**5. Diabetes and site – specific cancer**

#### **5.1. Diabetes and breast cancer**

Breast cancer is the leading cause death among females worldwide. An estimated 1.7 million new cases and more than 500,000 deaths occurred in 2012 [2]. Risk factors for breast cancer include age greater than 50 years, family history, genetics, female gender, Caucasian and African American Race, obesity and hormonal factors such as menstrual history, nulliparity and use of hormone replacement therapy [55].

The association of diabetes and breast cancer was studied extensively and appears to be connected via activation of insulin-IGF pathway through hyperinsulinemia and dysregulation of sex hormones [56, 57]. Cell proliferation in both normal human cell and in breast cancer cell has been shown to be influence by insulin. Insulin stimulates cell cycle progression and DNA synthesis of MCF-7 breast cancer cells in vitro [58, 59].

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 cancer [62].

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 comorbidities or certain antidiabetic medications [64].

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 of diabetic state.

#### **5.2. Diabetes and endometrial cancer**

**4. Diabetes treatment and cancer**

hyperglycemia are progressive [48, 49].

specific antidiabetic drug and cancer risk [18].

determine the potential role in cancer proliferation.

**5. Diabetes and site – specific cancer**

and use of hormone replacement therapy [55].

synthesis of MCF-7 breast cancer cells in vitro [58, 59].

**5.1. Diabetes and breast cancer**

and comorbidities.

124 Diabetes and Its Complications

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

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

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

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

Breast cancer is the leading cause death among females worldwide. An estimated 1.7 million new cases and more than 500,000 deaths occurred in 2012 [2]. Risk factors for breast cancer include age greater than 50 years, family history, genetics, female gender, Caucasian and African American Race, obesity and hormonal factors such as menstrual history, nulliparity

The association of diabetes and breast cancer was studied extensively and appears to be connected via activation of insulin-IGF pathway through hyperinsulinemia and dysregulation of sex hormones [56, 57]. Cell proliferation in both normal human cell and in breast cancer cell has been shown to be influence by insulin. Insulin stimulates cell cycle progression and DNA 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 from this disease every year [66–68].

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 unopposed by progesterone and diabetes.

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 by the binding with androgen could also increase the proliferation of endometrial cells by the Notch signaling pathway [66, 71]. Insulin resistance increases C-reactive protein (CRP) levels and was associated with an increased risk of endometrial cancer in postmenopausal women [66, 72]. This show that endometrial cancer could be associated with the chronic inflammation that present in type 2 diabetes.

**5.4. Diabetes and pancreatic cancer**

insulin resistance [85].

duced by Gullo et al. [86]

tion with prostate cancer.

diabetes and pancreatic cancer.

**5.5. Diabetes and prostate cancer**

tate cancer in diabetic patients (9–16%) [87, 88].

Cancer of the pancreas is one of the deadliest cancer types. Based on the GLOBOCAN 2012 evaluation it is estimated that pancreatic cancer is responsible for more than 330,000 deaths per year, putting pancreatic cancer on the seventh place of leading causes of cancer death in both sexes together. Worldwide, according to data available, more than 330,000 people had pancreatic cancer in 2012, making it the 11th most common cancer, and the highest incidence

Diabetes and Cancer: Is there a Link? http://dx.doi.org/10.5772/intechopen.72081 127

The causes of pancreatic cancer are still insufficiently known, but certain risk factors have been identified to have an impact in the development of pancreatic cancer. Risk factors implicated in pancreatic cancer are smoking, obesity, genetics, diabetes, diet, physical inactivity [81].

Diabetes mellitus is associated with an increased risk of pancreatic cancer; data in literature shown that both type I and type II diabetes have doubled the risk of pancreatic cancer [82]. Diabetes may be a risk factor for pancreatic cancer, but may also be the result of pancreatic cancer itself. Mechanism implicated is hyperinsulinemia, insulin has been shown to promote growth in pancreatic cell line and insulin resistance may enhance pancreatic carcinogenesis through enhanced proliferation of islet cells and increase cell turnover [83]. In type 2 diabetes exocrine pancreatic cells are exposed to high levels of insulin, and insulin act as mitogen leading to tumor growth. But this does not explain the increased risk of pancreatic cancer in type 1 diabetic patients and in patients treated with insulin therapy [84]. On the other hand, pancreatic cancer can be the cause of diabetes, through islet cell destruction and insulin resistance. It is not clear how pancreatic cancer can determine insulin resistance, but has been shown that diabetic patients with pancreatic cancer have increased plasma levels of islet amyloid polypeptide, a hormonal factor secreted by pancreatic cells that may cause

Insulin resistance may appear early in pancreatic cancer, and patients may be diagnosed with diabetes long before developing sign or symptoms of pancreatic cancer. This concept was intro-

In conclusion, further studies are necessary to explain this complicated association between

Unlike others cancers that were discussed before, prostate cancer have been shown to have a decreased incidence among type 2 diabetic patients, studies show a decreased risk for pros-

High testosterone levels are associated with prostate cancer and type 2 diabetic patients commonly have low levels of testosterone, are obese and elderly and both are associated with low levels of testosterone, and this may be one of the reason that can explain the negative associa-

and mortality rates due to pancreatic cancer are found in developed countries [2].

Obesity is a well-established risk factor form endometrial cancer, and due to close relationship between obesity and type 2 diabetes it is important to distinguish and there a very few studies that examined the effect of diabetes in endometrial cancer by body weight, and the findings in this studies is inconsistent [73]. There are many studies that examine the association between diabetes and the incidence of endometrial cancer, but only three studies adjusted for body mass index (BMI) and one study reported a significant association of endometrial cancer risk and diabetes [74, 75].

Association between diabetes and incidence of endometrial cancer and the potential effect of modification by obesity and physical activity was prospectively examined in the Swedish Mammography Cohort Study. Diabetes was associated with an increased risk for endometrial cancer, and combination of diabetes with obesity and low physical activity was associated with a further increased risk for endometrial cancer [76]. Interventions to reduce body weight and increase physical activity may have important implications in terms of endometrial cancer and future management of diabetic subjects.

#### **5.3. Diabetes and colorectal cancer**

In 2012, there were an estimated 1.4 million new colorectal cancer cases and 693,900 deaths. The highest colorectal cancer incidence rates in both males and females are in Japan, followed by Europe, Oceania, and North America. The lowest rates are found in Africa, some Asian countries, and Latin America and the Caribbean [2].

Type 2 diabetes was suggested as a risk factor for colorectal cancer [77]. Mechanisms implicated in this association are a slower bowel transit in patient with diabetes, that lead to increased exposure to toxins, increased production of carcinogenic bile acids and hyperinsulinemia [78].

Hyperinsulinemia has been associated with insulin resistance, increased levels of growth factors, including IGF-1, and alterations in NF-\_B and peroxisome proliferator-activated receptor signaling, which may promote colon cancer through their effects on colonocyte kinetics and was explored in most studies.

The Nurses' Health Study shown that patients with type 2 diabetes included in the study had a relative risk for colorectal cancer of 1.43 [79]. Several studies shown an increased risk for colorectal cancer in diabetic patients using insulin therapy [80] and also reported increased mortality in diabetic patients with colorectal cancer aged over 30 [77].

In conclusion, both colorectal cancer risk and mortality appear to be increased in patients with type 2 diabetes and hyperinsulinemia is mediating this association.

#### **5.4. Diabetes and pancreatic cancer**

by the binding with androgen could also increase the proliferation of endometrial cells by the Notch signaling pathway [66, 71]. Insulin resistance increases C-reactive protein (CRP) levels and was associated with an increased risk of endometrial cancer in postmenopausal women [66, 72]. This show that endometrial cancer could be associated with the chronic inflammation

Obesity is a well-established risk factor form endometrial cancer, and due to close relationship between obesity and type 2 diabetes it is important to distinguish and there a very few studies that examined the effect of diabetes in endometrial cancer by body weight, and the findings in this studies is inconsistent [73]. There are many studies that examine the association between diabetes and the incidence of endometrial cancer, but only three studies adjusted for body mass index (BMI) and one study reported a significant association of endometrial cancer risk and

Association between diabetes and incidence of endometrial cancer and the potential effect of modification by obesity and physical activity was prospectively examined in the Swedish Mammography Cohort Study. Diabetes was associated with an increased risk for endometrial cancer, and combination of diabetes with obesity and low physical activity was associated with a further increased risk for endometrial cancer [76]. Interventions to reduce body weight and increase physical activity may have important implications in terms of endometrial can-

In 2012, there were an estimated 1.4 million new colorectal cancer cases and 693,900 deaths. The highest colorectal cancer incidence rates in both males and females are in Japan, followed by Europe, Oceania, and North America. The lowest rates are found in Africa, some Asian coun-

Type 2 diabetes was suggested as a risk factor for colorectal cancer [77]. Mechanisms implicated in this association are a slower bowel transit in patient with diabetes, that lead to increased exposure to toxins, increased production of carcinogenic bile acids and hyperinsulinemia [78].

Hyperinsulinemia has been associated with insulin resistance, increased levels of growth factors, including IGF-1, and alterations in NF-\_B and peroxisome proliferator-activated receptor signaling, which may promote colon cancer through their effects on colonocyte kinetics and

The Nurses' Health Study shown that patients with type 2 diabetes included in the study had a relative risk for colorectal cancer of 1.43 [79]. Several studies shown an increased risk for colorectal cancer in diabetic patients using insulin therapy [80] and also reported increased mortality in

In conclusion, both colorectal cancer risk and mortality appear to be increased in patients with

that present in type 2 diabetes.

126 Diabetes and Its Complications

cer and future management of diabetic subjects.

tries, and Latin America and the Caribbean [2].

diabetic patients with colorectal cancer aged over 30 [77].

type 2 diabetes and hyperinsulinemia is mediating this association.

**5.3. Diabetes and colorectal cancer**

was explored in most studies.

diabetes [74, 75].

Cancer of the pancreas is one of the deadliest cancer types. Based on the GLOBOCAN 2012 evaluation it is estimated that pancreatic cancer is responsible for more than 330,000 deaths per year, putting pancreatic cancer on the seventh place of leading causes of cancer death in both sexes together. Worldwide, according to data available, more than 330,000 people had pancreatic cancer in 2012, making it the 11th most common cancer, and the highest incidence and mortality rates due to pancreatic cancer are found in developed countries [2].

The causes of pancreatic cancer are still insufficiently known, but certain risk factors have been identified to have an impact in the development of pancreatic cancer. Risk factors implicated in pancreatic cancer are smoking, obesity, genetics, diabetes, diet, physical inactivity [81].

Diabetes mellitus is associated with an increased risk of pancreatic cancer; data in literature shown that both type I and type II diabetes have doubled the risk of pancreatic cancer [82]. Diabetes may be a risk factor for pancreatic cancer, but may also be the result of pancreatic cancer itself. Mechanism implicated is hyperinsulinemia, insulin has been shown to promote growth in pancreatic cell line and insulin resistance may enhance pancreatic carcinogenesis through enhanced proliferation of islet cells and increase cell turnover [83]. In type 2 diabetes exocrine pancreatic cells are exposed to high levels of insulin, and insulin act as mitogen leading to tumor growth. But this does not explain the increased risk of pancreatic cancer in type 1 diabetic patients and in patients treated with insulin therapy [84]. On the other hand, pancreatic cancer can be the cause of diabetes, through islet cell destruction and insulin resistance. It is not clear how pancreatic cancer can determine insulin resistance, but has been shown that diabetic patients with pancreatic cancer have increased plasma levels of islet amyloid polypeptide, a hormonal factor secreted by pancreatic cells that may cause insulin resistance [85].

Insulin resistance may appear early in pancreatic cancer, and patients may be diagnosed with diabetes long before developing sign or symptoms of pancreatic cancer. This concept was introduced by Gullo et al. [86]

In conclusion, further studies are necessary to explain this complicated association between diabetes and pancreatic cancer.

#### **5.5. Diabetes and prostate cancer**

Unlike others cancers that were discussed before, prostate cancer have been shown to have a decreased incidence among type 2 diabetic patients, studies show a decreased risk for prostate cancer in diabetic patients (9–16%) [87, 88].

High testosterone levels are associated with prostate cancer and type 2 diabetic patients commonly have low levels of testosterone, are obese and elderly and both are associated with low levels of testosterone, and this may be one of the reason that can explain the negative association with prostate cancer.

Some studies have suggested that the link between prostate cancer and diabetes is mediated by the effect of hyperinsulinemia on testosterone levels [89]. Other studies have shown a negative association between hyperglycemia, hyperinsulinemia and prostate cancer. For example, Stocks and colleagues [90] in their prospective study reported that increased insulin resistance and low glycemic control is associated with low risk for prostate cancer in diabetic patients.

**6. Conclusions**

whelm health systems.

Andra-Iulia Suceveanu1

Ovidius University, Constanta, Romania

Ovidius University, Constanta, Romania

University, Constanta, Romania

**Author details**

Laura Mazilu3

**References**

Diabetes and cancer are common and serious global health problems, and incidence of both diseases is increasing all over the world. Many studies have suggested the relationship between diabetes and cancer and the fact that diabetes, may affect the risk of developing a variety of

It is important as a clinician to take in consideration all aspects when treating a cancer patient who has diabetes. It is important to consider all complications, cardiac, neurologic and renal complications that are commonly associated with diabetes. Continued improvement of cancer outcomes may be dependent also by the control of diabetes. Taking in consideration the results of numerous epidemiologic and clinical studies involving diabetes and cancer, clinicians must also pay attention to the increased risk of new or longstanding diabetics for some tumor entities by regularly screening diabetic patients for early development of cancer.

It is an important health problem worldwide, and scientists, clinicians and politicians have to develop national policies for early diagnosis and prevention of diabetes and cancer more effectively, otherwise both diseases with their biologic and sociologic relationships could over-

1 Faculty of Medicine, Department of Gastroenterology, Emergency Hospital of Constanta,

2 Faculty of Medicine, Department of Internal Medicine, Emergency Hospital of Constanta,

3 Faculty of Medicine, Department of Oncology, Emergency Hospital of Constanta, Ovidius

[1] International Agency for Research on Cancer Section of Cancer Surveillance. Cancer-

Mondial [cited 12-01-2015]. Available from: http://www-dep.iarc.fr/

, Andreea-Daniela Gheorghe<sup>3</sup>

and

Diabetes and Cancer: Is there a Link? http://dx.doi.org/10.5772/intechopen.72081 129

The association between diabetes and cancer is complex and need further studies.

\*, Adrian-Paul Suceveanu<sup>2</sup>

\*Address all correspondence to: andrasuceveanu@yahoo.com

cancers, and this association is also biological plausible.

Despite the fact that prostate cancer risk may be low in diabetic patients, they may have higher risk for cancer related mortality than non-diabetic patients.

Prostate cancer is an important example of the complexity of carcinogenesis associated with diabetes. On the one hand, an association between diabetes, IGF-1, hyperinsulinemia and insulin resistance appears plausible, but on the other, these features can be somewhat counterbalanced as well and can reduce the risk for the development of one of the leading cancer entities worldwide.

#### **5.6. Diabetes and hepatic cancer**

Hepatocellular carcinoma (HCC) represents the most common form of primary liver cancer. The association between HCC and type 2 diabetes was reported first 30 years ago, when Lawson documented that type 2 diabetes is more prevalent in patients with HCC, irrespective of viral hepatitis, alcoholic cirrhosis or hemochromatosis [91].

Since then, multiple studies have shown an association between type 2 diabetes and HCC, and documented the increased risk for HCC in diabetic patients, independent of age, sex, obesity, smoking, hypertension, presence of cirrhosis and hepatic steatosis [92–94].

The exact pathophysiological mechanisms linking type 2 diabetes and HCC are not completely understood, but the understanding of HCC pathophysiology has improved in recent years.

It is well known that type 2 diabetes is associated with increased hepatic and peripheral insulin resistance, lipotoxicity, increased oxidative stress and chronic low-grade inflammatory state, and several studies suggest that all these factors may contribute to the development of HCC by promoting hepatic cellular growth/proliferation and by inhibiting cellular apoptosis. In addition, in the presence of insulin resistance, insulin levels rise in blood, resulting in increased insulin-like growth factor-1 (IGF-1) production that is capable to stimulate hepatic cellular growth and proliferation and inhibit cellular apoptosis in the liver. Hyperinsulinemia also stimulates insulin receptor substrate-1 (IRS-1), which plays an important role in the activation of some intracellular cytokine signaling pathways implicated in hepatic carcinogenesis [95, 96].

There are ongoing studies trying to improve our knowledge about the pathophysiology of HCC. Recently, we have evidence that suggest that gut microbiota alteration may play a role in pathogenesis of type 2 diabetes [98], other studies reported some epigenetic alterations that might be also important for HCC development, for example, the hypermethylation of the E-cadherin-1 *(*CDH-1*)* gene has been related to increased incidence of NAFLD-related HCC [95–97].
