ueda2012 diabetes and cancer-d.i.daskalova

1. PROF. DR. I. DASKALOVA
Military Medical Academy, Sofia
BULGARIA

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.  Aging
 Sex
 Obesity
 Physical activity
 Diet
 Alcohol
 Smoking

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 age–adjusted risk of
diabetes than women
 Race/ethnicity

5.  Overweigh - (BMI >25 and <30kg/m2)
 Obesity – BMI > 30 kg/m2
 Weight change

6. 6

8.  Breast (postmenopausal women)
 Colon/rectum
 Endometrial
 Pancreas
 Adenocarcinoma of the esophagus
 Kidney
 Gallbladder
 liver

9.  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

10.  Low in red and processed meats
 Higher in vegetables, fruits
 Whole grains cereals
 Monounsaturated fatty acid
 Dietary fiber
 Low-carbohydrate diets

11.  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

12.  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

13.  Lower risk of colon
 Postmenopausal breast
 Endometrial cancer
 Prevent other cancer including
 Lung
 Aggressive prostate cancer

14.  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

16.  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.

17.  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

18.  Higher risk of postmenopausal women
 Breast
 Endometrial
 Other cancers

19.  Diabetes
 Diabetes treatment
 Cancer
 Insulin receptor activation may be a more
important variable than hyperglycemia in
determining tumor growth

20.  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)

21.  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

22. PAI-1антиген(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
*
*
*

23. Insulin
resistans
Type 2 DM
Vascular
inflamation
C-RP
CVD

24.  Metformin
 Thiazolidinediones
 Insulin secretagogues
 Incretin - based therapies
 Insulin and insulin analogs

25.  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.

26.  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.

27.  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

28.  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).

29.  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.

30.  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.

31.  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.

32.  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

33.  Risk factors between the two diseases
 Aging
 Obesity
 Diet
 Physical inactivity
 Hyperinsulinemia
 Hyperglycemia
 Inflammation

34.  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