Diabetes Care, Vol 15, Issue 6 755-772, Copyright © 1992 by American Diabetes Association

ARTICLES

Biguanides and NIDDM

CJ Bailey
Department of Pharmaceutical Sciences, Aston University, Birmingham, United Kingdom.

The main biguanides, metformin and phenformin, were introduced in 1957 as oral glucose-lowering agents to treat non-insulin-dependent diabetes mellitus (NIDDM). Phenformin was withdrawn in many countries because of an association with lactic acidosis, but metformin does not have the same risk if appropriately prescribed. Metformin is now widely used as a monotherapy and in combination with a sulfonylurea. Unlike sulfonylureas, metformin is not bound to plasma proteins, is not metabolized, and is eliminated rapidly by the kidney. The glucose-lowering effect occurs without stimulation of insulin secretion and results mainly from increased glucose utilization. The presence of insulin is required, and enhancement of insulin action at the postreceptor level occurs in peripheral tissues such as muscle. In peripheral tissues metformin increases insulin-mediated glucose uptake and oxidative metabolism. Metformin also increases glucose utilization by the intestine, primarily via nonoxidative metabolism. The extra lactate produced is largely extracted by the liver and serves as a substrate to sustain gluconeogenesis. This limits the extent to which metformin reduces hepatic glucose production but provides a safeguard against excessive glucose lowering. Because metformin does not cause clinical hypoglycemia, it is actually an antihyperglycemic drug. It does not cause weight gain, it helps combat hypertriglyceridemia, and it has been ascribed some vasoprotective properties. Metformin offers a useful treatment for insulin-resistant overweight NIDDM patients.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				T. Zhang, J. He, C. Xu, L. Zu, H. Jiang, S. Pu, X. Guo, and G. Xu Mechanisms of metformin inhibiting lipolytic response to isoproterenol in primary rat adipocytes J. Mol. Endocrinol., January 1, 2009; 42(1): 57 - 66. [Abstract] [Full Text] [PDF]

				J. T. Rodgers and P. Puigserver Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1 PNAS, July 31, 2007; 104(31): 12861 - 12866. [Abstract] [Full Text] [PDF]

				D. Q. Pham, H. Cohen, and V. Chu Inhaled Human [rDNA Origin] Insulin, a Novel Formulation for Diabetes Mellitus J. Clin. Pharmacol., July 1, 2007; 47(7): 890 - 903. [Abstract] [Full Text] [PDF]

				M. Kaminski, M. Kiessling, D. Suss, P. H. Krammer, and K. Gulow Novel Role for Mitochondria: Protein Kinase C{theta}-Dependent Oxidative Signaling Organelles in Activation-Induced T-Cell Death Mol. Cell. Biol., May 15, 2007; 27(10): 3625 - 3639. [Abstract] [Full Text] [PDF]

				I. W Campbell The role of metformin and pioglitazone in early combination treatment of type 2 diabetes mellitus The British Journal of Diabetes & Vascular Disease, September 1, 2006; 6(5): 207 - 215. [Abstract] [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]

				H. A. Spiller and T. S. Sawyer Toxicology of oral antidiabetic medications Am. J. Health Syst. Pharm., May 15, 2006; 63(10): 929 - 938. [Abstract] [Full Text] [PDF]

				K. M. Levri, E. Slaymaker, A. Last, J. Yeh, J. Ference, F. D'Amico, and S. A. Wilson Metformin as Treatment for Overweight and Obese Adults: A Systematic Review Ann. Fam. Med, September 1, 2005; 3(5): 457 - 461. [Abstract] [Full Text] [PDF]

				T. S. Hannon, G. Rao, and S. A. Arslanian Childhood Obesity and Type 2 Diabetes Mellitus Pediatrics, August 1, 2005; 116(2): 473 - 480. [Abstract] [Full Text] [PDF]

				D. Detaille, B. Guigas, C. Chauvin, C. Batandier, E. Fontaine, N. Wiernsperger, and X. Leverve Metformin Prevents High-Glucose-Induced Endothelial Cell Death Through a Mitochondrial Permeability Transition-Dependent Process Diabetes, July 1, 2005; 54(7): 2179 - 2187. [Abstract] [Full Text] [PDF]

				M.A. Checa, A. Requena, C. Salvador, R. Tur, J. Callejo, J.J. Espinos, F. Fabregues, J. Herrero, and (Reproductive Endocrinology Interest Group of the Insulin-sensitizing agents: use in pregnancy and as therapy in polycystic ovary syndrome Hum. Reprod. Update, July 1, 2005; 11(4): 375 - 390. [Abstract] [Full Text] [PDF]

				R Yanardag, O Ozsoy-Sacan, S Bolkent, H Orak, and O Karabulut-Bulan Protective effects of metformin treatment on the liver injury of streptozotocin-diabetic rats Human and Experimental Toxicology, March 1, 2005; 24(3): 129 - 135. [Abstract] [PDF]

				D. R. Cryer, S. P. Nicholas, D. H. Henry, D. J. Mills, and B. V. Stadel Comparative Outcomes Study of Metformin Intervention Versus Conventional Approach The COSMIC Approach Study Diabetes Care, March 1, 2005; 28(3): 539 - 543. [Abstract] [Full Text] [PDF]

				D. Schuster, T. Gaillard, S. Rhinesmith, D. Habash, and K. Osei Impact of Metformin on Glucose Metabolism in Nondiabetic, Obese African Americans: A placebo-controlled, 24-month randomized study Diabetes Care, November 1, 2004; 27(11): 2768 - 2769. [Full Text] [PDF]

				N. Yasuda, T. Inoue, T. Nagakura, K. Yamazaki, K. Kira, T. Saeki, and I. Tanaka Metformin Causes Reduction of Food Intake and Body Weight Gain and Improvement of Glucose Intolerance in Combination with Dipeptidyl Peptidase IV Inhibitor in Zucker fa/fa Rats J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 614 - 619. [Abstract] [Full Text] [PDF]

				H. A Spiller and D. A Quadrani Toxic Effects from Metformin Exposure Ann. Pharmacother., May 1, 2004; 38(5): 776 - 780. [Abstract] [Full Text] [PDF]

				P English and G Williams Hyperglycaemic crises and lactic acidosis in diabetes mellitus Postgrad. Med. J., May 1, 2004; 80(943): 253 - 261. [Abstract] [Full Text] [PDF]

				B. Ludvik, B. Neuffer, and G. Pacini Efficacy of Ipomoea batatas (Caiapo) on Diabetes Control in Type 2 Diabetic Subjects Treated With Diet Diabetes Care, February 1, 2004; 27(2): 436 - 440. [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]

				S. Gahagan, J. Silverstein, Committee on Native American Child Health, and Section on Endocrinology Prevention and Treatment of Type 2 Diabetes Mellitus in Children, With Special Emphasis on American Indian and Alaska Native Children Pediatrics, October 1, 2003; 112(4): e328 - e328. [Abstract] [Full Text] [PDF]

				D. M. Nathan Initial Management of Glycemia in Type 2 Diabetes Mellitus N. Engl. J. Med., October 24, 2002; 347(17): 1342 - 1349. [Full Text] [PDF]

				S. M. Strowig, M. L. Aviles-Santa, and P. Raskin Comparison of Insulin Monotherapy and Combination Therapy With Insulin and Metformin or Insulin and Troglitazone in Type 2 Diabetes Diabetes Care, October 1, 2002; 25(10): 1691 - 1698. [Abstract] [Full Text] [PDF]

				S. Z. Yanovski and J. A. Yanovski Obesity N. Engl. J. Med., February 21, 2002; 346(8): 591 - 602. [Full Text] [PDF]

				K. L. Jones, S. Arslanian, V. A. Peterokova, J.-S. Park, and M. J. Tomlinson Effect of Metformin in Pediatric Patients With Type 2 Diabetes: A randomized controlled trial Diabetes Care, January 1, 2002; 25(1): 89 - 94. [Abstract] [Full Text] [PDF]

				J. H. Scarpello Review: Optimal dosing strategies for maximising the clinical response to metformin in type 2 diabetes The British Journal of Diabetes & Vascular Disease, August 1, 2001; 1(1): 28 - 36. [Abstract] [PDF]

				M. Freemark and D. Bursey The Effects of Metformin on Body Mass Index and Glucose Tolerance in Obese Adolescents With Fasting Hyperinsulinemia and a Family History of Type 2 Diabetes Pediatrics, April 1, 2001; 107(4): e55 - e55. [Abstract] [Full Text] [PDF]

				E. Mannucci, A. Ognibene, F. Cremasco, G. Bardini, A. Mencucci, E. Pierazzuoli, S. Ciani, G. Messeri, and C. M. Rotella Effect of Metformin on Glucagon-Like Peptide 1 (GLP-1) and Leptin Levels in Obese Nondiabetic Subjects Diabetes Care, March 1, 2001; 24(3): 489 - 494. [Abstract] [Full Text]

				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]

				M.-Y. El-Mir, V. Nogueira, E. Fontaine, N. Averet, M. Rigoulet, and X. Leverve Dimethylbiguanide Inhibits Cell Respiration via an Indirect Effect Targeted on the Respiratory Chain Complex I J. Biol. Chem., January 7, 2000; 275(1): 223 - 228. [Abstract] [Full Text] [PDF]

				A. la Marca, T. O. Egbe, G. Morgante, T. Paglia, A. Ciani, and V. De Leo Metformin treatment reduces ovarian cytochrome P-450c17{alpha} response to human chorionic gonadotrophin in women with insulin resistance-related polycystic ovary syndrome Hum. Reprod., January 1, 2000; 15(1): 21 - 23. [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]

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

				J. Gueriguian, L. Green, R. I. Misbin, B. Stadel, G. A. Fleming, J.C. Deutsch, C.R. Santhosh-Kumar, J.F. Kolhouse, R. A. DeFronzo, and A. M. Goodman Efficacy of Metformin in Non-Insulin-Dependent Diabetes Mellitus N. Engl. J. Med., January 25, 1996; 334(4): 269 - 270. [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]

				B. Saulie, J. White, and R. K. Campbell Pharmacy Update: Metformin in the Treatment of Non-Insulin-Dependent Diabetes Mellitus The Diabetes Educator, January 1, 1995; 21(5): 441 - 445. [PDF]

				J. J. Tanja Jon J. Tanja, RPh, Ms, Fascp; Theresa M. Langlass, RPh, PharmD The Diabetes Educator, January 1, 1995; 21(6): 509 - 514. [PDF]