A large body of epidemiological evidence has established that excess body weight is a major risk factor for many cancer forms. Several biological mechanisms potentially mediating the association of excess body weight with cancer risk have been proposed, one of them being insulin resistance and bioavailability of insulin-like growth factor (IGF) I. However, until now, the role of insulin resistance as a mediator in the association of body mass index (BMI), a common measure of excess body weight, with site-specific cancer risk has never been systematically quantified. In our study, we used a newly proposed surrogate measure, the logarithmized triglyceride glucose product (TyG index), to determine to what extent insulin resistance mediates the effect of BMI on risk of ten common obesity-related cancers.
For this purpose, we analyzed longitudinal data of more than 500,000 individuals from the Metabolic Syndrome and Cancer Project 2.0, in whom, over a median follow-up time of 17.2 years, more than 16,000 obesity-related cancers were recorded. Our analyses, using novel, causal-inference based statistical approaches for mediation analysis and adjusting for relevant confounders, revealed that the TyG index significantly mediated the effect of overweight and obesity on risk of cancers of the pancreas (42% of total BMI effect mediated by the TyG index), rectum (34%), colon (20%), kidney (15%), and liver (11%). In contrast, little or no mediation was observed for cancers of the endometrium, ovary and breast.
As the TyG index is indicative of insulin resistance, our findings support the insulin-IGF hypothesis for cancers of the digestive organs and the kidney; that is, insulin and potentially IGFs may be important pathways through which obesity affects cancer risk. In contrast, although often claimed, our results provide limited evidence that insulin resistance connects excess body weight with risk of cancers of the female reproductive organs.
Link to the study published in the International Journal of Epidemiology