Vol 68, No 4 (2017)
Review paper
Published online: 2017-08-10
Metformin — a new old drug
Abstract
For many years metformin has been the gold standard in the treatment of type 2 diabetes. According to recommendations of the most important diabetes associations, this is the first-choice drug for use as monotherapy in patients with newly diagnosed type 2 diabetes. Metformin is also recommended in combined treatment when monotherapy is no longer effective. It is then combined with a sulfonylurea, an incretin, flozin, or insulin, irrespective of the number of insulin injections per day. Besides its properties used in the treatment of diabetes, metformin has been treated for some time as a drug of a so-called pleiotropic activity, as each year brings new reports about its favourable effect in different conditions. At present, the scope of reimbursed indications of this drug has been expanded to include prediabetes, insulin resistance syndromes, and polycystic ovary syndrome. Metformin does not stimulate insulin secretion by the beta cells of the pancreas, and thus it is a drug that does not cause hypoglycaemia. The blood glucose-lowering effect of the drug is a consequence of hepatic glucose production inhibition, and of peripheral tissue (muscle tissue, fatty tissue) sensitisation to the effect of insulin of both endogenous and exogenous origin. The exact mechanism of metformin action at the cellular level remained unknown for a long time. Studies performed in recent years have provided a great deal of information that enables better understanding of the mechanism of action of the drug as well as the clinical effects resulting from its use. Metformin, besides improvement of glycaemia, is neutral to body weight, is cardioprotective, improves lipid profile, and has a probable anti-cancer effect. Metformin accumulation in the intestinal mucosa may interfere with FDG (18F-deoxyglucose) PET-CT image assessment. The aim of this article is a detailed discussion of metformin properties, its mechanisms of action, and clinical effects.
Keywords: metforminmetformin propertiestype 2 diabetes
References
- Inzucchi SE, Bergenstal RM, Buse JB, et al. Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia. 2012; 55(6): 1577–1596.
- Polskie Towarzystwo Diabetologiczne. Zalecenia kliniczne dotyczące postępowania z chorym na cukrzycę 2016. Diabetol Klin. 2016; 2(supl. A).
- Stumvoll M, Nurjhan N, Perriello G, et al. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995; 333(9): 550–554.
- Sieradzki J. Cukrzyca. Via Medica, Gdańsk 2006.
- Owen MR, Doran E, Halestrap AP. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J. 2000; 348 Pt 3: 607–614.
- Hur KY, Lee MS. New mechanisms of metformin action: Focusing on mitochondria and the gut. J Diabetes Investig. 2015; 6(6): 600–609.
- Harding HP, Zhang Y, Zeng H, et al. An integrated stress response regulates amino acid metabolism and resistance to oxidative stress. Mol Cell. 2003; 11(3): 619–633.
- Kim KH, Jeong YT, Oh H, et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med. 2013; 19(1): 83–92.
- Zhang M, Liu Y, Xiong Zy, et al. Changes of plasma fibroblast growth factor-21 (FGF-21) in oral glucose tolerance test and effects of metformin on FGF-21 levels in type 2 diabetes mellitus. Endokrynol Pol. 2013; 64(3): 220–224.
- Klip A, Leiter LA. Cellular Mechanism of Action of Metformin. Diabetes Care. 1990; 13(6): 696–704.
- Madiraju AK, Erion DM, Rahimi Y, et al. Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature. 2014; 510(7506): 542–546.
- Klip A, Leiter LA. Cellular Mechanism of Action of Metformin. Diabetes Care. 1990; 13(6): 696–704.
- Miller RA, Chu Q, Xie J, et al. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. 2013; 494(7436): 256–260.
- Sieradzki J. Działanie inkretynopodobne metforminy. Diabetologia Praktyczna. 2011; 12: 6–10.
- Matveyenko AV, Dry S, Cox HI, et al. Beneficial endocrine but adverse exocrine effects of sitagliptin in the human islet amyloid polypeptide transgenic rat model of type 2 diabetes: interactions with metformin. Diabetes. 2009; 58(7): 1604–1615.
- Bailey CJ, Mynett KJ, Page T. Importance of the intestine as a site of metformin-stimulated glucose utilization. Br J Pharmacol. 1994; 112(2): 671–675.
- Bailey CJ, Wilcock C, Scarpello JHB. Metformin and the intestine. Diabetologia. 2008; 51(8): 1552–1553.
- Shin NR, Lee JC, Lee HY, et al. An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut. 2014; 63(5): 727–735.
- Derrien M, Van Baarlen P, Hooiveld G, et al. Modulation of Mucosal Immune Response, Tolerance, and Proliferation in Mice Colonized by the Mucin-Degrader Akkermansia muciniphila. Front Microbiol. 2011; 2: 166.
- Egan DF, Shackelford DB, Mihaylova MM, et al. Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science. 2011; 331(6016): 456–461.
- Houtkooper RH, Mouchiroud L, Ryu D, et al. Mitonuclear protein imbalance as a conserved longevity mechanism. Nature. 2013; 497(7450): 451–457.
- Martin-Montalvo A, Mercken EM, Mitchell SJ, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013; 4: 2192.
- Kurukulasuriya R, Banerji MA, Chaiken R, et al. Selective decrease in visceral fat is associated with weight loss during metformin treatment in African Americans with type 2 diabetes. Diabetes. 1999; 48: 315.
- Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). The Lancet. 1998; 352(9131): 837–853.
- Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008; 359(15): 1577–1589.
- Liu B, Fan Z, Edgerton SM, et al. Potent anti-proliferative effects of metformin on trastuzumab-resistant breast cancer cells via inhibition of erbB2/IGF-1 receptor interactions. Cell Cycle. 2011; 10(17): 2959–2966.
- Rocha GZ, Dias MM, Ropelle ER, et al. Metformin amplifies chemotherapy-induced AMPK activation and antitumoral growth. Clin Cancer Res. 2011; 17(12): 3993–4005.
- Brant WE, Helms CA. Podstawy diagnostyki radiologicznej. Lippincott Williams & Wilkins, Philadelphia 2007.
- Steenkamp DW, McDonnell ME, Meibom S. Metformin may be associated with false-negative cancer detection in the gastrointestinal tract on PET/CT. Endocr Pract. 2014; 20(10): 1079–1083.
- Habibollahi P, van den Berg NS, Kuruppu D, et al. Metformin--an adjunct antineoplastic therapy--divergently modulates tumor metabolism and proliferation, interfering with early response prediction by 18F-FDG PET imaging. J Nucl Med. 2013; 54(2): 252–258.
- Mashhedi H, Blouin MJ, Zakikhani M, et al. Metformin abolishes increased tumor (18)F-2-fluoro-2-deoxy-D-glucose uptake associated with a high energy diet. Cell Cycle. 2011; 10(16): 2770–2778.
- Capitanio S, Marini C, Sambuceti G, et al. Metformin and cancer: Technical and clinical implications for FDG-PET imaging. World J Radiol. 2015; 7(3): 57–60.
- www.diabetesatlas.com.
- Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the Incidence of Type 2 Diabetes with Lifestyle Intervention or Metformin. New England Journal of Medicine. 2002; 346(6): 393–403.
- Malin SK, Nightingale J, Choi SE, et al. Metformin modifies the exercise training effects on risk factors for cardiovascular disease in impaired glucose tolerant adults. Obesity (Silver Spring). 2013; 21(1): 93–100.
- Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004; 89(6): 2548–2556.
- Alberti KG, Eckel RH, Grundy SM, et al. International Diabetes Federation Task Force on Epidemiology and Prevention, Hational Heart, Lung, and Blood Institute, American Heart Association, World Heart Federation, International Atherosclerosis Society, International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009; 120(16): 1640–1645.
- Grundy SM. Pre-diabetes, metabolic syndrome, and cardiovascular risk. J Am Coll Cardiol. 2012; 59(7): 635–643.
- Jain SS, Ramteke KB, Raparti GT, et al. Pathogenesis and treatment of human immunodeficiency virus lipodystrophy. Indian J Endocrinol Metab. 2012; 16 Suppl 1: S20–S26.
- Lewandowski KC, Lewiński A, Dąbrowska K, et al. Familial partial lipodystrophy as differential diagnosis of polycystic ovary syndrome. Endokrynol Pol. 2015; 66(6): 550–554.
- Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev. 1997; 18(6): 774–800.
- Marx TL, Mehta AE. Polycystic ovary syndrome: pathogenesis and treatment over the short and long term. Cleve Clin J Med. 2003; 70(1): 31-33, 36-41, 45.
- Milewicz A. Endokrynologia kliniczna. Polskie Towarzystwo Endokrynologiczne, Wrocław 2012.
- Kruszyńska A, Słowińska-Srzednicka J, Jeske W, et al. Proinsulin, adiponectin and hsCRP in reproductive age women with polycystic ovary syndrome (PCOS)--the effect of metformin treatment. Endokrynol Pol. 2014; 65(1): 2–10.
- Vandermolen DT, Ratts VS, Evans WS, et al. Metformin increases the ovulatory rate and pregnancy rate from clomiphene citrate in patients with polycystic ovary syndrome who are resistant to clomiphene citrate alone. Fertil Steril. 2001; 75(2): 310–315.
- Lord JM, Flight IHK, Norman RJ. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. Cochrane Database Syst Rev. 2003(3): CD003053.
- Glueck CJ, Goldenberg N, Pranikoff J, et al. Effects of metformin-diet intervention before and throughout pregnancy on obstetric and neonatal outcomes in patients with polycystic ovary syndrome. Curr Med Res Opin. 2013; 29(1): 55–62.
