PROF. DR. I. DASKALOVA

Military Medical Academy, Sofia

BULGARIA

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.)

Aging

Sex

Obesity

Physical activity

Diet

Alcohol

Smoking

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

Overweigh - (BMI >25 and <30kg/m2)

Obesity – BMI > 30 kg/m2

Weight change

6

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

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

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

PA

I-1

антиген

(n

g/m

l)

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;

19:562–568.

n = 1551

*P < 0.001

*

*

*

Insulin

resistans

Type 2 DM

Vascular

inflamation

C-RP CVD

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