1. 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

2. 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

3. 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

4. 1. Typ 2 Diabetes & Cancer Epidemiology
Brath: DM

5. 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

6. Diabetes vs. Non-diabetes: Mortality
Framingham study, 1970 – 2005
Mortality rates vs
Preis RS et al:Circulation July 21; 120(3): 212–220
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7. (results of different metaanalyses)
Cancer risk
in Diabetes
(results of different metaanalyses)
Acta Diabetol 2010;47:87-95

8. 2. Diabetes & Cancer: Possible Etiologies
Brath: DM

9. 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
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10. Possible causal relations betw. T2DM & Cancer1 2 3 4
Insulin Resistance, Hyperinsulinemia
Common Causes: Obesity, Smoking, Nutrition…
Pathomechanisms assoc. with Diabetes
Hyperglycemia
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11. 1.
Insulin Resistance
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12. 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
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13. 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
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14. 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
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15. 2.
Common Causes
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16. 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

17. 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
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18. 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:
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19. Common Etiologies for T2DM & Cancer
Smoking
Too much (red) Meat
Chronic Inflammation
Visceral Obesity
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20. 3.
Diab. assoc. Mechanisms
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21. 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:

22. Waist Circumference: Diagnostic & Therapeutic Relevance
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23. 4.
Hyperglycemia
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24. « 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

25. 3. Own Data
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26. 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
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27. 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
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28. 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

29. Genomic instabilities1
Studies performed
DIAPLANT – Studie
Dietary intervention
Oxidative stress
Oxidative DNA damage
Genomic instabilities

30. DNA-Schäden
Müllner E, Brath H, …., Wagner KH, Mol Nutr Food Res Feb;57(2):328-38

31. 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.

32. 2 Studies performed MIKRODIAB – Studie Oxidative stress
Oxidative DNA damage
DNA repair
Genomic instabilities
Glycemic control (HbA1c)
Diabetes Duration
Medication

33. Mikrodiab-Studie – Chromosomenschäden
Grindel A, Brath H….. Wagner KH. Sci Rep Feb 2;7: doi: /srep41985

34. Clinical Consequences4.
Clinical Consequences
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35. Screening for People with Diabetes: Not only for CV Diseases,
but also for Cancer
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36. 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

37. Typ 2 Diabetes
Hypertension
Cancers
Carciovasc. Dis.

38. Typ 2 Diabetes
Hypertension
↓ exercise
obesity
genet. predisposition
unhealthy nutrition
smoking
Cancers
Cardiovasc. Dis.

39. Typ 2 Diabetes
Hypertension
↓ exercise
obesity
genet. predisposition
unhealthy nutrition
smoking
Cancers
Cardiovask. Dis.

40. Typ 2 Diabetes
Hypertension
smoking
↓ exercise
obesity
genet. predisposition
unhealthy nutrition
Cancers
cardiovask. Dis.

41. Typ 2 Diabetes
Hypertension
↓ exercise
obesity
genet. predisposition
Unhealthy nutrition
smoking
Cancers
Cardiovasc. Dis.

42. „inedible“
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43. Brath: DM