1. 1. PROF. DR. I. DASKALOVA Military Medical Academy, Sofia BULGARIA
2. 2. Link between diabetes and cancer have been an interesting question for clinical community since last century. But the results were not similar. The observations and investigations continue. Several meta-analyses indicate the strongest association between diabetes mellitus and increased cancer risk (metaanalyses of Vinery et all.)
3. 3. Aging Sex Obesity Physical activity Diet Alcohol Smoking
4. 4. Age 78% of all newly diagnosed cancer > 55 years and older Diabetes Type 2- increasingly common with age Sex sexspecific (cervix,uterine,testicular,prostate), breast Men have slightly higher ageadjusted risk of diabetes than women Race/ethnicity
5. 5. Overweigh - (BMI >25 and 30 kg/m2 Weight change
6. 6. 6
7. 7. Breast (postmenopausal women) Colon/rectum Endometrial Pancreas Adenocarcinoma of the esophagus Kidney Gallbladder liver
8. 8. Increase in adipose tissue rather than lean mass Total body fat a better measure of the risk than BMI Obesity Insulin resistance Type 2 diabetes Waist circumference Waist-to-hip ratio Measures of visceral adiposity
9. 9. Low in red and processed meats Higher in vegetables, fruits Whole grains cereals Monounsaturated fatty acid Dietary fiber Low-carbohydrate diets
10. 10. Lowers disease risk Decreases diabetes incidence DCCT Intensive lifestyle intervention of diet (5-7% weight loss) Physical activity 58% reduction in diabetes incidence Limit risk of gestational diabetes
11. 11. Obese women who underwent bariatric surgery were at lower risk of cancer (relative risks ranging from 0.58 to 0.62) compared with untreated obese women. Protective effect on breast and endometrial cancer Very effective treatment for Type 2 DM
12. 12. Lower risk of colon Postmenopausal breast Endometrial cancer Prevent other cancer including Lung Aggressive prostate cancer
13. 13. Diabetes may influence the neoplastic process by several mechanisms: Hyperinsulinemia (either endogenous due to insulin resistance or exogenous due to administered insulin or secretogogues) Hyperglycemia Chronic inflammation
14. 14. Most cancer cells express insulin and IGF-I receptors The A receptor isoform can stimulate insulin- mediated mitogenesis, even in cells deficient in IGF-I receptors The insulin receptor is also capable of stimulating cancer cell proliferation and metastasis.
15. 15. Reduction in the hepatic synthesis Sex hormone binding globulin, leading to increases in bioavailable estrogen in men and women Increased levels of bioavailable testosterone in women but not in men Androgen synthesis in the ovaries and adrenals is increased
16. 16. Higher risk of postmenopausal women Breast Endometrial Other cancers
17. 17. Diabetes Diabetes treatment Cancer Insulin receptor activation may be a more important variable than hyperglycemia in determining tumor growth
18. 18. Direct effects of insulin; type 2 DM Adipose tissue - active endocrine organ producing: Free fatty acids Interleukin - 6 (IL 6) Monocyte chemoatractant protein Plasminogen activator inhibitor-1 (PAI-1) Adiponectin Leptin Tumor necrosis factor (TNF)
19. 19. Each of these factors might play an etiologic role in regulating malignant transformation or cancer progression Plasminogen systemexpression of PAI- 1poor outcome in breast cancer IL-6enhance cancer cell proliferation, survival and invasion Suppressing host anti-tumor immunity
20. 20. PAI-1(ng/ml) 35 0 30 25 20 15 10 5 Normal GTT IGTT Type 2 DM Festa A, et al. Insulin Resistance Atherosclerosis Study Arterioscler Thromb Vasc Biol 1999; n = 1551 *P < 0.001 * * *
21. 21. Insulin resistans Type 2 DM Vascular inflamation C-RP CVD
22. 22. Metformin Thiazolidinediones Insulin secretagogues Incretin - based therapies Insulin and insulin analogs
23. 23. Furthermore, the cancer risk may be modified by treatment choices. In this respect, metformin may be protective, whereas insulin, insulin analogues and some oral hypoglycaemic agents can function as growth factors and therefore have theoretical potential to promote tumour proliferation.
24. 24. Endogenous or exogenous hyperinsulinemia /insulins or sulfanilureas/ causing inappropriate prolonged stimulation of the insulin receptor, or excess stimulation of the IGF-1 receptor, are the most likely to show mitogenic properties in laboratory studies. Some recent epidemiological studies appear to be consistent with these experimental findings, suggesting that there could be different relative risks for cancer associated with different therapy, although these studies have attracted some methodological criticism.
25. 25. The potential mechanisms to explain this higher risk are: mitogenic effect of insulin /endogenous or exogenous hyperinsulinemia/ metabolic disorders like oxidative stress, hyperlypidemia, overweight, hyperglycemia
26. 26. The results from the latest epidemiological studies are amazing. Several studies have shown metformin to be associated with a lower risk of cancer than insulin or sulfonylureas. Bowker and colleagues examined the relationship between diabetes treatment and mortality in a health database from Saskatchewan, and found that cancer mortality was almost doubled among insulin users (HR 1.9, 95% CI 1.52.4, p