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Diabetes mellitus und Krebs

Diabetes mellitus und Krebs

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Diabetes mellitus und Krebs

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  1. Diabetes mellitus und Krebs Peter Diem Endokrinologie, Diabetologie und Klin. Ernährung Inselspital – Univ. Bern

  2. Diabetes and mortality The Emerging Risk Factors Collaboration; NEJM 2011 2

  3. Diet • Physical activity • IGF-1 • Leptin • Adiponectin • Inflammation • Sex steroids • Hyperinsulinemia • Hyperglycemia • hyperlipidemia • Inflammation Obesity Diabetes Cancer

  4. Diabetes and cancer risk Breast (Larsson, Int J Can, 2007; N=36) 1.2 1.82 Pancreas (Huxley, Br J Cancer, 2005; N=16) 1.24 Bladder (Larsson, Diabetologia 2006; N=15) 1.30 Colorectal (Larsson, J Natl Can Inst 2007; N=16) 0.84 Prostate (Kasper, Cancer Epi 2006; N=19) OR 0.6 0.9 1 1.3 1.6 1.9 2.10 4

  5. Fasting insulin and outcome in early-stage breast cancer Distant Recurrence Free Survival Overall Survival Goodwin P J et al. JCO 2002;20:42-51 5

  6. Hyperglycemia and cancer Jee SH et al. JAMA 2005;293:194-202

  7. Intensive glycemic control and cancer risk in T2DM Johnson and BowkerDiabetologia 2011;54:25–31

  8. Weight and survival in early-stage breast cancer 15 Distant Recurrence, p=0.0005 Death, p=0.0007 10 Estimated Relative Risk of Adverse Event 5 0 20 25 30 35 40 45 50 55 BMI (kg/m2) Goodwin et al.; JCO 2002

  9. Insulin and IGF-1 Human insulin Human IGF-1 Metabolic activity ++ In vitro:mitogenic activity at high concentration1 Mitogenic activity++1,2 In vitro: metabolic activity Le Roith; N Engl J Med 336:633–40 (1997) Holt et al.; Diabet Med 20:3–15 (2003) 9

  10. Insulin receptors and IGF-1 receptors 10

  11. Insulin action (IR-A / IR-B)

  12. Receptor binding of insulin analogs Kurtzhals P et al.; Diabetes 49:999–1005 (2000)

  13. Glargine Aspart Lispro Hazard ratios for risk of all forms of cancer after various adjustments Adjustment None Age, gender Age, gender, dose Multiple covariates Higher 0.6 0.8 1.0 1.2 1.4 risk Hazard ratio (95% CI) vs. human insulin HemkensLG et al.; Diabetologia52:1732-44 (2009) 13

  14. Risk of malignancy with insulinglargine versus other insulins PocockSJ et al.; Lancet 374:511-3 (2009)

  15. Swedish database analysis:Main results Glargine alone vs other insulins Glargine ± other insulins vs other insulins Adjustment* All malignancy B All malignancy +in-situ tumours B C Breast A Prostate GI B Higher risk 0 1 2 3 4 Incidence rate ratio (95% CI) * Adjustment for: A: Age, BMI, smoking, age at DM onset, CVD; B: as A + gender; C: as B + age at birth of 1st child Jonasson JM, et al.; Diabetologia52:1745-54 (2009)

  16. Results : malignancy rates (1) Home &LagarenneDiabetologia52:2499-2506 (2009) 16

  17. Results : malignancy rates (2) Relative risk 0.90 (95% CI: 0.60–1.36) Home &LagarenneDiabetologia52:2499-2506 (2009) 17

  18. Metabolic and mitogenicpotency of glarginemetabolites aSaos-2 cells. IR: insulin receptor; IR-B: insulin receptor binding; CHO-IR: cells expressing normal human insulin receptor; autophos: autophosphorylation; hIGF-IR: human IGF-1 receptor. Agin A, et al. Diabetes Metab 2007;33:205−212 Sommerfeld MR et al. (2010) PLoS ONE 5(3): e9540. doi:10.1371/journal.pone.0009540 18

  19. Metformin: Effects on insulin, IGF-1, mTOR

  20. Progression to solid tumour cancers in people with T2DM Covariate HR 95% CI p value Treatment - Metformin 1 - Sulfonylureas 1.36 1.19-1.54 <0.001 - Metformin + SH 1.08 0.96-1.21 0.21 - Insulin-based therapies 1.42 1.27-1.60 <0.001 Currie CJ et al.; Diabetologia52:1766-77 (2009)

  21. Increased incidence of pancreatitis and cancer among patients given GLP-1 based therapyoder: vomWindeverweht Elashoff M et al. Gastroenterology, 2011 published online

  22. Conclusion • Diabetes andobesityareassociatedwithincreasedriskofcancer • Riskassociatedwithinsulintreatment? • Insulin ismitogenic / mutagenic • Insulin mayacceleratecarcinogenousprocess • RiskassociatedwithLantus (probably) similartootherinsulins • Riskassociatedwith SU, DPP-4 inhibitors, GLP-1 agonist? • RiskassociatedwithPioglitazone? • Metforminseems to protectagainstcancer

  23. ...affaire à suivre!