Multiple Hypotheses (continued)

Patients with T2DM have prolonged exposure to both hyperinsulinemia and hyperglycemia. The effect of frank hyperglycemia in cancer development is uncertain. Tumor cells create energy through relatively inefficient aerobic glycolysis. Although one hypothesis is that systemic hyperglycemia provides a fertile environment for tumor cell growth, IR overexpression on tumors allows efficient uptake of glucose, bringing into question whether hyperglycemia confers any additional advantage.1,21 A Swedish prospective study, with a 12-year follow up, found no association between hyperglycemia and incidence overall or for specific cancer types using glycated hemoglobin (A1C) as a glucose measure.22 Conversely, another Swedish study found significantly higher risk for all-site cancer, pancreatic cancer, and, in women, endometrial and premenopausal breast cancer. This study used fasting and postprandial glucose to determine hyperglycemia.23

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T2DM is also characterized by chronic, systemic inflammation related to insulin resistance and usually obesity. Both contribute to an upregulation of TNF-α and IL-6, accompanied by a change in adipocyte balance toward pre-growth leptin. This combination favors cell proliferation, survival, and metastasis, while suppressing host antitumor responses.1,19

Risk factors Cancer and diabetes share nonmodifiable risk factors, including aging, family history, and sex. Older age and family history increase an individual’s risk for developing either disease. Overall, men are at higher risk for cancer and have higher age-adjusted rates of T2DM than women.1 Both cancer and T2DM disproportionately affect African Americans in the United States.1 Shared modifiable risk factors include obesity, diet, low levels of physical activity, and excessive alcohol use.1

Drug therapy-related factors The association between medications and increased cancer risk is muddied by the fact that regimens tend to change over time. However, it appears that drugs that increase insulin sensitivity without increasing insulin levels, particularly metformin, may reduce cancer risk. Metformin is a widely used oral therapy that increases insulin sensitization, decreases glucose production in the liver, and does not affect endogenous insulin production.24 Figure 2 describes the percentage of patients with diabetes in the United States between 2007 and 2009 treated with insulin and/or oral medications.