PROF. DR. I. DASKALOVAMilitary Medical Academy, Sofia BULGARIA
Link between diabetes and cancer have beenan interesting question for clinical communitysince last century. But the results were notsimilar. The observations and investigationscontinue. Several meta-analyses indicate thestrongest association between diabetes mellitusand increased cancer risk(metaanalyses of Vinery et all.)
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 age–adjusted risk of diabetes than women Race/ethnicity
Breast (postmenopausal women) Colon/rectum Endometrial Pancreas Adenocarcinoma of the esophagus Kidney Gallbladder liver
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
Low in red and processed meats Higher in vegetables, fruits Whole grains cereals Monounsaturated fatty acid Dietary fiber Low-carbohydrate diets
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
Lower risk of colon Postmenopausal breast Endometrial cancer Prevent other cancer including Lung Aggressive prostate cancer
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
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.
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
Higher risk of postmenopausal women Breast Endometrial Other cancers
Diabetes Diabetes treatment Cancer Insulin receptor activation may be a more important variable than hyperglycemia in determining tumor growth
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 – α (TNF–α)
Each of these factors might play an etiologic role in regulating malignant transformation or cancer progression Plasminogen system→expression of PAI- 1→poor outcome in breast cancer IL-6→enhance cancer cell proliferation, survival and invasion Suppressing host anti-tumor immunity
35 * 30 * PAI-1 антиген (ng/ml) 25 20 * 15 10 5 0 Normal GTT IGTT Type 2 DMn = 1551*P < 0.001 Festa A, et al. Insulin Resistance Atherosclerosis Study Arterioscler Thromb Vasc Biol 1999;
Metformin Thiazolidinediones Insulin secretagogues Incretin - based therapies Insulin and insulin analogs
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.
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.
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
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 1.5–2.4, p<0.0001) relative to metformin users, and that sulfonylureas were also associated with increased mortality (HR 1.3, 95% CI 1.1–1.6, p=0.012).
The results from the well controlled and randomized studies with intensive glycaemic control, have showed that the improvement of the glycaemic control do not decrease the cancer risk. UKPDS in the group with metformin have shown 29 % decreased cancer mortality in overweight patients with intensive glycaemic control with metformin v.s group that have been controlled with diet. This results are similar to results from another, that investigated the relation metformin and cancer and shows that the cancer risk is decreased of therapy with metformin.
A case-controlled study in Scotland with newly diagnosed diabetes mellitus, the therapy with metformin reduces cancer risk at all. Observation data shows, that antitumor effect of metformin seems to be mediated via post-receptors changes and its ability to increase the AMP-activated protein kinase (AMPK) signalling pathway.
A study of human prostate cancer cells demonstrated a strong anti-proliferative effect of metformin. This effect was unaffected by inhibition of the AMPK pathway, but was associated with cell cycle arrest in G0/G1 phase, together with a major reduction in cyclin D1 levels. Laboratory findings show that metformin inhibits cells proliferation and cells arrest in carcinomas calls lines. It may selectively kills carcinomas steams cells and increases the cytostatic treatment.
Diabetes (primarily type 2) is associated with increased risk for some cancers: Liver Pancreas Endometrium Colon and rectum Breast Bladder Reduced risk of prostate cancer
Risk factors between the two diseases Aging Obesity Diet Physical inactivity Hyperinsulinemia Hyperglycemia Inflammation
Healthy diets Physical activity Weight management Appropriate cancer screenings for patients with diabetes Pharmacotherapy effects on cancer risk factors such as body weight, hyperinsulinemia, hyperglicemia