Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on sleep in brain health

LIVE: Thursday 2nd May 2024, 18:00-19:30 (CEST)

Quality sleep is essential for health. But what happens to our brains when sleep patterns are disturbed? Join our experts to explore the interplay between sleep disruption and neurological diseases, and the questions that you need to be asking your patients to help you prevent the harmful effects of sleep deprivation.
ADVANCED SEARCH
Log in
Top
Diabetologia
Published in: Diabetologia 9/2013

Open Access 01-09-2013 | Review

Molecular mechanism of action of metformin: old or new insights?

Authors: Graham Rena, Ewan R. Pearson, Kei Sakamoto

Published in: Diabetologia | Issue 9/2013

Login to get access

Abstract

Metformin is the first-line drug treatment for type 2 diabetes. Globally, over 100 million patients are prescribed this drug annually. Metformin was discovered before the era of target-based drug discovery and its molecular mechanism of action remains an area of vigorous diabetes research. An improvement in our understanding of metformin’s molecular targets is likely to enable target-based identification of second-generation drugs with similar properties, a development that has been impossible up to now. The notion that 5' AMP-activated protein kinase (AMPK) mediates the anti-hyperglycaemic action of metformin has recently been challenged by genetic loss-of-function studies, thrusting the AMPK-independent effects of the drug into the spotlight for the first time in more than a decade. Key AMPK-independent effects of the drug include the mitochondrial actions that have been known for many years and which are still thought to be the primary site of action of metformin. Coupled with recent evidence of AMPK-independent effects on the counter-regulatory hormone glucagon, new paradigms of AMPK-independent drug action are beginning to take shape. In this review we summarise the recent research developments on the molecular action of metformin.
Literature
1.
Nathan DM, Buse JB, Davidson MB et al (2009) Medical management of hyperglycaemia in type 2 diabetes mellitus: a consensus algorithm for the initiation and adjustment of therapy. A consensus statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetologia 52:17–30PubMedCrossRef
2.
Rodbard H, Jellinger P, Davidson J et al (2009) Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract 15:540–559PubMedCrossRef
3.
Inzucchi SE, Bergenstal RM, Buse JB et al (2012) 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 55:1577–1596PubMedCrossRef
4.
UK Prospective Diabetes Study (UKPDS) Group (1998) Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet 352:854–865CrossRef
5.
Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM (2009) New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care 32:1620–1625PubMedCrossRef
6.
Evans JMM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD (2005) Metformin and reduced risk of cancer in diabetic patients. BMJ 330:1304–1305PubMedCrossRef
7.
Noto H, Goto A, Tsujimoto T, Noda M (2012) Cancer risk in diabetic patients treated with metformin: a systematic review and meta-analysis. PLoS One 7:e33411PubMedCrossRef
8.
van Staa TP, Patel D, Gallagher AM, de Bruin ML (2012) Glucose-lowering agents and the patterns of risk for cancer: a study with the General Practice Research Database and secondary care data. Diabetologia 55:654–665PubMedCrossRef
9.
Watanabe CK (1918) Studies in the metabolism changes induced by administration of guanidine bases. J Biol Chem 33:253–265
10.
Frank E, Nothmann M, Wagner A (1926) Uber synthetisch dargestellte Körper mit insulinartiger Wirkung auf den normalen und diabetischen Organismus. Klin Wochenschr 5:2100–2107 [article in German]CrossRef
11.
Bischoff F, Sahyun M, Long ML (1929) Guanidine structure and hypoglycemia. J Biol Chem 81:325–349
12.
Blatherwick NR, Sahyun M, Hill E (1927) Some effects of synthalin on metabolism. J Biol Chem 75:671–683
13.
Luft D, Schilling RM, Eggstein M (1978) Lactic acidosis in biguanide-treated diabetics. Diabetologia 14:75–87PubMedCrossRef
14.
Bodo R, Marks HP (1928) The relation of synthalin to carbohydrate metabolism. J Physiol 65:83–99PubMed
15.
Chance B, Hollunger G (1963) Inhibition of electron and energy transfer in mitochondria. J Biol Chem 238:432–438PubMed
16.
Pressman BC (1963) The effects of guanidine and alkylguanidines on the energy transfer reactions of mitochondria. J Biol Chem 238:401–409
17.
Davidoff F (1971) Effects of guanidine derivatives on mitochondrial function. J Biol Chem 246:4017–4027PubMed
18.
Davidoff F (1968) Effects of guanidine derivatives on mitochondrial function: I. Phenethylbiguanide inhibition of respiration in mitochondria from guinea pig and rat tissues. J Clin Invest 47:2331–2343PubMedCrossRef
19.
Schafer G (1981) Guanidines and biguanides. In: Erecinska M, Wilson DF (eds) Inhibitors of mitochondrial functions. Pergamon Press, New York, pp 165–185
20.
Schafer G (1976) On the mechanism of action of hypoglycemia-producing biguanides, a reevaluation and a molecular theory. Biochem Pharm 25:2005–2014PubMedCrossRef
21.
22.
Davidoff F, Carr S (1972) Calcium-like action of phenethylbiguanide and related compounds: inhibition of pyruvate kinase. Proc Natl Acad Sci 69:1957–1961PubMedCrossRef
23.
Logie L, Harthill J, Patel K et al (2012) Cellular responses to the metal-binding properties of metformin. Diabetes 61:1423–1433PubMedCrossRef
24.
Sen D (1969) Ultraviolet spectral studies on metal-biguanide complexes. J Chem Soc A, 2900–2903
25.
Zhu M, Lu L, Yang P, Jin X (2002) Bis(1,1-dimethylbiguanido)copper(II) octahydrate. Acta Cryst E58:m217–m219
26.
Ray RK, Kauffman GB (1999) Metal and non-metal biguanide complexes. New Age International Publishers, New Delhi
27.
Ray RK, Kauffman GB (1990) An EPR Study of some copper (II) coordination compounds of substituted biguanides. Part IV. Inorg Chim Acta 174:257–262CrossRef
28.
Ray RK, Kauffman GB (1990) An EPR study of copper (II)-substituted biguanide complexes. Part III. Inorg Chim Acta 174:237–244CrossRef
29.
Meyer F, Ipaktchi M, Clauser H (1967) Specific inhibition of gluconeogenesis by biguanides. Nature 213:203–204PubMedCrossRef
30.
Cook DE, Blair JB, Lardy HA (1973) Mode of action of hypoglycemic agents. J Biol Chem 248:5272–5277PubMed
31.
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 348:607–614PubMedCrossRef
32.
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 275:223–228PubMedCrossRef
33.
Hawley SA, Ross FA, Chevtzoff C et al (2010) Use of cells expressing gamma subunit variants to identify diverse mechanisms of AMPK activation. Cell Metabolism 11:554–565PubMedCrossRef
34.
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. Biochem J 247:449–457PubMed
35.
Salpeter SR, Greyber E, Pasternak GA, Salpeter EE (2003) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus: systematic review and meta-analysis. Arch Intern Med 163:2594–2602PubMedCrossRef
36.
Salpeter SR, Greyber E, Pasternak GA, Salpeter EE (2010) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev, Issue 4. Art. no.: CD002967. doi:10.​1002/​14651858.​CD002967.​pub4
37.
Salpeter S, Greyber E, Pasternak G, Salpeter E (2006) Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev, Issue 1. Art. no.: CD002967. doi:10.​1002/​14651858.​CD002967.​pub2
38.
Brunmair B, Staniek K, Gras F et al (2004) Thiazolidinediones, like metformin, inhibit respiratory complex I: a common mechanism contributing to their antidiabetic actions? Diabetes 53:1052–1059PubMedCrossRef
39.
Zhou G, Myers R, Li Y et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108:1167–1174PubMed
40.
Hardie DG, Ross FA, Hawley SA (2012) AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Biol 13:251–262PubMedCrossRef
41.
Kahn BB, Alquier T, Carling D, Hardie DG (2005) AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metabolism 1:15–25PubMedCrossRef
42.
Perriello G, Misericordia P, Volpi E et al (1994) Acute antihyperglycemic mechanisms of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production. Diabetes 43:920–928PubMedCrossRef
43.
Bain J, Plater L, Elliott M et al (2007) The selectivity of protein kinase inhibitors; a further update. Biochem J 408:297–315PubMedCrossRef
44.
Vogt J, Traynor R, Sapkota GP (2011) The specificities of small molecule inhibitors of the TGFβ and BMP pathways. Cell Signal 23:1831–1842PubMedCrossRef
45.
Shaw RJ, Lamia KA, Vasquez D et al (2005) The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310:1642–1646PubMedCrossRef
46.
Altarejos JY, Montminy M (2011) CREB and the CRTC co-activators: sensors for hormonal and metabolic signals. Nat Rev Mol Cell Biol 12:141–151PubMedCrossRef
47.
Lin HV, Accili D (2011) Hormonal regulation of hepatic glucose production in health and disease. Cell Metab 14:9–19PubMedCrossRef
48.
Foretz M, Hébrard 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 120:2355–2369PubMedCrossRef
49.
Alessi DR, Sakamoto K, Bayascas JR (2006) LKB1-dependent signaling pathways. Annu Rev Biochem 75:137–163PubMedCrossRef
50.
Koepsell H, Lips K, Volk C (2007) Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications. Pharm Res 24:1227–1251PubMedCrossRef
51.
Rena G, Pearson ER, Sakamoto K (2012) Molecular action and pharmacogenetics of metformin: current understanding of an old drug. Diabetes Management 2:439–452CrossRef
52.
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 117:1422–1431PubMedCrossRef
53.
Bailey CJ, Puah JA (1986) Effect of metformin on glucose metabolism in mouse soleus muscle. Diabetes Metab 12:212–218
54.
Turban S, Stretton C, Drouin O et al (2012) Defining the contribution of AMPK and PKCs in the regulation of glucose uptake by metformin in skeletal muscle cells. J Biol Chem 287:20088–20099PubMedCrossRef
55.
Hundal HS, Ramlal T, Reyes R, Leiter LA, Klip A (1992) Cellular mechanism of metformin action involves glucose transporter translocation from an intracellular pool to the plasma membrane in L6 muscle cells. Endocrinology 131:1165–1173PubMedCrossRef
56.
Musi N, Hirshman MF, Nygren J et al (2002) Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes 51:2074–2081PubMedCrossRef
57.
58.
Hardie DG (2007) AMP-activated protein kinase as a drug target. Annu Rev Pharmacol Toxicol 47:185–210PubMedCrossRef
59.
Wilcock C, Bailey CJ (1994) Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 24:49–57PubMedCrossRef
60.
Morrow VA, Foufelle F, Connell JMC, Petrie JR, Gould GW, Salt IP (2003) Direct activation of AMP-activated protein kinase stimulates nitric-oxide synthesis in human aortic endothelial cells. J Biol Chem 278:31629–31639PubMedCrossRef
61.
Davis BJ, Xie Z, Viollet B, Zou MH (2006) Activation of the AMP-activated kinase by antidiabetes drug metformin stimulates nitric oxide synthesis in vivo by promoting the association of heat shock protein 90 and endothelial nitric oxide synthase. Diabetes 55:496–505PubMedCrossRef
62.
Ouslimani N, Peynet J, Bonnefont-Rousselot D, Thérond P, Legrand A, Beaudeux J-L (2005) Metformin decreases intracellular production of reactive oxygen species in aortic endothelial cells. Metabolism 54:829–834PubMedCrossRef
63.
Sanders MJ, Ali ZS, Hegarty BD, Heath R, Snowden MA, Carling D (2007) Defining the mechanism of activation of AMP-activated protein kinase by the small molecule A-769662, a member of the thienopyridone family. J Biol Chem 282:32539–32548PubMedCrossRef
64.
Scott JW, van Denderen BJ, Jorgensen SB et al (2008) Thienopyridone drugs are selective activators of AMP-activated protein kinase β1-containing complexes. Chem Biol 15:1220–1230PubMedCrossRef
65.
Miller RA, Birnbaum MJ (2010) An energetic tale of AMPK-independent effects of metformin. J Clin Invest 120:2267–2270PubMedCrossRef
66.
McGrane MM, El-Maghrabi MR, Pilkis SJ (1983) The interaction of fructose 2,6-bisphosphate and AMP with rat hepatic fructose 1,6-bisphosphatase. J Biol Chem 258:10445–10454PubMed
67.
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 494:256–260PubMedCrossRef
68.
Gawler DJ, Wilson A, Houslay MD (1989) Metformin treatment of lean and obese Zucker rats modulates the ability of glucagon and insulin to regulate hepatocyte adenylate cyclase activity. J Endocrinol 122:207–212PubMedCrossRef
69.
Alengrin F, Grossi G, Canivet B, Dolais-Kitabgi J (1987) Inhibitory effects of metformin on insulin and glucagon action in rat hepatocytes involve postreceptor alterations. Diabet Metab 13:591–597
70.
Yu B, Pugazhenthi S, Khandelwal RL (1994) Effects of metformin on glucose and glucagon regulated gluconeogenesis in cultured normal and diabetic hepatocytes. Biochem Pharmacol 48:949–954PubMedCrossRef
71.
Houslay MD, Milligan G (1997) Tailoring cAMP-signalling responses through isoform multiplicity. Trends Biochem Sci 22:217–224PubMedCrossRef
72.
Gelling RW, Du XQ, Dichmann DS et al (2003) Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci 100:1438–1443PubMedCrossRef
73.
Kazda CM, Garhyan P, Kelly RP et al (2012) 12-week treatment with glucagon receptor antagonist LY2409021 significantly lowers HbA1c and is well tolerated in patients with type 2 diabetes mellitus. Diabetologia 55(Suppl 1):S51, Abstr. 112
74.
Ouhilal S, Vuguin P, Cui L et al (2012) Hypoglycemia, hyperglucagonemia, and fetoplacental defects in glucagon receptor knockout mice: a role for glucagon action in pregnancy maintenance. Am J Physiol Endocrinol Metab 302:E522–E531PubMedCrossRef
75.
Wulffele MG, Kooy A, de Zeeuw D, Stehouwer CD, Gansevoort RT (2004) The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med 256:1–14PubMedCrossRef
76.
Winegrad AI, Davidson JK, Ricketts HT et al (1971) The University Group Diabetes Program Study pertaining to phenformin. JAMA 217:817CrossRef
77.
78.
Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F (2012) Cellular and molecular mechanisms of metformin: an overview. Clin Sci 122:253–270PubMedCrossRef
79.
Shu Y, Brown C, Castro RA et al (2008) Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther 83:273–280PubMedCrossRef
80.
Christensen MMH, Brasch-Andersen C, Green H et al (2011) The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c. Pharmacogenetics and Genomics 21:837–850PubMedCrossRef
81.
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 58:1434–1439PubMedCrossRef
82.
Van Leeuwen N, Nijpels G, Becker ML et al (2012) A gene variant near ATM is significantly associated with metformin treatment response in type 2 diabetes: a replication and meta-analysis of five cohorts. Diabetologia 55:1971–1977PubMedCrossRef
83.
The GoDARTS and UKPDS Diabetes Pharmacogenetics Study Group & The Wellcome Trust Case Control Consortium 2 (2011) Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Common variants near ATM are associated with glycemic response to metformin in type 2 diabetes. Nat Genet 43:117–120CrossRef
84.
Donnelly LA, Morris AD, Pearson ER (2009) Adherence in patients transferred from immediate release metformin to a sustained release formulation: a population-based study. Diabetes Obes Metab 11:338–342PubMedCrossRef
85.
Christensen M, Bagger JI, Vilsboll T, Knop FK (2011) The alpha-cell as target for type 2 diabetes therapy. The review of diabetic studies: Rev Diabet Stud 8:369–381PubMedCrossRef
86.
Beshgetoor D, Hambidge M (1998) Clinical conditions altering copper metabolism in humans. Am J Clin Nutr 67:1017S–1021SPubMed
87.
Cooper GJS, Chan YK, Dissanayake AM et al (2005) Demonstration of a hyperglycemia-driven pathogenic abnormality of copper homeostasis in diabetes and its reversibility by selective chelation: quantitative comparisons between the biology of copper and eight other nutritionally essential elements in normal and diabetic individuals. Diabetes 54:1468–1476PubMedCrossRef
88.
Cooper GJS, Phillips ARJ, Choong SY et al (2004) Regeneration of the heart in diabetes by selective copper chelation. Diabetes 53:2501–2508PubMedCrossRef
89.
Cooper G, Young A, Gamble G et al (2009) A copper(II)-selective chelator ameliorates left-ventricular hypertrophy in type 2 diabetic patients: a randomised placebo-controlled study. Diabetologia 52:715–722PubMedCrossRef
Metadata
Title
Molecular mechanism of action of metformin: old or new insights?
Authors
Graham Rena
Ewan R. Pearson
Kei Sakamoto
Publication date
01-09-2013
Publisher
Springer Berlin Heidelberg
Published in
Diabetologia / Issue 9/2013
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-013-2991-0

Other articles of this Issue 9/2013

Diabetologia 9/2013 Go to the issue

Retraction Note

RETRACTED ARTICLE: Common variation in PPARGC1A/B and progression to diabetes or change in metabolic traits following preventive interventions: the Diabetes Prevention Program

Commentary

Pancreatic safety of GLP-1-based therapeutic agents: further insights from rodent studies?

Article

A history of previous gestational diabetes mellitus is associated with adverse changes in insulin secretion and VLDL metabolism independently of increased intrahepatocellular lipid

Letter

Secondary analysis of electronic databases: potentials and limitations

Article

UKPDS Outcomes Model 2: a new version of a model to simulate lifetime health outcomes of patients with type 2 diabetes mellitus using data from the 30 year United Kingdom Prospective Diabetes Study: UKPDS 82

Article

Deficiency of APPL1 in mice impairs glucose-stimulated insulin secretion through inhibition of pancreatic beta cell mitochondrial function

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24 to hear Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits