Abstract 11824: Evidence of a Causal Relationship between Adiponectin Levels and Insulin Sensitivity: A Mendelian Randomization Study

Abstract

The adipocyte-secreted protein adiponectin has been associated with insulin sensitivity in observational studies. We aimed to evaluate whether this relationship is causal using a Mendelian randomization approach. In a sample of 71-year-old Swedish men (n=942) from the Uppsala Longitudinal Study of Adult Men (ULSAM), insulin sensitivity was measured by the euglycemic insulin clamp (M/I ratio). We used genetic variants in the ADIPOQ gene as instrumental variables to generate causal estimates for the effect of adiponectin on insulin sensitivity. These estimates were compared with those derived by conventional linear regression of insulin sensitivity on adiponectin. The three ADIPOQ variants, rs17300539, rs3774261 and rs6444175 were strongly associated with serum adiponectin levels (P<5.4x10^-9 for all SNPs). Each of the variants were also significantly associated with M/I ratio in the expected direction (P≤0.022 for all SNPs). Instrumental variable analysis confirmed that genetically determined adiponectin increased insulin sensitivity (β=0.470 for rs17300539, β=0.678 for rs3774261 and β=0.805 for rs6444175; P≤1.4x10^-3 for all SNPs) at similar effect sizes as observational estimates (β=0.498, P_difference ≥0.136 by Durbin-Wu-Hausman test). The genetically determined and observed adiponectin level associations remained similar after adjusting for body mass index (BMI) to address mediation by adiposity. The observed association between higher adiponectin levels and increased insulin sensitivity is likely to represent a causal relationship not mediated by adiposity.