**4. Diabetes treatment and cancer**

Type 2 diabetes is treated with different types of medications, so it may be a link between these drugs and the risk of cancer. Anti-diabetic medication includes drugs that increase insulin in circulation (insulin and sulfonylureas) and drugs that improve insulin action and decrease insulin levels (metformin, thiazolidinediones). The central goal of diabetes management is glucose control, this minimize morbidity and mortality related to diabetes by reducing diabetes associated complications. When selecting antidiabetic therapies, physician and patients consider several factors, these includes type of diabetes, glucose-lowering potential of the antidiabetic agent, adverse effect of treatment, costs, patient characteristic and comorbidities.

One mode of action of breast cancer gene 1 (BRCA-1) is a tumor suppressor activity which depends on its ability to mimicry a cellular low-energy status, which is also known to block tumor cell anabolism and suppress the malignant phenotype. Studies shown that increased physical activity and normal weight in young women and adolescence have been associated with significantly delayed breast cancer onset for Ashkenazi Jewish women carrying BRCA-1 gene mutations [60]. Similar to animal model, human studies demonstrated a link between hyperinsulinemia and the risk for breast cancer. One study, although was conducted on postmenopausal women without diabetes, the Women's Health Initiative, reported that fasting insulin levels, independent of obesity, were strongly associated with breast cancer risk [61]. Studies conducted on women with diabetes, demonstrated also the association between hyperinsulinemia and risk for breast cancer. The Nurses' Health Study was conducted on women with type 2 diabetes and concluded that women with type 2 diabetes had an elevated incidence of breast cancer, independent of body adiposity and also that the risk was observed on women with estrogen receptor positive breast

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Other studies explored the relationship between type 2 diabetes and breast cancer mortality and reported positive association. For example, prospective cohort study conducted by Coughlin et al. [63] showed that diabetic patient had an increased risk of breast cancer mortality in comparison with controls. Several factors may contribute to the increased mortality in diabetic breast cancer patients, these include delayed cancer diagnosis, suboptimal cancer treatments, direct tumor promoting effects of hyperinsulinemia, and adverse effects of diabetes-related

In conclusion, several studies have demonstrated an increased risk of breast cancer and breast cancer mortality in patients with type 2 diabetes and this may be related to biological effect

Worldwide in 2012, more than 500,000 women were diagnosed with uterine cancer, and the mortality rate was 1.7 to 2.4 per 100,000 women [65]. In developed countries, uterine cancer is the most common gynecologic neoplasia, counting over 50,000 new cases and over 10,000 deaths

An important and well known risk factor for endometrial cancer is obesity. Other risk factors are reproductive factors, hypertension, physical activity, exposure of endometrium to estrogen

In vitro studies have shown that endometrial cancer cells have an increased proliferation by activation of IGF-I, activation of insulin, and through the ovarian steroid hormone signaling pathways, such as estrogen and androgen [68, 69]. Although is not known to exist a direct correlation with insulin or IGF levels in endometrial cancer, additional factors such as ovarian steroid hormones or inflammatory cytokines make difficult to confirm if there is a single effect of insulin or IGF activation through insulin or IGF serum levels. Estrogen can activate IGF-I receptor on endometrial cancer cells, this will increase cellular proliferation through PI3K signaling, a link to IGF-I receptor activation [70]. The androgen receptor (AR) activated

comorbidities or certain antidiabetic medications [64].

**5.2. Diabetes and endometrial cancer**

from this disease every year [66–68].

unopposed by progesterone and diabetes.

cancer [62].

of diabetic state.

Type 2 diabetes represent the majority of diabetic population and account for 95% of diabetic population and majority of studies were conducted on this patients. It is generally associated with obesity and overweight in almost 80% of cases. In type 2 diabetes insulin resistance and hyperglycemia are progressive [48, 49].

The majority of studies on antidiabetic treatment and cancer risk have limitations, one limitation is that diabetic patients are treated with more than one antidiabetic agent, because of the progressive nature of type 2 diabetes. In this case is very difficult to assess an association between a specific antidiabetic drug and cancer risk [18].

There are 14 diabetes drugs available at this time, and data suggest a higher risk of cancer development with pioglitazone, insulin and insulin secretagogues [50–53]. Metformin have been identified in several studies in the past few years to improve survival in patient diagnosed with cancer and diabetes and to reduced cancer risk [54]. Insulin has been shown in studies to have a direct proliferative effect; for the insulin analogues, further studies are needed to determine the potential role in cancer proliferation.
