Insulin therapy and cancer.

Abstract

That diabetes is associated with an increased lifetime risk of developing malignancy is now well established (1,2). For some specific malignancies, explanation of that increased risk is possible, though usually unproven. For example, the marked increase in pancreatic cancer incidence in type 2 diabetes may or may not be due to misattribution of type of diabetes where the reality is secondary diabetes. Also markedly increased is hepatic malignancy—something that may be secondary to hepatic steatosis or, rather, hepatosteatitis and subsequent fibrotic/regenerative disease. Lesser increases in large-bowel malignancy are also found in association with obesity and modern low-residue high-fat diets, and both obesity and such diets are associated with diabetes (1,3). In contrast, it is notable that high-concentration insulin given repeatedly into the same injection site for many decades has not generated even one report of a subcutaneous sarcoma in >90 years in tens of millions of people. Type 2 diabetes and other types of diabetes, once vascular damage is occurring, are inflammatory states, which may provide an environment for oncogenesis of some malignancies. However, the inflammatory state might also might provide enhancement of immune cancer surveillance mechanisms. The reduction of prostate cancer incidence is potentially explainable in the context of relative reduction in circulating testosterone levels in men with type 2 diabetes. A second concern over diabetes and malignancy is regarding glucose-lowering therapies. However, only in the case of PPAR-αγ agonists is there reasonably strong data once information from preclinical studies, randomized controlled trials (RCTs), and observational studies is taken together (4–6). For insulin, the data are more complex to assess. Preclinical animal data of concern are limited to an analog with unusual receptor binding properties. However, mechanistic data do suggest mechanisms by which increased malignancy risk could operate, and this has raised concerns …