**3. Mechanisms underlying diabetes and cancer**

Carcinogenesis is a very complex process in which normal cells must undergo multiple genetic modification in order to appear malignant phenotype and invasion and metastasis occurs. This process of carcinogenesis is divided in three steps. First step is initiation, this is the irreversible step toward cancer, second step is promotion, the stimulation of growth of initiated cells, and the third step is progression. Any factors that have the capability to affect one of these steps could be associated with cancer incidence and mortality.

Diabetes may have an effect on carcinogenesis process by multiple mechanisms: hyperinsulinemia, either is exogenous due to administration of insulin or endogenous due to insulin resistance, hyperglycemia or chronic inflammation [18].

There are many epidemiologic evidence that support the link between diabetes and cancers. Diabetes and cancer may be related simply because these two diseases share common risk factors such as obesity, diet, physical inactivity, but several biologic mechanism have been described that may strengthen this link between diabetes and cancer.

Information regarding biologic mechanism is from in vivo and in vitro studies, research is ongoing currently to provide more clear understanding of these possible mechanisms, and the information from these studies may be important for prevention of the disease and management of the patient.

#### **3.1. Hyperinsulinemia**

Insulin and insulin-like growth factor (IGF) receptors form a complex network of cell surface receptors and majority of cancer cells express these receptors. The A isoform is commonly expressed on cells, and can stimulate insulin-mediated mitogenesis, even in cells that do have a deficiency in IGF-I receptors, and in addition to this function, the insulin receptor is capable to stimulate cell proliferation and to promote metastasis [18, 37, 38]. Interaction of insulin receptors or IGF-I receptors with their ligands activate multiple pathways, that can stimulate proliferation, resistance to apoptotic stimuli, invasion and metastasis. IGF-I have more important anti-apoptotic and mitogenic activities than insulin, and could act as growth factor in pre-neoplastic or cancer cells that express insulin and IGF-I receptors. In cancer cells these receptors are over-expressed and many cancer cell lines have been shown to be very responsive even to the mitogenic effect of normal concentrations of IGF-I [39–41].

High levels of IGF-I have been associated with an increased risk of postmenopausal breast cancer, colon and prostate cancer [18, 42, 43].

It is also possible that hyperinsulinemia may promote carcinogenesis by indirect mechanisms. Insulin reduces the hepatic production of insulin growth factor binding protein (IGFBP) and this will lead to increased levels of circulating free IGF-I.

Hyperinsulinemia have an indirect effect on reduction in hepatic production and blood levels of sex-hormone binding protein, which increase bioavailability of estrogen in both man and women and also increase bioavailability of testosterone in women which is also link to cancer, but not in man [18, 44].

In postmenopausal women, body fat is the primary site of estrogen synthesis, and obesity is related to high levels of serum estrogen this will increase the risk for breast and endometrial cancers in women who do not use hormonal replacement therapy [45].

### **3.2. Hyperglycemia**

digestive tract, bladder, pancreas, liver, kidney and uterine cervix. Studies have shown that smoking is an independent risk factor for diabetes, and it is well known to act as an adverse

Alcohol consumption increases the risk of many type of cancers, oral cavity, pharynx, colon, liver and female breast. For diabetes, increased alcohol consumption is a considered a risk, but moderate consumption was associated with reduced incidence of diabetes in both men and

Carcinogenesis is a very complex process in which normal cells must undergo multiple genetic modification in order to appear malignant phenotype and invasion and metastasis occurs. This process of carcinogenesis is divided in three steps. First step is initiation, this is the irreversible step toward cancer, second step is promotion, the stimulation of growth of initiated cells, and the third step is progression. Any factors that have the capability to affect one of these steps

Diabetes may have an effect on carcinogenesis process by multiple mechanisms: hyperinsulinemia, either is exogenous due to administration of insulin or endogenous due to insulin

There are many epidemiologic evidence that support the link between diabetes and cancers. Diabetes and cancer may be related simply because these two diseases share common risk factors such as obesity, diet, physical inactivity, but several biologic mechanism have been described

Information regarding biologic mechanism is from in vivo and in vitro studies, research is ongoing currently to provide more clear understanding of these possible mechanisms, and the information from these studies may be important for prevention of the disease and management of

Insulin and insulin-like growth factor (IGF) receptors form a complex network of cell surface receptors and majority of cancer cells express these receptors. The A isoform is commonly expressed on cells, and can stimulate insulin-mediated mitogenesis, even in cells that do have a deficiency in IGF-I receptors, and in addition to this function, the insulin receptor is capable to stimulate cell proliferation and to promote metastasis [18, 37, 38]. Interaction of insulin receptors or IGF-I receptors with their ligands activate multiple pathways, that can stimulate proliferation, resistance to apoptotic stimuli, invasion and metastasis. IGF-I have more

effect on diabetes complications [33, 34].

**3. Mechanisms underlying diabetes and cancer**

could be associated with cancer incidence and mortality.

resistance, hyperglycemia or chronic inflammation [18].

that may strengthen this link between diabetes and cancer.

**2.5. Alcohol consumption**

122 Diabetes and Its Complications

women [35, 36].

the patient.

**3.1. Hyperinsulinemia**

The link between effect of hyperglycemia and cancer is still unclear. Hyperglycemia increases production of free radicals which could lead to oxidative damage to DNA and mutation in oncogenes and tumor suppressor genes [18]. Research is still unclear about whether high levels of circulating glucose fuels malignant growth.

The recent interest in Warburg hypothesis emphasize the dependence of many cancers on glycolysis, creating a high requirement for glucose, so called "glucose addiction," because ATP generation glycolysis requires more glucose than oxidative phosphorylation. This is the basis for F-flurodeoxyglucose—positron emission tomography (PET) of cancer, that detects tissues with high glucose uptake [46].

Studies correlating hyperglycemia with cancer do not indicate that the high level of glucose itself mediate this correlation, because chronic hyperglycemia is associated with insulin resistance and often with excess of body fat, and hyperglycemia may act as surogate [18].

#### **3.3. Chronic inflammation**

Type 2 diabetes and obesity are characterized by chronic inflammation that increases the production of free radicals. This can disrupt insulin signaling and damage DNA. Adipose tissue is an active endocrine organ and is producing interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), adiponectin, leptin and tumor necrosis factor-α (TNF-α). All of these factors may play a role in malignant transformation and cancer progression, and some of these roles are well known [47].
