**Diabetes and Cancer: Is there a Link?**

**Diabetes and Cancer: Is there a Link?**

Andra-Iulia Suceveanu, Adrian-Paul Suceveanu, Andreea-Daniela Gheorghe and Laura Mazilu Andreea-Daniela Gheorghe and Laura Mazilu Additional information is available at the end of the chapter

Andra-Iulia Suceveanu, Adrian-Paul Suceveanu,

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.72081

#### **Abstract**

[10] Holmquist P, Torffvit O. Tubular function in diabetic children assessed by Tamm-Horsfall protein and glutathione S-transferase. Pediatric Nephrology. 2008;23:1079-1083

[11] Saif A, Soliman N. Urinary alfa1-microglobulin and albumin excretion in children and

[12] Mitch WE, Chesney RW. Amino acid metabolism by the kidney. Mineral and Electrolyte

[13] Newgard CB. Regulation of glucose metabolism in the liver. In: Defronzo RA, Ferrannini E, Keen H, Zimmet P, editors. International Textbook of Diabetes Mellitus. Chichester, England:

[14] Grill V, Björkman O, Gutniak M, Lindqvist M. Brain uptake and release of amino acids in nondiabetic and insulin-dependent diabetic subjects: Important role of glutamine release

[15] Hagenfeldt L, Dahlquist G, Persson B. Plasma amino acids in relation to metabolic control in insulin-dependent diabetic children. Acta Paediatrica Scandinavica. 1989;78:278-282

[16] Nelson AL, Cox MM. Glucolisis, gluconeogénesis y ruta de las pentosas fosfato. In:

[17] Bjornstad P, Roncal C, Milagres T, Pyle L, Lanaspa MA, Bishop FK, Snell-Bergeon JK, Johnson RJ, Wadwa RP, Maahs DM. Hyperfiltration and uricosuria in adolescents with

[18] Tonneijck L, Muskiet MH, Smits MM, van Bommel EJ, Heerspink HJ, van Raalte DH, Joles JA. Glomerular hyperfiltration in diabetes: Mechanisms, clinical significance, and

[19] Warady BA, Abraham AG, Schwartz GJ, Wong CS, Muñoz A, Betoko A, Mitsnefes M, Kaskel F, Greenbaum LA, Mak RH, Flynn J, Moxey-Mims MM, Furth S. Predictors of rapid progression of glomerular and nonglomerular kidney disease in children and adolescents. The chronic kidney disease in children (CkiD) cohort. American Journal of

[20] Rossi R, Danzebrink S, Linnenbürger K, Hillebrand D, Grüneberg M, Sablitzky V, Deufel T, Ullrich K, Harms E. Assessment of tubular reabsorption of sodium, glucosa, phosphate

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118 Diabetes and Its Complications

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Cancer and diabetes are two major health problems worldwide, and incidence is increasing globally for both diseases. Type 2 diabetes is characterized by hyperinsulinemia and insulin resistance and the effect of insulin and insulin growth factor I on cancer development and progression have been demonstrated in animal and human studies. The relationship between diabetes and cancer was reported for more than 60 years. Many epidemiological studies conducted over time suggested the association between diabetes and cancer. Epidemiological studies show an increased risk in type 2 diabetic patients for colon, breast, liver, pancreas, bladder cancers and non-Hodgkin's lymphoma, and a decrease risk for prostate cancer. Lung cancer does not appear to be related to diabetes and for renal cancer data are inconclusive. Diabetes, beside the fact that it is an independent risk factor for different type of cancer, can also have an impact on prognosis of cancer, and studies shown an increased cancer mortality in patients with diabetes.

DOI: 10.5772/intechopen.72081

**Keywords:** diabetes, cancer, hyperinsulinemia, insulin resistance

#### **1. Introduction**

Cancer and diabetes are two major health problems worldwide, and incidence is increasing globally for both diseases. In 2012, 14.1 million new cancer cases and 8.2 million death occurred worldwide, and the number of cases and deaths is expected to grow as populations adopt lifestyle behaviors that increase the cancer risk [1, 2]. Diabetes is also an important health problem associated with severe complications, and its growing worldwide In 2014 was estimated that 422 million adults were living with diabetes, the prevalence of diabetes globally is 8.5% in adult population and caused 1.5 million death in 2012 [3]. Globally, cancer is the 2nd cause of death, and diabetes is 12th cause of death [4]. The economic growth is accompanied

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© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

by lifestyle westernization, characterized by physical inactivity, high-calorie diet and obesity and may explain this change in incidence and mortality of lifestyle related diseases such as diabetes, cancer and cardiac disease.

the association of diabetes with different type of cancer is related to common risk factor for both diseases or diabetes with metabolic modification like insulin resistance and hyperinsulinemia is responsible for the increased risk of cancer. More studies are needed to understand the role of each component of lifestyle independent of other, to understand the relation between diabetes

Diabetes and Cancer: Is there a Link? http://dx.doi.org/10.5772/intechopen.72081 121

More than 60% of cancers are diagnosed in patients aged 60 years or more, and the prevalence of diabetes is 17% in this age group; the coexistence of cancer and diabetes is expected to raise

Diabetes is known to be related with overweight and obesity, studies shown over the years a strong association between obesity, insulin resistance and type 2 diabetes and early age diagnosis of diabetes is reported to be linked directly to obesity severity [21, 22]. Cancers most frequently associated with obesity and overweight are breast cancer in postmenopausal women, colon, pancreas, endometrium, gallbladder and liver, and may increase mortality in prostate

The association between weight loss and decreased risk of diabetes was strengthened by numerous studies. A randomized, prospective, multicenter Diabetes Prevention Trial, shown that lifestyle intervention and physical activity was associated with 58% reduction in inci-

The relation between weight loss and cancer risk is not that clear, and most data are derived from breast cancer studies, and in this studies association observed was very weak [26]. The Nurses' Health Study shown a statistical significant association between weight loss and decrease incidence of breast cancer, if the weight loss is maintained for more than 4 years [27].

Data from epidemiologic observational studies shown that physical activity is associated with lower risk of colon, breast and endometrial cancers, and may help to prevent lung or prostate

A protective role of increased physical activity in diabetes metabolism and outcomes has been demonstrated in studies. Data from observational studies suggest that approximately 30 to 60 minutes of moderate-intensity physical activity, at least 5 days per week reduces substan-

Smoking is a well-known risk factor for lung cancer incidence and mortality. Other types of cancer that is known to be associated with cigarette smoking are cancer of larynx, upper

and cancer.

**2.2. Obesity**

cancer [23, 24].

**2.3. Physical inactivity**

**2.4. Smoking**

as life expectancy increases [19, 20].

dence of diabetes in high risk individuals [25].

cancer, but in this case the link is not yet established [28–31].

tially, with 25–36%, the risk of developing type 2 diabetes [18, 32].

**2.1. Age**

The relationship between diabetes and cancer was reported for more than 60 years. Theodore Tuffier, a French surgeon, is probably the first one to hypothesize the existence of a relationship of type 2 diabetes mellitus and cancer risk in the second half of nineteenth century. He observed that patients with type 2 diabetes have a greater risk of certain cancers than those without diabetes and formulated some key questions: could diabetes affect the incidence of cancer? could diabetes influence the natural history of cancer? and could cancer affect the natural history of diabetes? [5].

Many epidemiological studies conducted over time suggested the association between diabetes and cancer. Studies show an increased risk in type 2 diabetic patients for colon, breast, liver, pancreas, bladder cancers and non-Hodgkin's lymphoma [6–12], and a decrease risk for prostate cancer [13]. Lung cancer does not appear to be related to diabetes and for renal cancer data are inconclusive [14].

Diabetes, beside the fact that is an independent risk factor for different type of cancer, can also have an impact on prognosis of cancer, and studies shown an increased cancer mortality in patients with diabetes. A meta-analysis of 23 studies comparing the overall survival in cancer patients with or without diabetes showed that diabetic patient have an increased mortality, HR of 1.41 (95% CI, 1.28 to 1.55) compared to non-diabetic patients in all cancer types [15].

The majority of the studies that explore the relation between diabetes and cancer do not make the difference between type 1 and type 2 diabetes. It is important to make that distinction, because type 1 diabetes is an autoimmune disease and it is caused by destruction of pancreatic β cells with resultant insulin deficiency and hyperglycemia, and on the other hand type 2 diabetes it appears because of peripheral insulin resistance and it is characterized by hyperinsulinemia and β cell hyperplasia. These 2 entities differ also in the age of onset, type 2 diabetes occurs in adults patients, while type 1 diabetes is usually observed in young people. Considering the differences in the physiopathology of these two diseases, it is important to make diagnostic distinction before any conclusion is made about the association of diabetes and cancer. But, the large majority of patients with diabetes have type 2 diabetes and most study have been conducted on patients with diabetes at older age, this can extrapolate that the majority of diabetic patients who develop cancer are patients with type 2 diabetes.

One Swedish study was conducted on patients with type one diabetes, but did not found an increased risk for pancreatic, breast or colorectal cancer in this patients [16, 17].

## **2. Diabetes and cancer – common risk factors**

Diabetes and cancer very often coexist in the same patients; up to 18% of patients with cancer have also diabetes. Risk factors that are common for both diseases, diabetes and cancer are age, obesity and overweight, physical inactivity, smoking [18]. An important problems is whether the association of diabetes with different type of cancer is related to common risk factor for both diseases or diabetes with metabolic modification like insulin resistance and hyperinsulinemia is responsible for the increased risk of cancer. More studies are needed to understand the role of each component of lifestyle independent of other, to understand the relation between diabetes and cancer.

#### **2.1. Age**

by lifestyle westernization, characterized by physical inactivity, high-calorie diet and obesity and may explain this change in incidence and mortality of lifestyle related diseases such as

The relationship between diabetes and cancer was reported for more than 60 years. Theodore Tuffier, a French surgeon, is probably the first one to hypothesize the existence of a relationship of type 2 diabetes mellitus and cancer risk in the second half of nineteenth century. He observed that patients with type 2 diabetes have a greater risk of certain cancers than those without diabetes and formulated some key questions: could diabetes affect the incidence of cancer? could diabetes influence the natural history of cancer? and could cancer affect the

Many epidemiological studies conducted over time suggested the association between diabetes and cancer. Studies show an increased risk in type 2 diabetic patients for colon, breast, liver, pancreas, bladder cancers and non-Hodgkin's lymphoma [6–12], and a decrease risk for prostate cancer [13]. Lung cancer does not appear to be related to diabetes and for renal cancer data

Diabetes, beside the fact that is an independent risk factor for different type of cancer, can also have an impact on prognosis of cancer, and studies shown an increased cancer mortality in patients with diabetes. A meta-analysis of 23 studies comparing the overall survival in cancer patients with or without diabetes showed that diabetic patient have an increased mortality, HR of 1.41 (95% CI, 1.28 to 1.55) compared to non-diabetic patients in all cancer types [15].

The majority of the studies that explore the relation between diabetes and cancer do not make the difference between type 1 and type 2 diabetes. It is important to make that distinction, because type 1 diabetes is an autoimmune disease and it is caused by destruction of pancreatic β cells with resultant insulin deficiency and hyperglycemia, and on the other hand type 2 diabetes it appears because of peripheral insulin resistance and it is characterized by hyperinsulinemia and β cell hyperplasia. These 2 entities differ also in the age of onset, type 2 diabetes occurs in adults patients, while type 1 diabetes is usually observed in young people. Considering the differences in the physiopathology of these two diseases, it is important to make diagnostic distinction before any conclusion is made about the association of diabetes and cancer. But, the large majority of patients with diabetes have type 2 diabetes and most study have been conducted on patients with diabetes at older age, this can extrapolate that the

majority of diabetic patients who develop cancer are patients with type 2 diabetes.

increased risk for pancreatic, breast or colorectal cancer in this patients [16, 17].

**2. Diabetes and cancer – common risk factors**

One Swedish study was conducted on patients with type one diabetes, but did not found an

Diabetes and cancer very often coexist in the same patients; up to 18% of patients with cancer have also diabetes. Risk factors that are common for both diseases, diabetes and cancer are age, obesity and overweight, physical inactivity, smoking [18]. An important problems is whether

diabetes, cancer and cardiac disease.

120 Diabetes and Its Complications

natural history of diabetes? [5].

are inconclusive [14].

More than 60% of cancers are diagnosed in patients aged 60 years or more, and the prevalence of diabetes is 17% in this age group; the coexistence of cancer and diabetes is expected to raise as life expectancy increases [19, 20].

#### **2.2. Obesity**

Diabetes is known to be related with overweight and obesity, studies shown over the years a strong association between obesity, insulin resistance and type 2 diabetes and early age diagnosis of diabetes is reported to be linked directly to obesity severity [21, 22]. Cancers most frequently associated with obesity and overweight are breast cancer in postmenopausal women, colon, pancreas, endometrium, gallbladder and liver, and may increase mortality in prostate cancer [23, 24].

The association between weight loss and decreased risk of diabetes was strengthened by numerous studies. A randomized, prospective, multicenter Diabetes Prevention Trial, shown that lifestyle intervention and physical activity was associated with 58% reduction in incidence of diabetes in high risk individuals [25].

The relation between weight loss and cancer risk is not that clear, and most data are derived from breast cancer studies, and in this studies association observed was very weak [26]. The Nurses' Health Study shown a statistical significant association between weight loss and decrease incidence of breast cancer, if the weight loss is maintained for more than 4 years [27].

#### **2.3. Physical inactivity**

Data from epidemiologic observational studies shown that physical activity is associated with lower risk of colon, breast and endometrial cancers, and may help to prevent lung or prostate cancer, but in this case the link is not yet established [28–31].

A protective role of increased physical activity in diabetes metabolism and outcomes has been demonstrated in studies. Data from observational studies suggest that approximately 30 to 60 minutes of moderate-intensity physical activity, at least 5 days per week reduces substantially, with 25–36%, the risk of developing type 2 diabetes [18, 32].

### **2.4. Smoking**

Smoking is a well-known risk factor for lung cancer incidence and mortality. Other types of cancer that is known to be associated with cigarette smoking are cancer of larynx, upper 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 effect on diabetes complications [33, 34].

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 respon-

Diabetes and Cancer: Is there a Link? http://dx.doi.org/10.5772/intechopen.72081 123

High levels of IGF-I have been associated with an increased risk of postmenopausal breast

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

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

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

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

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

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

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

and often with excess of body fat, and hyperglycemia may act as surogate [18].

sive even to the mitogenic effect of normal concentrations of IGF-I [39–41].

cancers in women who do not use hormonal replacement therapy [45].

cancer, colon and prostate cancer [18, 42, 43].

man [18, 44].

**3.2. Hyperglycemia**

this will lead to increased levels of circulating free IGF-I.

levels of circulating glucose fuels malignant growth.

tissues with high glucose uptake [46].

**3.3. Chronic inflammation**

roles are well known [47].

#### **2.5. Alcohol consumption**

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 women [35, 36].
