Diabetes, Insulin Use, and Cancer Risk: Are Observational Studies Part of the Solution–or Part of the Problem?

  1. Edwin A.M. Gale2
  1. 1School of Public Health, University of Alberta, Edmonton, Canada;
  2. 2Department of Diabetes and Metabolism, School of Medicine, Bristol University, Bristol, U.K.
  1. Corresponding author: Edwin A.M. Gale, edwin.gale{at}bristol.ac.uk.

Cancer has overtaken cardiovascular disease as the leading cause of death in individuals under the age of 65 in the general population, but it is still overshadowed by cardiovascular disease in those with diabetes. People with type 2 diabetes are nonetheless more likely to develop cancer—and to die from it—than members of the general population, so cancer should be numbered among the complications of diabetes (1). Furthermore, the number of cancer victims with diabetes will inevitably rise in proportion to our success in combating vascular disease in the diabetic population.

How can the increased cancer risk in diabetes be explained? To begin with, it should be noted that obesity, insulin resistance, and/or increased levels of IGF-1 and insulin are strongly associated with most (but not all) of the diabetes-related cancers in the nondiabetic population (1). This suggests that hyperglycemia does not play an essential role in the pathogenesis of these tumors, but does not exclude the possibility that it might have secondary effects such as enhanced tumor growth or resistance to anti-tumor therapy. IGF-1 and insulin offer a more plausible mechanistic explanation for the overlapping risk of cancer in the nondiabetic and diabetic populations. Both hormones are mitogenic (but not mutagenic), both are present at high levels in insulin-resistant states, and their receptors are overexpressed on the surface of cancer cells associated with diabetes. They thus have the potential to act as tumor growth factors in vivo as well as in vitro (2,3). On this argument, which we will refer to as the insulin supply hypothesis, drugs used to treat diabetes might influence the risk of cancer by modulating the insulin/IGF axis (1).

There is, however, a possible alternative explanation for the increased risk of cancer in diabetes, which we refer to as the glucose supply hypothesis. …

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