This Article Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by DEFRONZO, R. A. Articles by SIMONSON, D. C. Search for Related Content PubMed PubMed Citation Articles by DEFRONZO, R. A. Articles by SIMONSON, D. C.

Mechanism of Metformin Action in Obese and Lean Noninsulin-Dependent Diabetic Subjects^*

RALPH A. DEFRONZO, NIR BARZILAI and DONALD C. SIMONSON

Diabetes Division, Department of Medicine, University of Texas Health Science Center, and the AudieL. Murphy Veterans Administration Hospital San Antonio, Texas 78284

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.

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 (2.77– 1.52 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/m²· 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/m²-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/m²–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.

^* This work was supported by a grant from Lipha Chemicals.

Current address: Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215.

Received October 9, 1990.

This article has been cited by other articles:

				C. W. Chia and J. M. Egan Incretin-Based Therapies in Type 2 Diabetes Mellitus J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 3703 - 3716. [Abstract] [Full Text] [PDF]

				R. Basu, P. Shah, A. Basu, B. Norby, B. Dicke, V. Chandramouli, O. Cohen, B. R. Landau, and R. A. Rizza Comparison of the Effects of Pioglitazone and Metformin on Hepatic and Extra-Hepatic Insulin Action in People With Type 2 Diabetes Diabetes, January 1, 2008; 57(1): 24 - 31. [Abstract] [Full Text] [PDF]

				T. L. Skaer, D. A. Sclar, and L. M. Robison Trends in the Prescribing of Oral Agents for the Management of Type 2 Diabetes Mellitus in the United States, 1990-2001: Does Type of Insurance Influence Access to Innovation? The Diabetes Educator, November 1, 2006; 32(6): 940 - 953. [Abstract] [Full Text] [PDF]

				T. Ren, J. He, H. Jiang, L. Zu, S. Pu, X. Guo, and G. Xu Metformin reduces lipolysis in primary rat adipocytes stimulated by tumor necrosis factor-{alpha} or isoproterenol. J. Mol. Endocrinol., August 1, 2006; 37(1): 175 - 183. [Abstract] [Full Text] [PDF]

				P. Iozzo, A. Gastaldelli, M. J. Jarvisalo, J. Kiss, R. Borra, E. Buzzigoli, A. Viljanen, G. Naum, T. Viljanen, V. Oikonen, et al. 18F-FDG Assessment of Glucose Disposal and Production Rates During Fasting and Insulin Stimulation: A Validation Study J. Nucl. Med., June 1, 2006; 47(6): 1016 - 1022. [Abstract] [Full Text] [PDF]

				R. L. Hull, Z.-P. Shen, M. R. Watts, K. Kodama, D. B. Carr, K. M. Utzschneider, S. Zraika, F. Wang, and S. E. Kahn Long-Term Treatment With Rosiglitazone and Metformin Reduces the Extent of, but Does Not Prevent, Islet Amyloid Deposition in Mice Expressing the Gene for Human Islet Amyloid Polypeptide Diabetes, July 1, 2005; 54(7): 2235 - 2244. [Abstract] [Full Text] [PDF]

				J. Klein, S. Westphal, D. Kraus, B. Meier, N. Perwitz, V. Ott, M. Fasshauer, and H H. Klein Metformin inhibits leptin secretion via a mitogen-activated protein kinase signalling pathway in brown adipocytes J. Endocrinol., November 1, 2004; 183(2): 299 - 307. [Abstract] [Full Text] [PDF]

				A. Natali, S. Baldeweg, E. Toschi, B. Capaldo, D. Barbaro, A. Gastaldelli, J. S. Yudkin, and E. Ferrannini Vascular Effects of Improving Metabolic Control With Metformin or Rosiglitazone in Type 2 Diabetes Diabetes Care, June 1, 2004; 27(6): 1349 - 1357. [Abstract] [Full Text] [PDF]

				M. Hanefeld, P. Brunetti, G. H. Schernthaner, D. R. Matthews, and B. H. Charbonnel One-Year Glycemic Control With a Sulfonylurea Plus Pioglitazone Versus a Sulfonylurea Plus Metformin in Patients With Type 2 Diabetes Diabetes Care, January 1, 2004; 27(1): 141 - 147. [Abstract] [Full Text] [PDF]

				S. R. Salpeter, E. Greyber, G. A. Pasternak, and E. E. Salpeter Risk of Fatal and Nonfatal Lactic Acidosis With Metformin Use in Type 2 Diabetes Mellitus: Systematic Review and Meta-analysis Arch Intern Med, November 24, 2003; 163(21): 2594 - 2602. [Abstract] [Full Text] [PDF]

				C. A. Eagleson, A. B. Bellows, K. Hu, M. B. Gingrich, and J. C. Marshall Obese Patients with Polycystic Ovary Syndrome: Evidence that Metformin Does Not Restore Sensitivity of the Gonadotropin-Releasing Hormone Pulse Generator to Inhibition by Ovarian Steroids J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5158 - 5162. [Abstract] [Full Text] [PDF]

				V. De Leo, A. la Marca, and F. Petraglia Insulin-Lowering Agents in the Management of Polycystic Ovary Syndrome Endocr. Rev., October 1, 2003; 24(5): 633 - 667. [Abstract] [Full Text] [PDF]

				I. Pavo, G. Jermendy, T. T. Varkonyi, Z. Kerenyi, A. Gyimesi, S. Shoustov, M. Shestakova, M. Herz, D. Johns, B. J. Schluchter, et al. Effect of Pioglitazone Compared with Metformin on Glycemic Control and Indicators of Insulin Sensitivity in Recently Diagnosed Patients with Type 2 Diabetes J. Clin. Endocrinol. Metab., April 1, 2003; 88(4): 1637 - 1645. [Abstract] [Full Text] [PDF]

				F. Zangeneh, Y. C. Kudva, and A. Basu Insulin Sensitizers Mayo Clin. Proc., April 1, 2003; 78(4): 471 - 479. [Abstract] [PDF]

				J. E. Gunton, P. J. D. Delhanty, S.-I. Takahashi, and R. C. Baxter Metformin Rapidly Increases Insulin Receptor Activation in Human Liver and Signals Preferentially through Insulin-Receptor Substrate-2 J. Clin. Endocrinol. Metab., March 1, 2003; 88(3): 1323 - 1332. [Abstract] [Full Text] [PDF]

				K. A. Virtanen, K. Hallsten, R. Parkkola, T. Janatuinen, F. Lonnqvist, T. Viljanen, T. Ronnemaa, J. Knuuti, R. Huupponen, P. Lonnroth, et al. Differential Effects of Rosiglitazone and Metformin on Adipose Tissue Distribution and Glucose Uptake in Type 2 Diabetic Subjects Diabetes, February 1, 2003; 52(2): 283 - 290. [Abstract] [Full Text] [PDF]

				K. Hallsten, K. A. Virtanen, F. Lonnqvist, H. Sipila, A. Oksanen, T. Viljanen, T. Ronnemaa, J. Viikari, J. Knuuti, and P. Nuutila Rosiglitazone but Not Metformin Enhances Insulin- and Exercise-Stimulated Skeletal Muscle Glucose Uptake in Patients With Newly Diagnosed Type 2 Diabetes Diabetes, December 1, 2002; 51(12): 3479 - 3485. [Abstract] [Full Text] [PDF]

				G. Viberti, S. E. Kahn, D. A. Greene, W. H. Herman, B. Zinman, R. R. Holman, S. M. Haffner, D. Levy, J. M. Lachin, R. A. Berry, et al. A Diabetes Outcome Progression Trial (ADOPT): An international multicenter study of the comparative efficacy of rosiglitazone, glyburide, and metformin in recently diagnosed type 2 diabetes Diabetes Care, October 1, 2002; 25(10): 1737 - 1743. [Abstract] [Full Text] [PDF]

				E. Seli and A. J. Duleba Should patients with polycystic ovarian syndrome be treated with metformin? Hum. Reprod., September 1, 2002; 17(9): 2230 - 2236. [Abstract] [Full Text] [PDF]

				Z. Zhang and J. Radziuk Inverse relationship between peripheral insulin removal and action: studies with metformin Am J Physiol Endocrinol Metab, December 1, 2001; 281(6): E1240 - E1248. [Abstract] [Full Text] [PDF]

				L. Ciotta, A. E. Calogero, M. Farina, V. De Leo, A. La Marca, and A. Cianci Clinical, endocrine and metabolic effects of acarbose, an {alpha}-glucosidase inhibitor, in PCOS patients with increased insulin response and normal glucose tolerance Hum. Reprod., October 1, 2001; 16(10): 2066 - 2072. [Abstract] [Full Text] [PDF]

				S. Matthaei, M. Stumvoll, M. Kellerer, and H.-U. Häring Pathophysiology and Pharmacological Treatment of Insulin Resistance Endocr. Rev., December 1, 2000; 21(6): 585 - 618. [Abstract] [Full Text]

				L. C. Morin-Papunen, I. Vauhkonen, R. M. Koivunen, A. Ruokonen, H. K. Martikainen, and J. S. Tapanainen Endocrine and Metabolic Effects of Metformin Versus Ethinyl Estradiol-Cyproterone Acetate in Obese Women with Polycystic Ovary Syndrome: A Randomized Study J. Clin. Endocrinol. Metab., September 1, 2000; 85(9): 3161 - 3168. [Abstract] [Full Text]

				D. Deplewski and R. L. Rosenfield Role of Hormones in Pilosebaceous Unit Development Endocr. Rev., August 1, 2000; 21(4): 363 - 392. [Abstract] [Full Text] [PDF]

				Y. Shimoni, D. Severson, and H. S. Ewart Insulin resistance and the modulation of rat cardiac K+ currents Am J Physiol Heart Circ Physiol, August 1, 2000; 279(2): H639 - H649. [Abstract] [Full Text] [PDF]

				L. Ciotta, V. De Leo, F. Galvani, A. La Marca, and A. Cianci Endocrine and metabolic effects of octreotide, a somatostatin analogue, in lean PCOS patients with either hyperinsulinaemia or lean normoinsulinaemia Hum. Reprod., December 1, 1999; 14(12): 2951 - 2958. [Abstract] [Full Text] [PDF]

				R. A. DeFronzo Pharmacologic Therapy for Type 2 Diabetes Mellitus Ann Intern Med, August 17, 1999; 131(4): 281 - 303. [Abstract] [Full Text] [PDF]

				L. Aviles-Santa, J. Sinding, and P. Raskin Effects of Metformin in Patients with Poorly Controlled, Insulin-Treated Type 2 Diabetes Mellitus: A Randomized, Double-Blind, Placebo-Controlled Trial Ann Intern Med, August 3, 1999; 131(3): 182 - 188. [Abstract] [Full Text] [PDF]

				L. C. Morin-Papunen, R. M. Koivunen, C. Tomás, A. Ruokonen, and H. K. Martikainen Decreased Serum Leptin Concentrations during Metformin Therapy in Obese Women with Polycystic Ovary Syndrome J. Clin. Endocrinol. Metab., July 1, 1998; 83(7): 2566 - 2568. [Abstract] [Full Text]

				A. Dunaif Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis Endocr. Rev., December 1, 1997; 18(6): 774 - 800. [Abstract] [Full Text]

				J. E. Nestler and D. J. Jakubowicz Lean Women with Polycystic Ovary Syndrome Respond to Insulin Reduction with Decreases in Ovarian P450c17{alpha} Activity and Serum Androgens J. Clin. Endocrinol. Metab., December 1, 1997; 82(12): 4075 - 4079. [Abstract] [Full Text] [PDF]

				R. Bressler and D. G. Johnson Pharmacological Regulation of Blood Glucose Levels in Non--Insulin-Department Diabetes Mellitus Arch Intern Med, April 28, 1997; 157(8): 836 - 848. [Abstract] [PDF]

				J. E. Nestler and D. J. Jakubowicz Decreases in Ovarian Cytochrome P450c17{alpha} Activity and Serum Free Testosterone after Reduction of Insulin Secretion in Polycystic Ovary Syndrome N. Engl. J. Med., August 29, 1996; 335(9): 617 - 623. [Abstract] [Full Text] [PDF]

				J. S. Petersen and G. F. DiBona Acute Sympathoinhibitory Actions of Metformin in Spontaneously Hypertensive Rats Hypertension, March 1, 1996; 27(3): 619 - 625. [Abstract] [Full Text]

				C. J. Bailey and R. C. Turner Metformin N. Engl. J. Med., February 29, 1996; 334(9): 574 - 579. [Full Text] [PDF]

				H. R. Robert Glucose Control and Insulin Resistance in Non-Insulin-dependent Diabetes Mellitus Ann Intern Med, January 1, 1996; 124(1_Part_2): 97 - 103. [Abstract] [Full Text]

				R. A. DeFronzo, A. M. Goodman, and The Multicenter Metformin Study Group Efficacy of Metformin in Patients with Non-Insulin-Dependent Diabetes Mellitus N. Engl. J. Med., August 31, 1995; 333(9): 541 - 549. [Abstract] [Full Text] [PDF]

				M. Stumvoll, N. Nurjhan, G. Perriello, G. Dailey, and J. E. Gerich Metabolic Effects of Metformin in Non-Insulin-Dependent Diabetes Mellitus N. Engl. J. Med., August 31, 1995; 333(9): 550 - 554. [Abstract] [Full Text] [PDF]