Diabetes Research and Clinical Practice
Volume 95, Issue 1 , Pages 1-9 , January 2012

Metformin effects revisited

  • P. Andújar-Plata

      Affiliations

    • Department of Endocrinology and Nutrition, Complejo Hospitalario Universitario de Santiago de Compostela, 15706 Santiago de Compostela, Spain
    • Corresponding Author InformationCorresponding author. Tel.: +34 669550602; fax: +34 981951546.
    • ,
  • X. Pi-Sunyer

      Affiliations

    • Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, St. Luke's Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY 10025, United States
    • ,
  • B. Laferrère

      Affiliations

    • Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, St. Luke's Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY 10025, United States

Received 13 June 2011 ,Revised 19 September 2011 ,Accepted 20 September 2011.

References 

  1. International Diabetes Federation . Diabetes atlas. fourth ed.. Brussels: International Diabetes Federation; 2009;
  2. Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. Ann Intern Med. 2002;137:25–33
  3. Stumvoll M, Nurjhan N, Perriello G, Dailey G, Gerich JE. Metabolic effects of metformin in non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333:550–554
  4. DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995;333:541–549
  5. The global challenge of diabetes. Lancet. 2008;371:1723
  6. Campbell IW, Howlett HC. Worldwide experience of metformin as an effective glucose-lowering agent: a meta-analysis. Diabetes Metab Rev. 1995;11(Suppl. 1):S57–S62
  7. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334:574–579
  8. UK Prospective Diabetes Study (UKPDS) . VIII. Study design, progress and performance. Diabetologia. 1991;34:877–890
  9. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403
  10. Nathan DM, Buse JB, Davidson MB, Ferrannini E, Holman RR, Sherwin R, et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2009;32:193–203
  11. United Kingdom Prospective Diabetes Study (UKPDS) . 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ. 1995;310:83–88
  12. Wright AD, Cull CA, Macleod KM, Holman RR. Hypoglycemia in Type 2 diabetic patients randomized to and maintained on monotherapy with diet, sulfonylurea, metformin, or insulin for 6 years from diagnosis: UKPDS73. J Diabetes Complications. 2006;20:395–401
  13. Turner RC, Cull CA, Frighi V, Holman RR. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). UK Prospective Diabetes Study (UKPDS) Group. JAMA. 1999;281:2005–2012
  14. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352:854–865
  15. Clarke P, Gray A, Adler A, Stevens R, Raikou M, Cull C, et al. Cost-effectiveness analysis of intensive blood-glucose control with metformin in overweight patients with type II diabetes (UKPDS No. 51). Diabetologia. 2001;44:298–304
  16. Ong CR, Molyneaux LM, Constantino MI, Twigg SM, Yue DK. Long-term efficacy of metformin therapy in nonobese individuals with type 2 diabetes. Diabetes Care. 2006;29:2361–2364
  17. Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–1589
  18. Diabetes Prevention Program Research Group . Within-trial cost-effectiveness of lifestyle intervention or metformin for the primary prevention of type 2 diabetes. Diabetes Care. 2003;26:2518–2523
  19. Fujimoto WY, Jablonski KA, Bray GA, Kriska A, Barrett-Connor E, Haffner S, et al. Body size and shape changes and the risk of diabetes in the Diabetes Prevention Program. Diabetes. 2007;56:1680–1685
  20. Lachin JM, Christophi CA, Edelstein SL, Ehrmann DA, Hamman RF, Kahn SE, et al. Factors associated with diabetes onset during metformin versus placebo therapy in the Diabetes Prevention Program. Diabetes. 2007;56:1153–1159
  21. Ratner RE, Christophi CA, Metzger BE, Dabelea D, Bennett PH, Pi-Sunyer X, et al. Prevention of diabetes in women with a history of gestational diabetes: effects of metformin and lifestyle interventions. J Clin Endocrinol Metab. 2008;93:4774–4779
  22. Perreault L, Kahn SE, Christophi CA, Knowler WC, Hamman RF. Regression from pre-diabetes to normal glucose regulation in the Diabetes Prevention Program. Diabetes Care. 2009;32:1583–1588
  23. Kitabchi AE, Temprosa M, Knowler WC, Kahn SE, Fowler SE, Haffner SM, et al. Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the Diabetes Prevention Program: effects of lifestyle intervention and metformin. Diabetes. 2005;54:2404–2414
  24. Orchard TJ, Temprosa M, Goldberg R, Haffner S, Ratner R, Marcovina S, et al. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med. 2005;142:611–619
  25. Haffner S, Temprosa M, Crandall J, Fowler S, Goldberg R, Horton E, et al. Intensive lifestyle intervention or metformin on inflammation and coagulation in participants with impaired glucose tolerance. Diabetes. 2005;54:1566–1572
  26. Ratner R, Goldberg R, Haffner S, Marcovina S, Orchard T, Fowler S, et al. Impact of intensive lifestyle and metformin therapy on cardiovascular disease risk factors in the Diabetes Prevention Program. Diabetes Care. 2005;28:888–894
  27. Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, Brenneman AT, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet. 2009;374:1677–1686
  28. Salpeter SR, Greyber E, Pasternak GA, Salpeter EE. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2010;CD002967
  29. Scarpello JH, Howlett HC. Metformin therapy and clinical uses. Diab Vasc Dis Res. 2008;5:157–167
  30. Gunton JE, Delhanty PJ, Takahashi S, Baxter RC. Metformin rapidly increases insulin receptor activation in human liver and signals preferentially through insulin-receptor substrate-2. J Clin Endocrinol Metab. 2003;88:1323–1332
  31. Luo Z, Zang M, Guo W. AMPK as a metabolic tumor suppressor: control of metabolism and cell growth. Future Oncol. 2010;6:457–470
  32. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108:1167–1174
  33. Yoshida T, Okuno A, Tanaka J, Takahashi K, Nakashima R, Kanda S, et al. Metformin primarily decreases plasma glucose not by gluconeogenesis suppression but by activating glucose utilization in a non-obese type 2 diabetes Goto-Kakizaki rats. Eur J Pharmacol. 2009;623:141–147
  34. Zou MH, Kirkpatrick SS, Davis BJ, Nelson JS, Wiles WG, Schlattner U, et al. Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo. Role of mitochondrial reactive nitrogen species. J Biol Chem. 2004;279:43940–43951
  35. Fujita Y, Hosokawa M, Fujimoto S, Mukai E, Abudukadier A, Obara A, et al. Metformin suppresses hepatic gluconeogenesis and lowers fasting blood glucose levels through reactive nitrogen species in mice. Diabetologia. 2010;53:1472–1481
  36. Foretz M, Hebrard S, Leclerc J, Zarrinpashneh E, Soty M, Mithieux G, et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J Clin Invest. 2010;120:2355–2369
  37. Maida A, Lamont BJ, Cao X, Drucker DJ. Metformin regulates the incretin receptor axis via a pathway dependent on peroxisome proliferator-activated receptor-alpha in mice. Diabetologia. 2011;54:339–349
  38. Scarpello JH, Hodgson E, Howlett HC. Effect of metformin on bile salt circulation and intestinal motility in type 2 diabetes mellitus. Diabet Med. 1998;15:651–656
  39. Carter D, Howlett HC, Wiernsperger NF, Bailey CJ. Differential effects of metformin on bile salt absorption from the jejunum and ileum. Diabetes Obes Metab. 2003;5:120–125
  40. Carter D, Howlett HC, Wiernsperger NF, Bailey C. Effects of metformin on bile salt transport by monolayers of human intestinal Caco-2 cells. Diabetes Obes Metab. 2002;4:424–427
  41. Thomas C, Gioiello A, Noriega L, Strehle A, Oury J, Rizzo G, et al. TGR5-mediated bile acid sensing controls glucose homeostasis. Cell Metab. 2009;10:167–177
  42. Patti ME, Houten SM, Bianco AC, Bernier R, Larsen PR, Holst JJ, et al. Serum bile acids are higher in humans with prior gastric bypass: potential contribution to improved glucose and lipid metabolism. Obesity (Silver Spring). 2009;17:1671–1677
  43. Hull RL, Shen ZP, Watts MR, Kodama K, Carr DB, Utzschneider KM, et al. 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. 2005;54:2235–2244
  44. Saydah SH, Loria CM, Eberhardt MS, Brancati FL. Abnormal glucose tolerance and the risk of cancer death in the United States. Am J Epidemiol. 2003;157:1092–1100
  45. Michels KB, Solomon CG, Hu FB, Rosner BA, Hankinson SE, Colditz GA, et al. Type 2 diabetes and subsequent incidence of breast cancer in the Nurses Health Study. Diabetes Care. 2003;26:1752–1758
  46. La Vecchia C, Negri E, Franceschi S, D’Avanzo B, Boyle P. A case–control study of diabetes mellitus and cancer risk. Br J Cancer. 1994;70:950–953
  47. Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ. 2005;330:1304–1305
  48. Bowker SL, Majumdar SR, Veugelers P, Johnson JA. Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care. 2006;29:254–258
  49. Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009;32:1620–1625
  50. Monami M, Colombi C, Balzi D, Dicembrini I, Giannini S, Melani C, et al. Metformin and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care. 2011;34:129–131
  51. Landman GW, Kleefstra N, van Hateren KJ, Groenier KH, Gans RO, Bilo HJ. Metformin associated with lower cancer mortality in type 2 diabetes: ZODIAC-16. Diabetes Care. 2010;33:322–326
  52. Hosono K, Endo H, Takahashi H, Sugiyama M, Sakai E, Uchiyama T, et al. Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res (Phila). 2010;3:1077–1083
  53. Home PD, Kahn SE, Jones NP, Noronha D, Beck-Nielsen H, Viberti G. Experience of malignancies with oral glucose-lowering drugs in the randomised controlled ADOPT (A Diabetes Outcome Progression Trial) and RECORD (Rosiglitazone Evaluated for Cardiovascular Outcomes and Regulation of Glycaemia in Diabetes) clinical trials. Diabetologia. 2010;53:1838–1845
  54. Jiralerspong S, Palla SL, Giordano SH, Meric-Bernstam F, Liedtke C, Barnett CM, et al. 2009 Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol. 2009;27:3297–3302
  55. Bodmer M, Meier C, Krahenbuhl S, Jick SS, Meier CR. Long-term metformin use is associated with decreased risk of breast cancer. Diabetes Care. 2010;33:1304–1308
  56. Li D, Yeung SC, Hassan MM, Konopleva M, Abbruzzese JL. Antidiabetic therapies affect risk of pancreatic cancer. Gastroenterology. 2009;137:482–488
  57. Wright JL, Stanford JL. Metformin use and prostate cancer in Caucasian men: results from a population-based case–control study. Cancer Causes Control. 2009;20:1617–1622
  58. He XX, Tu SM, Lee MH, Yeung SC. Thiazolidinediones and metformin associated with improved survival of diabetic prostate cancer patients. Ann Oncol. 2011;Epub ahead of print
  59. Vazquez-Martin A, Oliveras-Ferraros C, Menendez JA. The antidiabetic drug metformin suppresses HER2 (erbB-2) oncoprotein overexpression via inhibition of the mTOR effector p70S6K1 in human breast carcinoma cells. Cell Cycle. 2009;8:88–96
  60. Alimova IN, Liu B, Fan Z, Edgerton SM, Dillon T, Lind SE, et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle. 2009;8:909–915
  61. Hirsch HA, Iliopoulos D, Tsichlis PN, Struhl K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 2009;69:7507–7511
  62. Vazquez-Martin A, Oliveras-Ferraros C, Cufi S, Del Barco S, Martin-Castillo B, Menendez JA. Metformin regulates breast cancer stem cell ontogeny by transcriptional regulation of the epithelial–mesenchymal transition (EMT) status. Cell Cycle. 2010;9:3807–3814
  63. Liu B, Fan Z, Edgerton SM, Deng XS, Alimova IN, Lind SE, et al. Metformin induces unique biological and molecular responses in triple negative breast cancer cells. Cell Cycle. 2009;8:2031–2040
  64. Maatela J, Aromaa A, Salmi T, Pohja M, Vuento M, Gronroos M. The risk of endometrial cancer in diabetic and hypertensive patients: a nationwide record-linkage study in Finland. Ann Chir Gynaecol Suppl. 1994;208:20–24
  65. Cantrell LA, Zhou C, Mendivil A, Malloy KM, Gehrig PA, Bae-Jump VL. Metformin is a potent inhibitor of endometrial cancer cell proliferation—implications for a novel treatment strategy. Gynecol Oncol. 2010;116:92–98
  66. Tan BK, Adya R, Chen J, Lehnert H, Sant Cassia LJ, Randeva HS. Metformin treatment exerts antiinvasive and antimetastatic effects in human endometrial carcinoma cells. J Clin Endocrinol Metab. 2011;96:808–816
  67. Rattan R, Giri S, Hartmann LC, Shridhar V. Metformin attenuates ovarian cancer cell growth in an AMP-kinase dispensable manner. J Cell Mol Med. 2011;15:166–178
  68. Yasmeen A, Beauchamp MC, Piura E, Segal E, Pollak M, Gotlieb WH. Induction of apoptosis by metformin in epithelial ovarian cancer: involvement of the Bcl-2 family proteins. Gynecol Oncol. 2011;Epub ahead of print
  69. Kisfalvi K, Eibl G, Sinnett-Smith J, Rozengurt E. Metformin disrupts crosstalk between G protein-coupled receptor and insulin receptor signaling systems and inhibits pancreatic cancer growth. Cancer Res. 2009;69:6539–6545
  70. Algire C, Amrein L, Zakikhani M, Panasci L, Pollak M. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer. 2010;17:351–360
  71. Algire C, Zakikhani M, Blouin MJ, Shuai JH, Pollak M. Metformin attenuates the stimulatory effect of a high-energy diet on in vivo LLC1 carcinoma growth. Endocr Relat Cancer. 2008;15:833–839
  72. Memmott RM, Mercado JR, Maier CR, Kawabata S, Fox SD, Dennis PA. Metformin prevents tobacco carcinogen—induced lung tumorigenesis. Cancer Prev Res (Phila). 2010;3:1066–1076
  73. Iliopoulos D, Hirsch HA, Struhl K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res. 2011;71:3196–3201
  74. Anisimov VN, Berstein LM, Popovich IG, Zabezhinski MA, Egormin PA, Piskunova TS, et al. If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging (Albany, NY). 2011;3:148–157

PII: S0168-8227(11)00524-9

doi: 10.1016/j.diabres.2011.09.022

Diabetes Research and Clinical Practice
Volume 95, Issue 1 , Pages 1-9 , January 2012

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