Insulin Resistance: Clinical Implications for Cancer Treatment and Prevention

  • Saroj Niraula
  • Pamela J. GoodwinEmail author
Part of the Energy Balance and Cancer book series (EBAC, volume 1)


Obesity is a major threat to health worldwide and if the current trend continues, more than 50% of the world’s population is projected to be obese by the year 2030 [1]. As reviewed by Irwin et al. in another chapter [2], obesity has been linked to both cancer risk and cancer outcome. Although obesity, insulin resistance and hyperinsulinemia are interrelated [3], until recently the primary focus of epidemiologic and clinical cancer research has been on obesity. Eugenia Calle et al. [4] provided an elegant demonstration of the association between body size and mortality from cancer in the prospective Cancer Prevention Study II, conducted by the American Cancer Society. Studying over 900,000 American adults, they found that individuals with a body mass index (BMI  =  weight(kg)/height(m)2) of at least 40 had death rates from cancer that were 52% higher (for men) and 62% higher (for women) than the rates seen in normal weight individuals. Higher BMI was significantly associated with increased death rates from a number of common cancers, including colon and rectum, breast, uterus and prostate as well as from less common cancers such as liver, gallbladder, pancreas, kidney, stomach, cervix, non-Hodgkin’s lymphoma and multiple myeloma. The only cancer demonstrating an inverse association between BMI and future cancer mortality was lung cancer. The results of this study (which combine the effect of obesity on cancer risk and cancer progression) suggest that obesity may contribute to 14% of all deaths from cancer in men and 20% of all deaths from cancer in women, evidence of an important contribution of obesity to cancer death. Similar results were obtained in a recent study by Whitlock et al. [5] in an analysis involving approximately 90,000 subjects that ­obesity was associated with significantly increased mortality from several causes, including cancer; with every 5 kg/m2 increase in BMI, risk of cancer-specific ­mortality increased by 10%. Furthermore, a recent meta-analysis by Renehan et al. [6] that focused on cancer incidence rather than mortality, reported that increased BMI was associated with increased risk of several different cancers including esophageal, thyroid, colon, rectal, renal, endometrial, gallbladder, breast (postmenopausal) and pancreatic, as well as melanoma, leukaemia, multiple myeloma, and non-Hodgkin lymphoma.


Breast Cancer Physical Activity Insulin Resistance Cancer Risk Lifestyle Intervention 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Kelly T et al (2008) Global burden of obesity in 2005 and projections to 2030. Int J Obes (Lond) 32(9):1431–1437CrossRefGoogle Scholar
  2. 2.
    Pierce JP et al (2007) Re: dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study. J Natl Cancer Inst 99(11):900; author reply 900–901Google Scholar
  3. 3.
    Clegg D (2009) Mechanisms of insulin resistance, obesity and metabolic syndrome. In: Fantus IG (ed) Insulin resistance and cancer. Springer, New YorkGoogle Scholar
  4. 4.
    Calle EE, Rodriguez C, Walker-Thurmond K et al (2003) Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 348:1625–1638PubMedCrossRefGoogle Scholar
  5. 5.
    Whitlock G et al (2009) Body-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet 373(9669):1083–1096PubMedCrossRefGoogle Scholar
  6. 6.
    Renehan AG et al (2008) Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371(9612):569–578PubMedCrossRefGoogle Scholar
  7. 7.
    Friedenreich CM, Orenstein MR (2002) Physical activity and cancer prevention: etiologic ­evidence and biological mechanisms. J Nutr 132(11 Suppl):3456S–3464SPubMedGoogle Scholar
  8. 8.
    Friedenreich CM, Cust AE (2008) Physical activity and breast cancer risk: impact of timing, type and dose of activity and population subgroup effects. Br J Sports Med 42:636–647PubMedCrossRefGoogle Scholar
  9. 9.
    Hursting SD et al (2008) Reducing the weight of cancer: mechanistic targets for breaking the obesity-carcinogenesis link. Best Pract Res Clin Endocrinol Metab 22(4):659–669PubMedCrossRefGoogle Scholar
  10. 10.
    Moore SC et al (2009) Age-specific physical activity and prostate cancer risk among white men and black men. Cancer 115(21):5060–5070PubMedCrossRefGoogle Scholar
  11. 11.
    Renehan AG, Roberts DL, Dive C (2008) Obesity and cancer: pathophysiological and biological mechanisms. Arch Physiol Biochem 114(1):71–83PubMedCrossRefGoogle Scholar
  12. 12.
    Lipscombe L (2009) Insulin, insulin resistance and cancer associations. In: Fantus IG (ed) insulin resistance and cancer. Springer, New YorkGoogle Scholar
  13. 13.
    LeRoith D (2009) Animal models of hyperinsulinemia, insulin resistance and cancer. In: Fantus IG (ed) insulin resistance and cancer. Springer, New YorkGoogle Scholar
  14. 14.
    Fantus IG (2009) Potential mechanisms linking insulin to cancer. In: Fantus IG (ed) Insulin resistance and cancer. Springer, New YorkGoogle Scholar
  15. 15.
    Sonnenberg N (2009) Actions of insulin as a survival and growth factor: Akt/PKB, mTOR and regulation of translation. In: Fantus IG (ed) Insulin resistance and cancer. Springer, New YorkGoogle Scholar
  16. 16.
    Cantley LC (2009) Cancer cell metabolism and AMPK: regulation of cell proliferation and apoptosis. In: Fantus IG (ed) Insulin resistance and cancer. Springer, New YorkGoogle Scholar
  17. 17.
    Brodt P (2009) Insulin-like growth factors and cancer. In: Fantus IG (ed) Insulin resistance and cancer. Springer, New YorkGoogle Scholar
  18. 18.
    Belfiore A (2009) Insulin, IGF receptors and cancer. In: Fantus IG (ed) Insulin resistance and cancer. Springer, New YorkGoogle Scholar
  19. 19.
    Pisani P (2008) Hyper-insulinaemia and cancer, meta-analyses of epidemiological studies. Arch Physiol Biochem 114:63–70PubMedCrossRefGoogle Scholar
  20. 20.
    Zhou XH et al (2010) Diabetes, prediabetes and cancer mortality. Diabetologia 53(9):1867–1876PubMedCrossRefGoogle Scholar
  21. 21.
    Gunter MJ et al (2009) Insulin, insulin-like growth factor-I, and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 101(1):48–60PubMedGoogle Scholar
  22. 22.
    Vinikoor LC, Long MD, Keku TO et al (2009) The Association between diabetes, insulin use, and colorectal cancer among Whites and African Americans. Cancer Epidemiol Biomark Prev 18:1239–1242CrossRefGoogle Scholar
  23. 23.
    von Kriegstein E, von Kriegstein K (2007) Inhaled insulin for diabetes mellitus. N Engl J Med 356(20):2106; author reply 2108Google Scholar
  24. 24.
    Hemkens LG et al (2009) Risk of malignancies in patients with diabetes treated with human insulin or insulin analogues: a cohort study. Diabetologia 52(9):1732–1744PubMedCrossRefGoogle Scholar
  25. 25.
    Jonasson JM et al (2009) Insulin glargine use and short-term incidence of malignancies-a population-based follow-up study in Sweden. Diabetologia 52(9):1745–1754PubMedCrossRefGoogle Scholar
  26. 26.
    Mannucci E et al (2010) Doses of insulin and its analogues and cancer occurrence in insulin-treated type 2 diabetic patients. Diabetes Care 33(9):1997–2003PubMedCrossRefGoogle Scholar
  27. 27.
    Colhoun HM (2009) Use of insulin glargine and cancer incidence in Scotland: a study from the Scottish Diabetes Research Network Epidemiology Group. Diabetologia 52(9):1755–1765PubMedCrossRefGoogle Scholar
  28. 28.
    Currie CJ, Poole CD, Gale EA (2009) The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia 52(9):1766–1777PubMedCrossRefGoogle Scholar
  29. 29.
    Home PD, Lagarenne P (2009) Combined randomised controlled trial experience of malignancies in studies using insulin glargine. Diabetologia 52(12):2499–2506PubMedCrossRefGoogle Scholar
  30. 30.
    Lipscombe LL et al (2006) Diabetes mellitus and breast cancer: a retrospective population-based cohort study. Breast Cancer Res Treat 98(3):349–356PubMedCrossRefGoogle Scholar
  31. 31.
    Lipscombe LL et al (2006) Increased prevalence of prior breast cancer in women with newly diagnosed diabetes. Breast Cancer Res Treat 98(3):303–309PubMedCrossRefGoogle Scholar
  32. 32.
    Xue F, Michels KB (2007) Diabetes, metabolic syndrome, and breast cancer: a review of the current evidence. Am J Clin Nutr 86(3):s823–s835PubMedGoogle Scholar
  33. 33.
    Pierce BL et al (2008) Diabetes mellitus and prostate cancer risk. Prostate 68(10):1126–1132PubMedCrossRefGoogle Scholar
  34. 34.
    Jee SH et al (2008) Body mass index and cancer risk in Korean men and women. Int J Cancer 123(8):1892–1896PubMedCrossRefGoogle Scholar
  35. 35.
    Trevisan M et al (2001) Markers of insulin resistance and colorectal cancer mortality. Cancer Epidemiol Biomark Prev 10(9):937–941Google Scholar
  36. 36.
    Protani M, Coory M, Martin JH (2010) Effect of obesity on survival of women with breast cancer: systematic review and meta-analysis. Breast Cancer Res Treat 123(3):627–635PubMedCrossRefGoogle Scholar
  37. 37.
    Goodwin P (2006) Energy balance and prognosis: breast cancer. In: McTiernan A (ed) Cancer prevention and management through exercise and weight control. Taylor and Francis Group, Boca RatonGoogle Scholar
  38. 38.
    Goodwin PJ et al (2009) High insulin levels in newly diagnosed breast cancer patients reflect underlying insulin resistance and are associated with components of the insulin resistance syndrome. Breast Cancer Res Treat 114(3):517–525PubMedCrossRefGoogle Scholar
  39. 39.
    Goodwin PJ et al (2002) Fasting insulin and outcome in early-stage breast cancer: results of a prospective cohort study. J Clin Oncol 20(1):42–51PubMedCrossRefGoogle Scholar
  40. 40.
    Pasanisi P et al (2008) Serum insulin-like growth factor-I and platelet-derived growth factor as biomarkers of breast cancer prognosis. Cancer Epidemiol Biomark Prev 17(7):1719–1722CrossRefGoogle Scholar
  41. 41.
    Pollak M et al (2006) Insulin resistance, estimated by serum C-peptide level, is associated with reduced event-free survival for postmenopausal women in NCIC CTG MA.14 adjuvant breast cancer trial. J Clin Oncol ASCO Ann Meet Proc I 24(Suppl 18S):Abstract 524Google Scholar
  42. 42.
    Irwin ML et al (2011) Fasting C-peptide levels and death resulting from all causes and breast cancer: the health, eating, activity, and lifestyle study. J Clin Oncol 29(1):47–53PubMedCrossRefGoogle Scholar
  43. 43.
    Duggan C et al (2011) Associations of insulin resistance and adiponectin with mortality in women with breast cancer. J Clin Oncol 29(1):32–39PubMedCrossRefGoogle Scholar
  44. 44.
    Emaus A et al (2010) Metabolic profile, physical activity, and mortality in breast cancer patients. Breast Cancer Res Treat 121(3):651–660PubMedCrossRefGoogle Scholar
  45. 45.
    Erickson K et al (2011) Clinically defined type 2 diabetes mellitus and prognosis in early-stage breast cancer. J Clin Oncol 29(1):54–60PubMedCrossRefGoogle Scholar
  46. 46.
    Law JH et al (2008) Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 68(24):10238–10246PubMedCrossRefGoogle Scholar
  47. 47.
    Holmes MD et al (2005) Physical activity and survival after breast cancer diagnosis. JAMA 293(20):2479–2486PubMedCrossRefGoogle Scholar
  48. 48.
    Abrahamson PE et al (2006) Recreational physical activity and survival among young women with breast cancer. Cancer 107(8):1777–1785PubMedCrossRefGoogle Scholar
  49. 49.
    Holick CN et al (2008) Physical activity and survival after diagnosis of invasive breast cancer. Cancer Epidemiol Biomark Prev 17(2):379–386CrossRefGoogle Scholar
  50. 50.
    Irwin ML et al (2003) Physical activity levels before and after a diagnosis of breast carcinoma: the health, eating, activity, and lifestyle (HEAL) study. Cancer 97(7):1746–1757PubMedCrossRefGoogle Scholar
  51. 51.
    Sternfeld B et al (2009) Physical activity and risk of recurrence and mortality in breast cancer survivors: findings from the LACE study. Cancer Epidemiol Biomark Prev 18(1):87–95CrossRefGoogle Scholar
  52. 52.
    Enger SM, Bernstein L (2004) Exercise activity, body size and premenopausal breast cancer survival. Br J Cancer 90(11):2138–2141PubMedGoogle Scholar
  53. 53.
    Borugian MJ et al (2004) Insulin, macronutrient intake, and physical activity: are potential indicators of insulin resistance associated with mortality from breast cancer? Cancer Epidemiol Biomark Prev 13(7):1163–1172Google Scholar
  54. 54.
    Mulligan AM et al (2007) Insulin receptor is an independent predictor of a favorable outcome in early stage breast cancer. Breast Cancer Res Treat 106(1):39–47PubMedCrossRefGoogle Scholar
  55. 55.
    Mathieu MC et al (1997) Insulin receptor expression and clinical outcome in node-negative breast cancer. Proc Assoc Am Physicians 109(6):565–571PubMedGoogle Scholar
  56. 56.
    Frasca F et al (2008) The role of insulin receptors and IGF-I receptors in cancer and other diseases. Arch Physiol Biochem 114(1):23–37PubMedCrossRefGoogle Scholar
  57. 57.
    Hsing AW, Sakoda LC, Chua S Jr (2007) Obesity, metabolic syndrome, and prostate cancer. Am J Clin Nutr 86(3):s843–s857PubMedGoogle Scholar
  58. 58.
    Skolarus TA, Wolin KY, Grubb RL 3rd (2007) The effect of body mass index on PSA levels and the development, screening and treatment of prostate cancer. Nat Clin Pract Urol 4(11):605–614PubMedCrossRefGoogle Scholar
  59. 59.
    Magheli A et al (2008) Impact of body mass index on biochemical recurrence rates after radical prostatectomy: an analysis utilizing propensity score matching. Urology 72(6):1246–1251PubMedCrossRefGoogle Scholar
  60. 60.
    Motamedinia P et al (2008) Body mass index trends and role of obesity in predicting outcome after radical prostatectomy. Urology 72(5):1106–1110PubMedCrossRefGoogle Scholar
  61. 61.
    Freedland SJ et al (2008) Obesity and oncological outcome after radical prostatectomy: impact of prostate-specific antigen-based prostate cancer screening: results from the Shared Equal Access Regional Cancer Hospital and Duke Prostate Center databases. BJU Int 102(8):969–974PubMedCrossRefGoogle Scholar
  62. 62.
    King CR, Spiotto MT, Kapp DS (2009) Obesity and risk of biochemical failure for patients receiving salvage radiotherapy after prostatectomy. Int J Radiat Oncol Biol Phys 73(4):1017–1022PubMedCrossRefGoogle Scholar
  63. 63.
    Stroup SP et al (2007) Effect of obesity on prostate-specific antigen recurrence after radiation therapy for localized prostate cancer as measured by the 2006 Radiation Therapy Oncology Group-American Society for Therapeutic Radiation and Oncology (RTOG-ASTRO) Phoenix consensus definition. Cancer 110(5):1003–1009PubMedCrossRefGoogle Scholar
  64. 64.
    Spangler E et al (2007) Association of obesity with tumor characteristics and treatment failure of prostate cancer in African-American and European American men. J Urol 178(5):1939–1944; discussion 1945Google Scholar
  65. 65.
    Paaskesen CE, Borre M (2008) Body mass index and prognostic markers at radical prostatectomy. Scand J Urol Nephrol 42:230–236PubMedCrossRefGoogle Scholar
  66. 66.
    Merrick GS et al (2007) Obesity is not predictive of overall survival following permanent prostate brachytherapy. Am J Clin Oncol 30(6):588–596PubMedCrossRefGoogle Scholar
  67. 67.
    Halabi S et al (2007) Inverse correlation between body mass index and clinical ­outcomes in men with advanced castration-recurrent prostate cancer. Cancer 110(7):1478–1484PubMedCrossRefGoogle Scholar
  68. 68.
    Lehrer S et al (2002) Serum insulin level, disease stage, prostate specific antigen (PSA) and Gleason score in prostate cancer. Br J Cancer 87(7):726–728PubMedCrossRefGoogle Scholar
  69. 69.
    Hammarsten J, Hogstedt B (2005) Hyperinsulinaemia: a prospective risk factor for lethal clinical prostate cancer. Eur J Cancer 41(18):2887–2895PubMedCrossRefGoogle Scholar
  70. 70.
    Ma J et al (2008) Prediagnostic body-mass index, plasma C-peptide concentration, and prostate cancer-specific mortality in men with prostate cancer: a long-term survival analysis. Lancet Oncol 9(11):1039–1047PubMedCrossRefGoogle Scholar
  71. 71.
    Cox ME et al (2009) Insulin receptor expression by human prostate cancers. Prostate 69(1):33–40PubMedCrossRefGoogle Scholar
  72. 72.
    Dignam JJ et al (2006) Body mass index and outcomes in patients who receive adjuvant chemotherapy for colon cancer. J Natl Cancer Inst 98(22):1647–1654PubMedCrossRefGoogle Scholar
  73. 73.
    Meyerhardt JA et al (2003) Influence of body mass index on outcomes and treatment-related toxicity in patients with colon carcinoma. Cancer 98(3):484–495PubMedCrossRefGoogle Scholar
  74. 74.
    Meyerhardt JA et al (2008) Impact of body mass index and weight change after treatment on cancer recurrence and survival in patients with stage III colon cancer: findings from Cancer and Leukemia Group B 89803. J Clin Oncol 26(25):4109–4115PubMedCrossRefGoogle Scholar
  75. 75.
    Moon HG et al (2008) Visceral obesity may affect oncologic outcome in patients with colorectal cancer. Ann Surg Oncol 15(7):1918–1922PubMedCrossRefGoogle Scholar
  76. 76.
    Wolpin BM et al (2009) Insulin, the insulin-like growth factor axis, and mortality in patients with nonmetastatic colorectal cancer. J Clin Oncol 27(2):176–185PubMedCrossRefGoogle Scholar
  77. 77.
    Siddiqui AA et al (2008) Elevated HbA1c is an independent predictor of aggressive clinical behavior in patients with colorectal cancer: a case-control study. Dig Dis Sci 53(9):2486–2494PubMedCrossRefGoogle Scholar
  78. 78.
    Nickelsen TN, Jorgensen T, Kronborg O (2005) Lifestyle and 30-day complications to surgery for colorectal cancer. Acta Oncol 44(3):218–223PubMedCrossRefGoogle Scholar
  79. 79.
    Haydon AM et al (2006) Effect of physical activity and body size on survival after diagnosis with colorectal cancer. Gut 55(1):62–67PubMedCrossRefGoogle Scholar
  80. 80.
    Dray X et al (2003) Influence of dietary factors on colorectal cancer survival. Gut 52(6):868–873PubMedCrossRefGoogle Scholar
  81. 81.
    Meyerhardt JA et al (2006) Physical activity and survival after colorectal cancer diagnosis. J Clin Oncol 24(22):3527–3534PubMedCrossRefGoogle Scholar
  82. 82.
    Meyerhardt JA et al (2009) Interaction of molecular markers and physical activity on mortality in patients with colon cancer. Clin Cancer Res 15(18):5931–5936PubMedCrossRefGoogle Scholar
  83. 83.
    Meyerhardt JA et al (2009) Physical activity and male colorectal cancer survival. Arch Intern Med 169(22):2102–2108PubMedCrossRefGoogle Scholar
  84. 84.
    Hickish T et al (2009) Glucose intolerance during adjuvant chemotherapy for breast cancer. J Natl Cancer Inst 101(7):537PubMedCrossRefGoogle Scholar
  85. 85.
    Siviero-Miachon AA, Spinola-Castro AM, Guerra-Junior G (2008) Detection of metabolic syndrome features among childhood cancer survivors: a target to prevent disease. Vasc Health Risk Manag 4(4):825–836PubMedGoogle Scholar
  86. 86.
    Barone BB et al (2008) Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 300(23):2754–2764PubMedCrossRefGoogle Scholar
  87. 87.
    Peairs KS et al (2011) Diabetes mellitus and breast cancer outcomes: a systematic review and meta-analysis. J Clin Oncol 29(1):40–6Google Scholar
  88. 88.
    Chlebowski RT et al (2006) Dietary fat reduction and breast cancer outcome: interim efficacy results from the Women’s Intervention Nutrition Study. J Natl Cancer Inst 98(24):1767–1776PubMedCrossRefGoogle Scholar
  89. 89.
    ACS report: half of cancer deaths could be prevented. CA Cancer J Clin 2005; 55(4):209–210Google Scholar
  90. 90.
    Miller JP et al (1994) Strength training increases insulin action in healthy 50- to 65-yr-old men. J Appl Physiol 77(3):1122–1127PubMedGoogle Scholar
  91. 91.
    Kirwan JP et al (1993) Endurance exercise training reduces glucose-stimulated insulin levels in 60- to 70-year-old men and women. J Gerontol 48(3):M84–M90PubMedGoogle Scholar
  92. 92.
    Craig BW, Everhart J, Brown R (1989) The influence of high-resistance training on glucose tolerance in young and elderly subjects. Mech Ageing Dev 49(2):147–157PubMedCrossRefGoogle Scholar
  93. 93.
    Gill T, King L, Caterson I (2005) Obesity prevention: necessary and possible. A structured approach for effective planning. Proc Nutr Soc 64(2):255–261PubMedCrossRefGoogle Scholar
  94. 94.
    Glenny AM et al (1997) The treatment and prevention of obesity: a systematic review of the literature. Int J Obes Relat Metab Disord 21(9):715–737PubMedCrossRefGoogle Scholar
  95. 95.
    Franz MJ et al (2007) Weight-loss outcomes: a systematic review and meta-analysis of weight-loss clinical trials with a minimum 1-year follow-up. J Am Diet Assoc 107(10):1755–1767PubMedCrossRefGoogle Scholar
  96. 96.
    Ogden CL et al (2007) The epidemiology of obesity. Gastroenterology 132(6):2087–2102PubMedCrossRefGoogle Scholar
  97. 97.
    Gill T (2002) Importance of preventing weight gain in adulthood. Asia Pac J Clin Nutr 11(Suppl 3):S632–S636PubMedCrossRefGoogle Scholar
  98. 98.
    Lemmens VE et al (2008) A systematic review of the evidence regarding efficacy of obesity prevention interventions among adults. Obes Rev 9(5):446–455PubMedCrossRefGoogle Scholar
  99. 99.
    Van Dorsten B, Lindley EM (2008) Cognitive and behavioral approaches in the treatment of obesity. Endocrinol Metab Clin North Am 37(4):905–922PubMedCrossRefGoogle Scholar
  100. 100.
    Shaw M et al (2009) Effect of a successful intensive lifestyle program on insulin sensitivity and glucose tolerance in obese youth. Diabetes Care 32(1):45–47PubMedCrossRefGoogle Scholar
  101. 101.
    Cummings S, Apovian CM, Khaodhiar L (2008) Obesity surgery: evidence for diabetes prevention/management. J Am Diet Assoc 108(4 Suppl 1):S40–S44PubMedCrossRefGoogle Scholar
  102. 102.
    Sjostrom L et al (2007) Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 357(8):741–752PubMedCrossRefGoogle Scholar
  103. 103.
    Knowler WC et al (2002) Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med 346(6):393–403PubMedCrossRefGoogle Scholar
  104. 104.
    Orchard TJ et al (2005) The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med 142(8):611–619PubMedGoogle Scholar
  105. 105.
    Tuomilehto J et al (2001) Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med 344(18):1343–1350PubMedCrossRefGoogle Scholar
  106. 106.
    Ilanne-Parikka P et al (2008) Effect of lifestyle intervention on the occurrence of metabolic syndrome and its components in the Finnish Diabetes Prevention Study. Diabetes Care 31(4):805–807PubMedCrossRefGoogle Scholar
  107. 107.
    Oh EG et al (2011) Effects of a therapeutic lifestyle modification program on inflammatory chemokines and insulin resistance in subjects with metabolic syndrome. Biol Res Nurs 13(2):182–188CrossRefGoogle Scholar
  108. 108.
    Hemmingsson E, Udden J, Rossner S (2011) Diet and physical activity interventions in severely obese adults. JAMA 305(6):563–564; author reply 564Google Scholar
  109. 109.
    Howell A, Chapman M, Harvie M (2009) Energy restriction for breast cancer prevention. Recent Results Cancer Res 181:97–111PubMedCrossRefGoogle Scholar
  110. 110.
    Rooney M, Wald A (2007) Interventions for the management of weight and body composition changes in women with breast cancer. Clin J Oncol Nurs 11(1):41–52PubMedCrossRefGoogle Scholar
  111. 111.
    Markes M, Brockow T, Resch KL (2006) Exercise for women receiving adjuvant therapy for breast cancer. Cochrane Database Syst Rev (4):CD005001Google Scholar
  112. 112.
    Schmitz KH et al (2005) Controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. Cancer Epidemiol Biomark Prev 14(7):1588–1595CrossRefGoogle Scholar
  113. 113.
    McNeely ML et al (2006) Effects of exercise on breast cancer patients and survivors: a systematic review and meta-analysis. CMAJ 175(1):34–41PubMedCrossRefGoogle Scholar
  114. 114.
    Knols R et al (2005) Physical exercise in cancer patients during and after medical treatment: a systematic review of randomized and controlled clinical trials. J Clin Oncol 23(16):3830–3842PubMedCrossRefGoogle Scholar
  115. 115.
    Courneya KS, Friedenreich CM (2007) Physical activity and cancer control. Semin Oncol Nurs 23(4):242–252PubMedCrossRefGoogle Scholar
  116. 116.
    Blackburn GL, Wang KA (2007) Dietary fat reduction and breast cancer outcome: results from the Women’s Intervention Nutrition Study (WINS). Am J Clin Nutr 86(3):s878–s881PubMedGoogle Scholar
  117. 117.
    Pierce JP et al (2007) Influence of a diet very high in vegetables, fruit, and fiber and low in fat on prognosis following treatment for breast cancer: the Women’s Healthy Eating and Living (WHEL) randomized trial. JAMA 298(3):289–298PubMedCrossRefGoogle Scholar
  118. 118.
    Rock CL et al (2009) Longitudinal biological exposure to carotenoids is associated with breast cancer-free survival in the Women’s Healthy Eating and Living Study. Cancer Epidemiol Biomark Prev 18(2):486–494CrossRefGoogle Scholar
  119. 119.
    Schmitz KH, Ahmed RL, Hannan PJ et al (2005) Safety and efficacy of weight training in recent breast cancer survivors to alter body composition, insulin, and insulin-like growth factor axis proteins. Cancer Epidemiol Biomark Prev 14:1672–1680CrossRefGoogle Scholar
  120. 120.
    Ligibel JA et al (2008) Impact of a mixed strength and endurance exercise intervention on insulin levels in breast cancer survivors. J Clin Oncol 26(6):907–912PubMedCrossRefGoogle Scholar
  121. 121.
    Irwin ML et al (2009) Randomized controlled trial of aerobic exercise on insulin and insulin-like growth factors in breast cancer survivors: the Yale Exercise and Survivorship study. Cancer Epidemiol Biomark Prev 18(1):306–313CrossRefGoogle Scholar
  122. 122.
    Schmitz KH et al (2005) Safety and efficacy of weight training in recent breast cancer survivors to alter body composition, insulin, and insulin-like growth factor axis proteins. Cancer Epidemiol Biomark Prev 14(7):1672–1680CrossRefGoogle Scholar
  123. 123.
    Fairey AS et al (2003) Effects of exercise training on fasting insulin, insulin resistance, insulin-like growth factors, and insulin-like growth factor binding proteins in postmenopausal breast cancer survivors: a randomized controlled trial. Cancer Epidemiol Biomark Prev 12(8):721–727Google Scholar
  124. 124.
    Goodwin PJ (2008) Insulin in the adjuvant breast cancer setting: a novel therapeutic target for lifestyle and pharmacologic interventions? J Clin Oncol 26(6):833–834PubMedCrossRefGoogle Scholar
  125. 125.
    Padwal R, Li SK, Lau DC (2004) Long-term pharmacotherapy for obesity and overweight. Cochrane Database Syst Rev (3):CD004094Google Scholar
  126. 126.
    Sachdev D (2010) Targeting the type 1 insulin-like growth factor system for breast cancer therapy. Curr Drug Targets 11:1121–1132PubMedCrossRefGoogle Scholar
  127. 127.
    Padwal R, Li SK, Lau DC (2004). Cochrane Database Syst Rev CD004094Google Scholar
  128. 128.
    Cusi K, DeFronzo RA (1998) Metformin: a review of its metabolic effects. Diab Rev 6:89–131Google Scholar
  129. 129.
    Zhou G et al (2001) Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 108(8):1167–1174PubMedGoogle Scholar
  130. 130.
    Towler MC, Hardie DG (2007) AMP-activated protein kinase in metabolic control and insulin signaling. Circ Res 100(3):328–341PubMedCrossRefGoogle Scholar
  131. 131.
    Inoki K, Zhu T, Guan KL (2003) TSC2 mediates cellular energy response to control cell growth and survival. Cell 115(5):577–590PubMedCrossRefGoogle Scholar
  132. 132.
    Anisimov VN et al (2005) Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Exp Gerontol 40(8–9):685–693PubMedCrossRefGoogle Scholar
  133. 133.
    Huang X et al (2008) Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J 412(2):211–221PubMedCrossRefGoogle Scholar
  134. 134.
    Buzzai M et al (2007) Systemic treatment with the antidiabetic drug metformin selectively impairs p53-deficient tumor cell growth. Cancer Res 67(14):6745–6752PubMedCrossRefGoogle Scholar
  135. 135.
    Zhuang Y, Miskimins WK (2008) Cell cycle arrest in Metformin treated breast cancer cells involves activation of AMPK, downregulation of cyclin D1, and requires p27Kip1 or p21Cip1. J Mol Signal 3:18PubMedCrossRefGoogle Scholar
  136. 136.
    Wang LW et al (2008) Metformin induces apoptosis of pancreatic cancer cells. World J Gastroenterol 14(47):7192–7198PubMedCrossRefGoogle Scholar
  137. 137.
    Beckner ME et al (2005) Glycolytic glioma cells with active glycogen synthase are sensitive to PTEN and inhibitors of PI3K and gluconeogenesis. Lab Invest 85(12):1457–1470PubMedGoogle Scholar
  138. 138.
    Isakovic A et al (2007) Dual antiglioma action of metformin: cell cycle arrest and mitochondria-dependent apoptosis. Cell Mol Life Sci 64(10):1290–1302PubMedCrossRefGoogle Scholar
  139. 139.
    Decensi A et al (2010) Metformin and cancer risk in diabetic patients: a systematic review and meta-analysis. Cancer Prev Res (Phila) 3(11):1451–1461CrossRefGoogle Scholar
  140. 140.
    Jiralerspong S et al (2009) Metformin and pathologic complete responses to neoadjuvant chemotherapy in diabetic patients with breast cancer. J Clin Oncol 27(20):3297–3302PubMedCrossRefGoogle Scholar
  141. 141.
    Mazzone PJ et al (2010) The effect of metformin and thiazolidinedione use on lung cancer. Chest 138:882ACrossRefGoogle Scholar
  142. 142.
    Hosono K et al (2010) Metformin suppresses colorectal aberrant crypt foci in a short-term clinical trial. Cancer Prev Res (Phila) 3(9):1077–1083CrossRefGoogle Scholar
  143. 143.
    Niraula S et al (2010) Clinical and biologic effects of metformin in early stage breast cancer [PD03-06]. San Antonio Breast Cancer Symphosium. pp 8–10Google Scholar
  144. 144.
    Bonanni B et al (2010) A randomized pre-surgical trial of metformin in breast cancer. Preliminary feasibility and safety results. San Antonio Breast Cancer Symphosium [PD03-02]Google Scholar
  145. 145.
    Hadad S et al (2009) The effect of neoadjuvant metformin on breast cancer related genes clinical trial – a preliminary result. San Antonio Breast Cancer Symphosium (Abstract# 3145)Google Scholar
  146. 146.
    Goodwin PJ, Ligibel JA, Stambolic V (2009) Metformin in breast cancer: time for action. J Clin Oncol 27(20):3271–3273PubMedCrossRefGoogle Scholar
  147. 147.
    Cazzaniga M et al (2009) Is it time to test metformin in breast cancer clinical trials? Cancer Epidemiol Biomark Prev 18(3):701–705CrossRefGoogle Scholar
  148. 148.
    Blanquicett C, Roman J, Hart CM (2008) Thiazolidinediones as anti-cancer agents. Cancer Ther 6(A):25–34PubMedGoogle Scholar
  149. 149.
    Govindarajan R et al (2007) Thiazolidinediones and the risk of lung, prostate, and colon cancer in patients with diabetes. J Clin Oncol 25(12):1476–1481PubMedCrossRefGoogle Scholar
  150. 150.
    Hassan MM et al (2010) Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma. Cancer 116(8):1938–1946PubMedCrossRefGoogle Scholar
  151. 151.
    Tolman KG (2011) The safety of thiazolidinediones. Expert Opin Drug SafGoogle Scholar
  152. 152.
    Holmes MD, Chen WY, Feskanich D et al (2005) Physical activity and survival after breast cancer diagnosis. JAMA 293:2479–2486PubMedCrossRefGoogle Scholar
  153. 153.
    Pierce JP et al (2007) Greater survival after breast cancer in physically active women with high vegetable-fruit intake regardless of obesity. J Clin Oncol 25(17):2345–2351PubMedCrossRefGoogle Scholar
  154. 154.
    Irwin ML et al (2008) Influence of pre- and postdiagnosis physical activity on mortality in breast cancer survivors: the health, eating, activity, and lifestyle study. J Clin Oncol 26(24):3958–3964PubMedCrossRefGoogle Scholar
  155. 155.
    Friedenreich CM et al (2009) Prospective cohort study of lifetime physical activity and breast cancer survival. Int J Cancer 124(8):1954–1962PubMedCrossRefGoogle Scholar
  156. 156.
    West-Wright CN et al (2009) Long-term and recent recreational physical activity and survival after breast cancer: the California Teachers Study. Cancer Epidemiol Biomark Prev 18(11):2851–2859CrossRefGoogle Scholar
  157. 157.
    Keegan TH et al (2010) Past recreational physical activity, body size, and all-cause mortality following breast cancer diagnosis: results from the Breast Cancer Family Registry. Breast Cancer Res Treat 123(2):531–542PubMedCrossRefGoogle Scholar
  158. 158.
    Bertram LA et al (2011) Physical activity, additional breast cancer events, and mortality among early-stage breast cancer survivors: findings from the WHEL Study. Cancer Causes Control 22(3):427–435PubMedCrossRefGoogle Scholar
  159. 159.
    Fairey AS, Courneya KS, Field CJ et al (2003) Effects of exercise training on fasting insulin, insulin resistance, insulin-like growth factors, and insulin-like growth factor binding proteins in postmenopausal breast cancer survivors: a randomized controlled trial. Cancer Epidemiol Biomark Prev 12:721–727Google Scholar
  160. 160.
    Ligibel JA, Campbell N, Partridge A et al (2008) Impact of a mixed strength and endurance exercise intervention on insulin levels in breast cancer survivors. J Clin Oncol 26:907–912PubMedCrossRefGoogle Scholar
  161. 161.
    Irwin ML, Varma K, Alvarez-Reeves M et al (2009) Randomized controlled trial of aerobic exercise on insulin and insulin-like growth factors in breast cancer survivors: the Yale Exercise and Survivorship study. Cancer Epidemiol Biomark Prev 18:306–313CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Samuel Lunenfeld Research Institute, Mount Sinai Hospital and Princess Margaret HospitalUniversity of TorontoTorontoCanada

Personalised recommendations