Evidence for Association Between T2DM and Certain Cancers (continued)

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For most other cancer types, only moderate increases in risk are seen. Diabetes appears to lower the risk for developing prostate cancer and to have no influence on risks for esophageal or lung cancer.1,2,8,11 In addition, cancer-related mortality is higher among patients with diabetes.7,8,12-14 Recent studies have found an approximately 20% increase in breast cancer risk with diabetes that is skewed toward postmenopausal women, possibly due to obesity-mediated increased estrogen exposure.7,12,14 In this instance, non-Hispanic white women are at higher risk than Hispanic, Native American, and Asian women.12,16

Diabetes confers an approximately 30% increased risk for colorectal cancer in both men (29%) and women (33%) when adjusted for risk factors, including smoking, family history, physical activity, and body mass index.8,14 Slower bowel transit times associated with T2DM and the influence of hyperinsulinemia on colon cell growth and tumorigenesis have also been implicated.8,17 Interestingly, factors that contribute to hyperinsulinemia—namely, obesity, low physical activity levels, diets low in fruits/high in red meat—are also known risk factors for colon cancer.17

Evidence linking hematologic cancers and T2DM has been inconclusive, but a 2012 meta-analysis of observational studies found a highly significant relationship with non-Hodgkin lymphoma (NHL).1,2,18 There was a 22% increase in overall risk for NHL (P<0.001), and a similar, but less statistically robust increased risk for leukemia (P=0.02) and myeloma (P=0.08); patients in Asia were at higher risk than those in Europe or the Americas.18 Within NHL subtypes, increased risk was limited to peripheral T-cell leukemia.18

Multiple Hypotheses

Despite epidemiological evidence linking diabetes with cancer risk, it is still unclear whether the association is related directly to changes in glucose and insulin metabolism, shared risk factors such as obesity, or the effects of antihyperglycemic medications—or whether a causal relationship exists at all.1

Diabetes-specific factors A leading disease-related hypothesis is that hyperinsulinemia related to insulin resistance promotes tumorigenesis through downstream effects on insulin growth factors. Insulin resistance, defined as the impaired uptake of insulin in muscle, liver, and fat tissues, is a defining characteristic of metabolic syndrome and T2DM.19 Pancreatic beta cells respond to insulin resistance by increasing insulin output, leading to hyperinsulinemia, over the short term, and the progressive decline of beta cells that characterizes T2DM over the long term. Insulin receptors (IR) are not unique to the target tissues mentioned; they are ubiquitous and a necessary part of cell growth pathways. Most tumors express or overexpress IR, particularly their A isoform, and receptors for insulin growth factor (IGF), which stimulates mitogenesis and may promote proliferation and metastasis in tumor cells. Downstream pathways activated by insulin are involved in the growth and proliferation of both normal cells and tumors; subsequently, these pathways may aid tumor progression.1,19 By suppressing proteins that bind IGF-1, hyperinsulinemia increases circulating levels of this potent growth hormone, which has antiapoptotic, mitogenic, and potential neoplastic properties.1,19 High circulating levels of insulin also lead to increased levels of bioavailable estrogen, with resultant effects on postmenopausal breast, endometrial, and possibly other cancers.1 The roles of insulin and IGF-1 in cancer development have led researchers to investigate compounds that target them as possible therapeutic agents. Several are currently being studied in clinical trials.20