The triglyceride-glucose index as a measure of insulin resistance and risk of obesity-related cancers

Abstract

Background The role of insulin resistance as a mediator in the association of body mass index (BMI) with site-specific cancer risk has, to our knowledge, never been systematically quantified. Methods Altogether 510 471 individuals from six European cohorts, with a mean age of 43.1 years, were included. We used the triglyceride glucose product (TyG index) as a surrogate measure for insulin resistance. We fitted Cox models, adjusted for relevant confounders, to investigate associations of TyG index with 10 common obesity-related cancers, and quantified the proportion of the effect of BMI mediated through TyG index on the log-transformed hazard ratio (HR) scale. Results During a median follow-up of 17.2 years, 16 052 individuals developed obesity-related cancers. TyG index was associated with the risk of cancers of the kidney HR per one standard deviation increase 1.13, 95% confidence interval: 1.07 to 1.20], liver (1.13, 1.04 to 1.23), pancreas (1.12, 1.06 to 1.19), colon (1.07, 1.03 to 1.10) and rectum (1.09, 1.04 to 1.14). Substantial proportions of the effect of BMI were mediated by TyG index for cancers of the pancreas (42%), rectum (34%) and colon (20%); smaller proportions for kidney (15%) and liver (11%). Little or no mediation was observed for breast (postmenopausal), endometrial and ovarian cancer. Results were similar for males and females, except for pancreatic cancer where the proportions mediated were 20% and 91%, respectively. Conclusions The TyG index was associated with increased risk of cancers of the digestive system and substantially mediated the effect of BMI, suggesting that insulin resistance plays a promoting role in the pathogenesis of gastrointestinal cancers.

Explaining the link between adiposity and colorectal cancer risk in men and postmenopausal women in the UK Biobank: A sequential causal mediation analysis

“…The authors repeated the mediation analysis separately for the two biomarker groups, assuming that the pathways were independent. Although the HPFS included more inflammatory biomarkers compared with ours, similar to our results, the observed indirect effect through inflammation was small (OR NIE 40 . The strength of the mediating effect was similar in men and women, and after excluding participants who did not have diabetes 40 .…”

“…Although the HPFS included more inflammatory biomarkers compared with ours, similar to our results, the observed indirect effect through inflammation was small (OR NIE 40 . The strength of the mediating effect was similar in men and women, and after excluding participants who did not have diabetes 40 . In our study, we did not observe any mediating effect through HbA1c.…”

“…In our study, we did not observe any mediating effect through HbA1c. The observed indirect effect through TyG in the study by Fritz et al may have been overestimated because the analysis did not allow for potential confounding by the preceding inflammatory pathway 40 . In our study, the estimated indirect effect through HbA1c excluded the possible influence of CRP on HbA1c, thus removed the confounding effect of CRP 17 .…”

Role of Overweight and Obesity in Gastrointestinal Disease

“…One plausible molecular mechanism for obesity-associated carcinogenesis is the chronic inflammatory state, which is the result of the activity of the visceral adipose tissue leading to the release of inflammatory cytokines and mediators [79]. Moreover, insulin resistance plays a promoting role in the pathogenesis of GI cancers [80].…”

Comparison of obesity indices and triglyceride glucose related parameters to predict type 2 diabetes mellitus among normal-weight elderly in China

“…The mechanism of TyG in T2DM is not clear, and several studies have provided clues to unpack the underlying mechanisms. First, previous studies demonstrated that TyG might have strong predictive ability for IR [41,42]. TyG has better predictive performance of IR than homeostatic model assessment (HOMA) in the Brazilian population [43].…”