Cancer risks from diabetes therapies: evaluating the evidence

Epidemiological studies have identified positive associations between diabetes, obesity and cancer. Insulin, metformin and thiazolidinediones (TDZs) are among the major diabetes therapies that improve glycaemic control by acting via molecular targets including the insulin receptor and insulin-like growth factor pathways, adenosine monophosphate-activated kinase and peroxisome proliferator-activated receptor γ. It is well-established that clinical application of insulin and TDZs is associated with weight gain, but the potential of these therapies to promote tumourigenesis is less well-studied. In addition, although anti-tumour properties of metformin have been proposed, recently published data do not support a protective effect of metformin against cancer in diabetic patients. Given that diabetes and cancer each account for 8% and 13% of global deaths and there is a substantial financial burden incurred by both disorders, developing diabetes therapies that are safe, efficacious and cost-effective has never been more desirable. This timely review examines recent progress in delineating the molecular mechanisms responsible for the anti-diabetic actions of insulin, metformin and TZDs and considers evidence implicating these therapies in cell transformation and tumourigenesis. In addition, since the endocannabinoid signalling system (ECS) is now considered a therapeutic target and biomarker candidate for hyperglycaemia, obesity and cell growth, a brief section covering recent scientific advances regarding the ECS, particularly its functions in regulating glucose metabolism and cell survival, is also included in this review.