The mechanisms of action of metformin

Graham Rena1, D. Grahame Hardie2, Ewan R. Pearson1
1Division of Molecular & Clinical Medicine, School of Medicine, University of Dundee, Dundee, DD1 9SY, UK
2Division of Cell Signalling & Immunology, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK

Tóm tắt

Từ khóa


Tài liệu tham khảo

Howlett HCS, Bailey CJ (2007) Galegine and antidiabetic plants. In: Bailey CJ, Campbell IW, Chan JCN, Davidson JA, Howlett HCS, Ritz P (eds) Metformin—the gold standard. Wiley, Chichester, pp 3–9

Muller H, Reinwein H (1927) Zur pharmakologie des Galegins. Arch Exp Pathol Pharmakol 125:212–228

Howlett HCS, Bailey CJ (2007) Discovery of metformin. In: Bailey CJ, Campbell IW, Chan JCN, Davidson JA, Howlett HCS, Ritz P (eds) Metformin—the gold standard. Wiley, Chichester, pp 11–16

Graham GG, Punt J, Arora M et al (2011) Clinical pharmacokinetics of metformin. Clin Pharmacokinet 50:81–98

Bailey CJ, Wilcock C, Scarpello JH (2008) Metformin and the intestine. Diabetologia 51:1552–1553

Gormsen LC, Sundelin EI, Jensen JB et al (2016) In vivo imaging of human 11C-metformin in peripheral organs: dosimetry, biodistribution, and kinetic analyses. J Nucl Med 57:1920–1926

Madiraju AK, Erion DM, Rahimi Y et al (2014) Metformin suppresses gluconeogenesis by inhibiting mitochondrial glycerophosphate dehydrogenase. Nature 510:542–546

Griffin SJ, Leaver JK, Irving GJ (2017) Impact of metformin on cardiovascular disease: a meta-analysis of randomised trials among people with type 2 diabetes. Diabetologia DOI: 10.1007/s00125-017-4337-9

Heckman-Stoddard B (2017) Repurposing metformin for the prevention of cancer and cancer recurrence. Diabetologia DOI: 10.1007/s00125-017-4372-6

Valencia WM, Palacio A, Tamariz L, Florez H (2017) Metformin and ageing: improving ageing outcomes beyond glycaemic control. Diabetologia DOI: 10.1007/s00125-017-4349-5

Wang DS, Jonker JW, Kato Y, Kusuhara H, Schinkel AH, Sugiyama Y (2002) Involvement of organic cation transporter 1 in hepatic and intestinal distribution of metformin. J Pharmacol Exp Ther 302:510–515

Shu Y, Sheardown SA, Brown C et al (2007) Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 117:1422–1431

Natali A, Ferrannini E (2006) Effects of metformin and thiazolidinediones on suppression of hepatic glucose production and stimulation of glucose uptake in type 2 diabetes: a systematic review. Diabetologia 49:434–441

Owen MR, Doran E, Halestrap AP (2000) Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348:607–614

Bridges HR, Jones AJ, Pollak MN, Hirst J (2014) Effects of metformin and other biguanides on oxidative phosphorylation in mitochondria. Biochem J 462:475–487

El-Mir MY, Nogueira V, Fontaine E, Averet N, Rigoulet M, Leverve X (2000) Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J Biol Chem 275:223–228

Hawley SA, Ross FA, Chevtzoff C et al (2010) Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metab 11:554–565

Pryor HJ, Smyth JE, Quinlan PT, Halestrap AP (1987) Evidence that the flux control coefficient of the respiratory chain is high during gluconeogenesis from lactate in hepatocytes from starved rats. Implications for the hormonal control of gluconeogenesis and action of hypoglycaemic agents. Biochem J 247:449–457

Baur JA, Birnbaum MJ (2014) Control of gluconeogenesis by metformin: does redox trump energy charge? Cell Metab 20:197–199

Schafer G (1976) On the mechanism of action of hypoglycemia-producing biguanides. A reevaluation and a molecular theory. Biochem Pharmacol 25:2005–2014

Logie L, Harthill J, Patel K et al (2012) Cellular responses to the metal-binding properties of metformin. Diabetes 61:1423–1433

Repiscak P, Erhardt S, Rena G, Paterson MJ (2014) Biomolecular mode of action of metformin in relation to its copper binding properties. Biochemistry 53:787–795

Quan X, Uddin R, Heiskanen A et al (2015) The copper binding properties of metformin--QCM-D, XPS and nanobead agglomeration. Chem Commun 51:17313–17316

Ross FA, MacKintosh C, Hardie DG (2016) AMP-activated protein kinase: a cellular energy sensor that comes in 12 flavours. FEBS J 283:2987–3001

Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13:251–262

Zhou G, Myers R, Li Y et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174

Zhang CS, Li M, Ma T et al (2016) Metformin activates AMPK through the lysosomal pathway. Cell Metab 24:521–522

Corton JM, Gillespie JG, Hawley SA, Hardie DG (1995) 5-Aminoimidazole-4-carboxamide ribonucleoside: a specific method for activating AMP-activated protein kinase in intact cells? Eur J Biochem 229:558–565

Lochhead PA, Salt IP, Walker KS, Hardie DG, Sutherland C (2000) 5-Aminoimidazole-4-carboxamide riboside mimics the effects of insulin on the expression of the 2 key gluconeogenic genes PEPCK and glucose-6-phosphatase. Diabetes 49:896–903

Vincent MF, Marangos PJ, Gruber HE, Van den Berghe G (1991) Inhibition by AICA riboside of gluconeogenesis in isolated rat hepatocytes. Diabetes 40:1259–1266

Foretz M, Hebrard S, Leclerc J et al (2010) Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest 120:2355–2369

Miller RA, Chu Q, Xie J, Foretz M, Viollet B, Birnbaum MJ (2013) Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494:256–260

Johanns M, Lai YC, Hsu MF et al (2016) AMPK antagonizes hepatic glucagon-stimulated cyclic AMP signalling via phosphorylation-induced activation of cyclic nucleotide phosphodiesterase 4B. Nat Commun 7:10856

Fullerton MD, Galic S, Marcinko K et al (2013) Single phosphorylation sites in ACC1 and ACC2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin. Nat Med 19:1649–1654

Bailey CJ, Mynett KJ, Page T (1994) Importance of the intestine as a site of metformin-stimulated glucose utilization. Br J Pharmacol 112:671–675

Sundelin EI, Gormsen LC, Jensen JB et al (2017) Genetic polymorphisms in organic cation transporter 1 attenuates hepatic metformin exposure in humans. Clin Pharmacol Ther doi: 10.1002/cpt.701

Dujic T, Zhou K, Yee SW et al (2016) Variants in pharmacokinetic transporters and glycemic response to metformin: a metgen meta-analysis. Clin Pharmacol Ther 101:763–772

Zhou K, Donnelly LA, Kimber CH et al (2009) Reduced-function SLC22A1 polymorphisms encoding organic cation transporter 1 and glycemic response to metformin: a GoDARTS study. Diabetes 58:1434–1439

Buse JB, DeFronzo RA, Rosenstock J et al (2016) The primary glucose-lowering effect of metformin resides in the gut, not the circulation: results from short-term pharmacokinetic and 12-week dose-ranging studies. Diabetes Care 39:198–205

McCreight LJ, Bailey CJ, Pearson ER (2016) Metformin and the gastrointestinal tract. Diabetologia 59:426–435

Massollo M, Marini C, Brignone M et al (2013) Metformin temporal and localized effects on gut glucose metabolism assessed using 18F-FDG PET in mice. J Nucl Med 54:259–266

Preiss D, Dawed A, Welsh P et al (2017) Sustained influence of metformin therapy on circulating glucagon-like peptide-1 levels in individuals with and without type 2 diabetes. Diabetes Obes Metab 19:356–363

DeFronzo RA, Buse JB, Kim T et al (2016) Once-daily delayed-release metformin lowers plasma glucose and enhances fasting and postprandial GLP-1 and PYY: results from two randomised trials. Diabetologia 59:1645–1654

Duca FA, Cote CD, Rasmussen BA et al (2015) Metformin activates a duodenal Ampk-dependent pathway to lower hepatic glucose production in rats. Nat Med 21:506–511

Kirpichnikov D, McFarlane SI, Sowers JR (2002) Metformin: an update. Ann Intern Med 137:25–33

Cubeddu LX, Bonisch H, Gothert M et al (2000) Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT3 receptors. Naunyn Schmiedeberg's Arch Pharmacol 361:85–91

Dujic T, Zhou K, Donnelly LA, Tavendale R, Palmer CN, Pearson ER (2015) Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a GoDARTS study. Diabetes 64:1786–1793

Dujic T, Zhou K, Tavendale R, Palmer CN, Pearson ER (2016) Effect of serotonin transporter 5-HTTLPR polymorphism on gastrointestinal intolerance to metformin: a GoDARTS study. Diabetes Care 39:1896–1901

Cabreiro F, Au C, Leung KY et al (2013) Metformin retards aging in C. elegans by altering microbial folate and methionine metabolism. Cell 153:228–239

Shin NR, Lee JC, Lee HY et al (2014) An increase in the Akkermansia spp. population induced by metformin treatment improves glucose homeostasis in diet-induced obese mice. Gut 63:727–735

Forslund K, Hildebrand F, Nielsen T et al (2015) Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 528:262–266

Vasamsetti SB, Karnewar S, Kanugula AK, Thatipalli AR, Kumar JM, Kotamraju S (2015) Metformin inhibits monocyte-to-macrophage differentiation via AMPK-mediated inhibition of STAT3 activation: potential role in atherosclerosis. Diabetes 64:2028–2041

Cameron AR, Morrison VL, Levin D et al (2016) Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res 119:652–665

Bannister CA, Holden SE, Jenkins-Jones S et al (2014) Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab 16:1165–1173

Martin-Montalvo A, Mercken EM, Mitchell SJ et al (2013) Metformin improves healthspan and lifespan in mice. Nat Commun 4:2192

Wu L, Zhou B, Oshiro-Rapley N et al (2016) An ancient, unified mechanism for metformin growth inhibition in C. elegans and cancer. Cell 167:1705-1718.e13

Howell JJ, Hellberg K, Turner M et al (2017) Metformin inhibits hepatic mTORC1 signaling via dose-dependent mechanisms involving AMPK and the TSC complex. Cell Metab 25:463–471

Florez JC (2017) The pharmacogenetics of metformin. Diabetologia DOI: 10.1007/s00125-017-4335-y

Zhou K, Bellenguez C, Spencer CC et al (2011) Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet 43:117–120

Zhou K, Yee SW, Seiser EL et al (2016) Variation in the glucose transporter gene SLC2A2 is associated with glycemic response to metformin. Nat Genet 48:1055–1059

Koo SH, Flechner L, Qi L et al (2005) The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437:1109–1114

Patel K, Foretz M, Marion A et al (2014) The LKB1-salt-inducible kinase pathway functions as a key gluconeogenic suppressor in the liver. Nat Commun 5:4535