The Causal Role of Adiponectin in Type 2 Diabetes across Ages and Sexes - An Observational and Mendelian Randomization Study.

Abstract

Aims: The obesity pandemic has increased the prevalence of Type 2 Diabetes (T2D) across all ages and sexes. Adiponectin, an insulin-sensitizing hormone, shows protective effects against T2D in observational studies. However, it is unclear whether low adiponectin levels cause T2D, as this association might be driven by confounding factors. We aimed to investigate if the association of adiponectin with T2D is causal.

Materials and methods: We assessed causality with Two-Sample Mendelian Randomization (MR) using Single Nucleotide Polymorphisms (SNPs) from multi-ancestry genome-wide association studies (GWAS). Multivariable MR (MVMR) and Two-Step network MR evaluated whether the effect of adiponectin on T2D was influenced by adiposity-related phenotypes. Using the Avon Longitudinal Study of Parents and Children (ALSPAC), we examined mediation and longitudinal associations between adiponectin, T2D-related traits, and adiposity in youth.

Results: Initial inverse variance-weighted MR estimates suggested protective effects. However, the identified causal association did not persist after removing SNPs linked to adiposity-related traits or adjusting for these traits in MVMR. Two-Step network MR showed that adiponectin could mediate the relationship between visceral fat and T2D in women. ALSPAC results suggest that adiponectin may mediate the relationship between adiposity and fasting glucose levels in youth.

Conclusions: Taken together, our MR results did not show a causal association between adiponectin levels and T2D. Instead, adiponectin potentially plays a sex-specific mediating role in the relationship between visceral fat and T2D in women.