Evidence of a Causal Relationship Between Adiponectin Levels and Insulin Sensitivity A Mendelian Randomization Study

The adipocyte-secreted protein adiponectin is associated with insulin sensitivity in observational studies. We aimed to evaluate whether this relationship is causal using a Mendelian randomi-zation approach. In a sample of Swedish men aged 71 years (n = 942) from the Uppsala Longitudinal Study of Adult Men (ULSAM), insulin sensitivity (M/I ratio) was measured by the euglycemic insulin clamp. We used three genetic variants in the ADIPOQ locus as instrumental variables (IVs) to estimate the potential causal effect of adiponectin on insulin sensitivity and compared these with results from conventional linear regression. The three ADIPOQ variants, rs17300539, rs3774261, and rs6444175, were strongly associated with serum adiponectin levels (all P # 5.3 3 1029) and were also significantly associated with M/I ratio in the expected direction (all P # 0.022). IV analysis confirmed that genetically determined adiponectin increased insulin sensi