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Type 2 Diabetes & Cancer Beirut, 30. 6. 2017 Helmut Brath
First Secretary of Austrian Diabetes Association Diabetes Outpatient Clinic, Health Centre South, Vienna, Austria Type 2 Diabetes & Cancer Beirut, Brath: DM
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Potential Conflicts of Interest
Lectures, Symposia, Seminars: all relevant Diabetes & Lipid Companies Advisory Boards: all relevant Diabetes Companies Phase III Studies: GSK, Johnson&Johnson, Takeda, Sanofi, Novartis, MSD, Novo Nordisk, Eli-Lilly, Grünenthal, Lexicon, Astra Zeneca Reviewer: Ethics Committee Vienna, various Scientific Journals Employer: Social Insurance Fund of Vienna, Austria Boardmember: Austrian Diabetes Assocation, Austrian Council on Smoking and Health For this lecture: no Conflict of Interest Brath: DM
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1. Diabetes & Cancer: Epidemiology 2. Possible Etiologies 3. Own Data
Contents 1. Diabetes & Cancer: Epidemiology 2. Possible Etiologies 3. Own Data 4. Discussion Brath: DM
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1. Typ 2 Diabetes & Cancer Epidemiology
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Diabetes: assoc. with signifikant loss of life years
Men Women 7 6 5 4 3 2 1 40 50 60 70 80 90 Age (years) Years of life lost 7 6 5 4 3 2 1 40 50 60 70 80 90 Age (years) Non-vascular deaths Vascular deaths On average, a 50-year-old individual with diabetes and no history of vascular disease will die 6 years earlier compared to someone without diabetes . Seshasai et al. N Engl J Med 2011;364:829-41 Brath: DM
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Diabetes vs. Non-diabetes: Mortality
Framingham study, 1970 – 2005 Mortality rates vs Preis RS et al:Circulation July 21; 120(3): 212–220 Brath: DM
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(results of different metaanalyses)
Cancer risk in Diabetes (results of different metaanalyses) Acta Diabetol 2010;47:87-95
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2. Diabetes & Cancer: Possible Etiologies
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Genetic susceptibiltiy Environmental factors
Obesity Insulin resistance CANCER Inflammation ↑FFS ↑TNF α ↑IL 6 ↑Gluconeogenesis Hyper- glycemia A multidimensional model of cancer development, which suggests insulin resistance and inflammation as driving forces behind cancer. TG: triglycerides; FFA: free fatty acids; TNF-α: tumor necrosis factor α; IL-6: interleukin-6; ROS: reactive oxygen species; SHBG: sex-hormone-binding globulin; IGF-I: insulin-like growth factor I; PAI-1: plasminogen activator inhibitor-1; IGFBPs IGF-I binding proteins; VEGF, vascular endothelial growth factor. : ↓ SHBP* ↑Estradiol ↑IGF 1* ↓IGFBPs* ↑PAI-1 ↑VEGF Hyper- insulinemia E2, Testost. bioactive ↑ ↑ROS ↑Leptin Mitosis DNA damage Anti-apoptosis Migration Angiogenesis B Arcidiacono et al, Exp Diabetes Res. 2012; 2012: doi: /2012/789174 * by insuline Brath: DM
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Possible causal relations betw. T2DM & Cancer
1 2 3 4 Insulin Resistance, Hyperinsulinemia Common Causes: Obesity, Smoking, Nutrition… Pathomechanisms assoc. with Diabetes Hyperglycemia Brath: DM
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1. Insulin Resistance Brath: DM
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Hyperinsulinemia n = 10.309, t = 5.4 +/- 1.9 a HR 1,3 1,9 % 5,8 %
(1,1–1,6) 1,9 % (1,5–2,4) 6 % 5 % 5,8 % 4 % 4,9 % RR Cancer (95% CI) 3 % 3,5 % 2 % 1 % 0 % Metformin-Monother. SU- Monother. Therapy with Insulin Bowker et, Diabetes Care 2006 Brath: DM
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Molecular Mechanisms of Insulin Induced Glucose Transport
Exercise GLUT-4 Glucosetransporter 4 GLUT-4 Insulin Insulin- Receptor GLUT-4 Vesicle How does Insulin Resistance change this system? Protein Kinases + 13 Shepherd PR, Kahn BB N Engl J Med. 1999;341(4):248-57 Brath: DM
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Pathological Pathways of Insulin Resistance
Overweight Inflammation Glucose Insulin GLUT-4 Glucosetransporter 4 Insulin- Receptor Glucose- transporter Kinases + - MAP-Kinases: Atherosclerosis M-TOR Pathway: Cancer 14 Shepherd PR et al, NEJM. 1999 MAP: mitogen-activated protein; M-TOR: mammalian target of rapamycin Brath: DM
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2. Common Causes Brath: DM
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Overweight & Cancer Risk
Men Women Calle et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med Apr 24;348(17): Brath: DM
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Active- & Passive Smoking in Young Adults: Glucose Tolerance
Prospective, CARDIA-study, n = 4742, age at inclusion: 18 – 30 yrs. Incidence of Glucose Intolerance within 15 yrs. HR adjusted to biolog., behavioural- & sociodemographic factors 21,8 % HR: 1,65 (1,27-2,13) 17,2 % HR: 1,35 (1,06-1,71) 14,4 % NS 11,5 % Houston TK et al: BMJ May 6;332(7549):1064-9 Brath: DM
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Second hand smoke → Diabetes
Metaanalysis: 7 prospective studies, 162,001 subjects OR: 1,33 (1,20 – 1,46) Xiaomin Wei et al: A meta-analysis of passive smoking and risk of developing T2DM. Diabetes Res Clin Pract Jan;107(1):9-14. doi: Brath: DM
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Common Etiologies for T2DM & Cancer
Smoking Too much (red) Meat Chronic Inflammation Visceral Obesity Brath: DM
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3. Diab. assoc. Mechanisms Brath: DM
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Adiposity in the development of NASH
Adipose Insulin Leptin Adiponectin Adiposity in the development of NASH The slide depicts the pathogenesis of nonalcoholic fatty liver disease. Accumulation of fat in adipocytes is associated with development of insulin resistance, increased leptin levels, and decreased adiponectin levels. The lipolysis rate in adipocytes is also increased, leading to influx of fatty acids into the liver. Accumulation of fat in hepatocytes (steatosis) generates reactive oxygen species, enhances lipid peroxidation, and promotes generation of cytokines. Subsequent infiltration of inflammatory cells and activation of stellate cells marks the transition to steatohepatitis and, eventually, fibrosis. Fatty acids Liver Normal Steatosis (fatty liver) Steatohepatitis (steatosis and inflammation) Fibrosis (collagen deposition) Adapted from Ahima RS. Gastroenterology. 2007;132:444-6. Angulo P. N Engl J Med. 2002;346:
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Waist Circumference: Diagnostic & Therapeutic Relevance
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4. Hyperglycemia Brath: DM
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« we were able to show the independent
Hazard-Risiko (HR) for Cancer n=4623 pat. with T2DM 1 % ↑ HbA1c → 26 % ↑ Cancer Risk Authors conclude: « we were able to show the independent cancer risk with A1C and that of reduction of cancer with insulin therapy » X Yang et al, Diabetes, 2010 Brath: DM
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3. Own Data Brath: DM
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Oxidative Stress & DNA-Damage in T2DM Oxidative Stress Hyperglycaemia
Cell Death Healthy Cell Cell with damaged DNA Important to control predisposing factors (glucose metabolism, lipid metabolism, blood pressure) and thereby reduce the risk for diabetes complications Hyperglycaemia derived oxidative stress is the key initiator of complications Cell with chromosom. Damage 8-oxodG DNA Repair Brath: DM
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Methoden Oxidative damage to DNA/RNA Chromosomal damage
Comet Assay (Lysis, FPG-sensitive sites, 100 µM H2O2) 8-oxodG and 8-oxoGuo in urine (UPLC with tandem MS) Chromosomal damage BMCyt Assay in buccal cells CBMN-Assay in lymphocytes Brath: DM
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Studies performed DIAPLANT – Studie MIKRODIAB – Studie
Dietary intervention Oxidative stress Oxidative DNA damage Genomic instabilities MIKRODIAB – Studie Oxidative stress Oxidative DNA damage DNA repair Genomic instabilities Glycemic control (HbA1c) Diabetes Duration Medication
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Genomic instabilities
1 Studies performed DIAPLANT – Studie Dietary intervention Oxidative stress Oxidative DNA damage Genomic instabilities
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DNA-Schäden Müllner E, Brath H, …., Wagner KH, Mol Nutr Food Res Feb;57(2):328-38
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Glykäm. Kontrolle & Chromosom. Schäden (Micronuclei)
Müllner E, Brath H, …., Wagner KH: Genome damage in periph blood lymphocytes of diabetic and non-diabetic individuals after intervention with vegetables and plant oil. Mutagenesis Jan 21. [Epub ahead of print] Brath: Inkr.
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2 Studies performed MIKRODIAB – Studie Oxidative stress
Oxidative DNA damage DNA repair Genomic instabilities Glycemic control (HbA1c) Diabetes Duration Medication
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Mikrodiab-Studie – Chromosomenschäden
Grindel A, Brath H….. Wagner KH. Sci Rep Feb 2;7: doi: /srep41985
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Clinical Consequences
4. Clinical Consequences Brath: DM
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Screening for People with Diabetes: Not only for CV Diseases,
but also for Cancer Brath: DM
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Cancer Prevention stay insuline sensitive prevent diabetes
stay (viserally) slim, don´t smoke, eat healthy DM medication: Metformin protective? old sulfonylurea? high insuline dosages? pioglitazone: bladder? SGLT-inhib.: bladder, breast? Brath: DM
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Typ 2 Diabetes Hypertension Cancers Carciovasc. Dis.
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Typ 2 Diabetes Hypertension ↓ exercise obesity genet. predisposition unhealthy nutrition smoking Cancers Cardiovasc. Dis.
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Typ 2 Diabetes Hypertension ↓ exercise obesity genet. predisposition unhealthy nutrition smoking Cancers Cardiovask. Dis.
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Typ 2 Diabetes Hypertension smoking ↓ exercise obesity genet. predisposition unhealthy nutrition Cancers cardiovask. Dis.
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Typ 2 Diabetes Hypertension ↓ exercise obesity genet. predisposition Unhealthy nutrition smoking Cancers Cardiovasc. Dis.
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„inedible“ Brath: DM
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Brath: DM
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