affecting baseline GLP-1 levels. No variations of GLP-1 levels were observed in the control group. In pooled human plasma, metformin (0.1–0.5 μg/ml) significantly inhibited degradation of GLP-1(7–36)amide after a 30-min incubation at 37°C; similar results were obtained in a buffer solution containing DPP-IV. CONCLUSIONS —Metformin significantly increases GLP-1 levels after an oral glucose load in obese nondiabetic subjects; this effect could be due to an inhibition of GLP-1 degradation. ANOVA, analysis of variance CV, coefficient of variation DPP-IV, dipeptidyl peptidase IV GLP-1, glucagon-like peptide 1 Footnotes Address correspondence and reprint requests to Prof. Carlo M. Rotella, Insegnamento di Malattie Metaboliche e del Ricambio, Dipartimento di Fisiopatologia Clinica, Viale Pieraccini, 6-50134 Firenze, Italy. E-mail: c.rotella{at}dfc.unifi.it . Received for publication 13 July 2000 and accepted in revised form 10 November 2000. C.M.R. is a member of the International Advisory Board on GLP-1 analogs of Novo Nordisk, Denmark. He has received honoraria from Molteni Farmaceutici, Firenze, and Bayer Farmaceutici, Milan, Italy, which are currently marketing metformin in Italy. E.M. is a paid consultant for Molteni Farmaceutici. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.