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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #109: Type 2 Diabetes and Cancer Part 2

Jan 23, 2018
 

Links between diabetes and cancer

Common risk factors

Epidemiologic studies demonstrate that those with diabetes are more likely to develop cancer, but the mechanisms through which this may occur are incompletely understood. The American Diabetes Association and the American Cancer Society published a consensus report in 2010, with the aim of examining the knowledge regarding the association between diabetes and cancer, exploring the risk factors for both conditions, to examine their possible biologic links and to determine whether certain treatments for diabetes modify cancer risk [4]. In the report they identified certain risk factors that increase the chance of developing both conditions. These were listed as “non-modifiable” and “modifiable” risk factors that are common to diabetes and cancer and may explain in part the increased risk of cancer. Non-modifiable risk factors include age, sex, and race/ethnicity. While modifiable risk factors include overweight/obesity, smoking, alcohol intake, and physical activity and diet (Table 21.2). In addition there are biologic factors that may be common to the two conditions. With advancing age the risk of both T2DM and cancer increase: 78% of newly diagnosed cancers occur in those over 55 years of age, the prevalence of diabetes also increases with age, from 10.8% in those aged 40–59 years, but increases to 23.8% in those aged 60 years or more. Men have a slightly higher risk of developing diabetes than women, additionally, with the exception of certain sex-specific or almost sex-specific cancers (e.g. prostate, testicular, cervical, endometrial, and breast cancer), men are also more likely than women to develop cancer. Certain racial groups (e.g. African Americans) are more likely to develop cancer and diabetes than other racial groups. Overweight and obesity have been associated with cancers for many years. Large epidemiologic studies, including the Cancer Prevention Study II in the USA and the Million Women’s Study in the UK reported that for both men and women an increased body mass index (BMI) was associated with a greater risk of developing colorectal, esophageal, pancreatic, and kidney cancer, non-Hodgkin’s lymphoma and multiple myeloma; additionally they reported an increased risk of endometrial cancer, ovarian cancer, and postmenopausal breast cancer in women. In fact the results of the CPS II study suggest that 14% of cancer deaths in men and 20% in women could be attributed to obesity. Currently over a third of Americans are obese. Overweight and obesity also increase the risk of developing T2DM. A number of studies have now shown that smoking is an independent risk factor for developing T2DM and is also a risk factor for multiple cancers. Moderate to high alcohol consumption is known to increase the risk of certain cancers and in certain populations, such as in lean Japanese individuals moderate to high alcohol intake is also a risk factor for the development of diabetes [18]. A sedentary lifestyle is associated with an increase in many chronic diseases, amongst them are diabetes and cancer. Finally, consuming a diet rich in fruits and vegetables has been shown in studies to be protective against the development of T2DM and cancer.

Biologic links

Identifying the increased risk of cancer in those with T2DM or obesity let to the hypothesis that there must be common biologic links between these conditions that increase the risk of cancer. Additionally, recent studies have shown that those with the metabolic syndrome, a syndrome on the continuum between obesity and T2DM also have an increased risk of cancer. Physiologic changes that may occur in individuals with obesity, the metabolic syndrome and T2DM and may contribute to cancer development include hyperglycemia, insulin resistance and hyperinsulinemia, increased insulin-like growth factor-I (IGF-I) levels, dyslipidemia, visceral adiposity and increased inflammatory cytokines, altered levels of circulating adipokines, and altered circulating and tissue levels of estrogens (Table 21.3). Epidemiologic and animal studies have been conducted to examine these individual biologic factors on cancer development.

Hyperglycemia

It is well known that cancers take up glucose, a phenomenon that is exploited in the visualization of fluorodeoxyglucose (FDG) uptake by positron emission tomography (PET) for the detection of tumors and metastases. Some epidemiologic studies have examined how glucose levels alter cancer risk. A European study of individuals with the metabolic syndrome (The Me-Can study) found that higher glucose levels were associated with an increased risk of liver, gallbladder, respiratory, thyroid cancer, and multiple myeloma in men, as well as pancreatic, bladder, endometrial, cervical, and stomach cancer in women. However, in a meta-analysis of prospective diabetes studies (VADT, ACCORD, UKPDS33, UKPDS34), complications were compared in patients receiving intensive glucose control and A1c values of 6.9%, 6.4%, 7%, and 7.9% with those receiving standard diabetes control and A1c values of 8.4%, 7.5%, 7.9%, and 8.5%, respectively. They determined that there was no difference in cancer outcome between the standard and intensively controlled groups. These studies were not designed to examine cancer incidence as a primary outcome; some of the treatments for diabetes may potentially have increased the risk. Additionally, all of the patients in these studies had a diagnosis of diabetes, and therefore were all at potentially increased risk of cancer as well as having abnormal glucose levels, compared to the normal nondiabetic population. Other prospective studies on over 60,000 individuals in the Vasterbotten Intervention Project in Sweden and the Hong Kong diabetes registry did report an increased risk of cancer in those with hyperglycemia. Thus, human studies assessing the effect of hyperglycemia on tumor growth are inconclusive due to confounding biologic and diabetes treatment effects.

Insulin and IGF-I

In many of the previously mentioned prospective epidemiologic studies, such as the WHI, the Physicians’ Health Study and the EPIC studies, serum samples were stored at the time of recruitment and these samples were subsequently analyzed to determine whether there was an association between a specific biomarker (e.g. endogenous insulin levels) and the risk of certain cancers. In the WHI study insulin levels were measured in the study population and then the population was divided into quartiles based on their endogenous insulin levels. Comparing those with insulin levels in the highest quartile with the lowest quartile, they found that women with higher insulin levels who did not take hormone replacement had a greater risk of breast cancer. The Nurses’ Health Study II, which consisted mostly of premenopausal women, did not find an association between insulin and premenopausal breast cancer. C-peptide is used in some studies as a marker of endogenous insulin secretion. Higher C-peptide levels have also been associated with postmenopausal breast cancer. In the Physicians’ Health Study and the Nurses’ Health Study higher levels of C-peptide were associated with an increased risk of colorectal cancer. Subsequent studies have also reported that high plasma C-peptide levels are associated with colonic adenomas, suggesting that hyperinsulinemia may act as an early etiological factor in the development of colon cancer. A meta-analysis of studies reported that individuals who develop colorectal and pancreatic cancer have increased prediagnostic insulin/C-peptide levels. Interestingly, the Physicians’ Health Study also found that high C-peptide levels were associated with an increased risk of prostate cancer and prostate cancer mortality. In a study from Finland, fasting insulin concentrations were higher in men who subsequently developed prostate cancer, an association that was independent of glucose levels. Some variability in results has been observed in studies on insulin/C-peptide and cancer risk and data are only available on a few cancer types. Many of these studies did not collect serum for insulin and C-peptide in fasting conditions, and these samples were collected and stored for many years long before analysis and before the development of cancer, therefore these may contribute to some variability between the epidemiologic studies.

Hyperinsulinemia directly increases hepatic IGF-I expression via the IR and leads indirectly to increased hepatic IGF-I production, by increasing hepatic growth hormone receptor levels. Growth hormone then acting through the growth hormone receptors stimulates IGF-I expression. High normal levels of circulating IGF-I are associated with increased risk of certain cancers including colorectal, breast, and prostate cancer in prospective epidemiologic studies and meta-analyses [19–21]. No association has been found between circulating IGF-I and lung cancer.

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