Diabetes and cancer: A critical appraisal of the pathogenetic and therapeutic links.

Diabetes and cancer represent two common, multifactorial, chronic and potentially fatal diseases, not infrequently co-diagnosed in the same patient. Epidemiological data demonstrate significant increases of the cancer incidence in patients with obesity and diabetes, which is more evident for certain site-specific cancers. Although there is increasing evidence that strongly indicates an augmented risk of cancer in diabetic patients, several confounding factors complicate the ability to precisely assess the risk. Mainly in insulin-resistant states (such as in type 2 diabetes mellitus and in metabolic syndrome), direct associations between obesity-related hyperinsulinemia and increasing circulating insulin-like growth factor-1 (IGF-1) levels have been implicated as key factors in the mechanisms involved in carcinogenesis. Whilst anti-diabetic drugs can increase the cancer risk, anti-proliferative drugs may cause diabetes or aggravate pre-existing diabetes. Additionally, an increasing number of targeted anti-cancer therapies may interfere with the pathways shared by IGF-1 and insulin receptors, showing a adverse effect on glucose metabolism through various mechanisms. Although there is a requirement for large-scale randomized evidence, the present review summarizes the majority of the epidemiological association studies between diabetes and various types of cancer, discussing the pathophysiological mechanisms that may be involved in promoting carcinogenesis in diabetes and the potential impact of different anti-diabetic therapies on cancer risk.