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International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #110: Type 2 Diabetes and Cancer Part 3

Jan 30, 2018


The relationship between cholesterol and cancer risk has been difficult to discern from epidemiologic studies. Individuals with the metabolic syndrome and T2DM frequently have a dyslipidemic profile with elevated triglycerides and decreased high-density lipoprotein cholesterol (HDL-C). In the Metabolic Syndrome Cancer (Me-Can) European cohort elevated triglyceride levels were associated with colon, respiratory, kidney, thyroid cancers, and melanoma in men and respiratory, cervical, and nonmelanoma skin cancers in women [22]. An inverse relationship was found between elevated HDL-C and incident cancer risk in a meta-analysis of 24 randomized control trials, with inverse relationships also being found for both prostate and breast cancer risk. A recent Danish population study reported that the use of statins before the diagnosis of cancer was associated with reduced cancer-related mortality compared to nonusers of statins [23]. There is a relative dearth of studies examining the association between cholesterol and cancer, as elevated cholesterol is associated with such significant increases in cardiovascular mortality that many individuals died of cardiovascular disease before developing cancer.

Additionally, caution should be applied when interpreting studies on cholesterol and cancer as low cholesterol levels are associated with chronic diseases, thus individuals with metastatic lung cancer may have low cholesterol levels, which may be a cause of the chronic illness rather than low cholesterol levels being associated with metastatic lung cancer. Further epidemiologic studies in the area of cholesterol and cancer are necessary to determine whether a true association between these conditions exists.

Inflammatory cytokines and adipokines

Abdominal obesity is considered a state of chronic inflammation and this inflammation is often thought to contribute to the insulin resistance that leads to the development of the metabolic syndrome and T2DM. Macrophages found in adipose tissue secrete inflammatory cytokines including interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-α) and these cytokines have also been implicated in the development of numerous cancers. Examination of serum TNF-α and IL-6 levels in the EPIC cohort have found that higher circulating levels of these cytokines were associated with a significantly increased risk of endometrial cancer; however, adjusting for body mass index resulted in a loss of a significant association between IL-6 and endometrial cancer. This should not be considered surprising as the increase in inflammatory cytokines is thought to be associated with increased adiposity.

The circulating levels of the adipokine leptin increase in the setting of obesity, the metabolic syndrome, and T2DM, while circulating levels of adiponectin decrease. High leptin levels and low adiponectin levels have been associated with certain cancers, although epidemiologic studies have shown inconsistent results. In a cohort from the WHI, low adiponectin and high leptin levels were associated with an increased risk of colorectal cancers; however, the effect of low adiponectin was not independent of insulin. Low adiponectin has also been associated with an increased risk of breast, renal, and prostate cancer as well as multiple myeloma in some studies. Although leptin is hypothesized to increase tumor growth, the Physicians’ Health Study found no association between leptin and prostate cancer; no association has been found between leptin and renal cancer or multiple myeloma in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, and the Nurses’ Health Study found that leptin levels were inversely associated with premenopausal breast cancer risk. Overall, these epidemiologic studies suggest that both inflammatory cytokines and adipokines may be playing a role in the development of cancers in individuals with obesity, the metabolic syndrome, and T2DM. Whether these effects are independent of insulin remains to be determined.

Altered estrogen levels in T2DM and cancer

Obese postmenopausal women are known to have higher circulating levels of estrogen than their lean counterparts due to increased aromatase activity in adipose tissue. Additionally, obese insulin-resistant women have decreased hepatic production of sex hormone-binding globulin (SHBG) leading to more bioavailable estrogens in the circulation. Recent studies have shown that in the breast tissue from obese individuals, aromatase expression is increased approximately twofold, compared to the expression level in the breast tissue of normal weight women [24,25]. This increased expression may lead to higher estrogen concentrations in the breasts of obese women and may drive the growth of tumors that are hormone responsive, such as common postmenopausal breast cancers.

Overall, epidemiologic studies have demonstrated a consistent increase in the risk of many epithelial cancers in those with T2DM. Many risk factors have been identified that are associated with an increased risk of both T2DM and cancer development. Biologic links that are known to be associated with obesity, the metabolic syndrome, and T2DM have been identified, including hyperinsulinemia, increased IGF-I, dyslipidemia, inflammatory cytokines, adipokines and estrogens, and the association between these factors and cancer have been explored in epidemiologic studies. However, the current epidemiologic studies cannot directly determine whether these factors can actually cause cancer or increase tumor growth, or the mechanisms through which they may exert these effects. Therefore, animal models have been created in order to understand the links between diabetes and cancer.

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