Evidence of a causal relationship between adiponectin levels and insulin sensitivity: a Mendelian randomization study

Abstract

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 randomization 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 × 10(-9)) 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 sensitivity (β = 0.47-0.81, all P ≤ 0.014) comparable with observational estimates (β = 0.50, all P(difference) ≥ 0.136). Adjustment for BMI and waist circumference partly explained the association of both genetically determined and observed adiponectin levels with insulin sensitivity. The observed association between higher adiponectin levels and increased insulin sensitivity is likely to represent a causal relationship partly mediated by reduced adiposity.

FIG. 1.

Hypothetical model for the relationship between ADIPOQ, adiponectin, and insulin sensitivity. This paradigm illustrates the key relationships in the study of the influence of adiponectin on insulin sensitivity using a Mendelian randomization design. Solid arrows represent causal influences that are expected, and dotted arrows are causal influences that are assumed not to exist. Genetic variants from the ADIPOQ gene are used as IVs based on three main assumptions: 1) The IVs are robustly associated with the exposure of interest, i.e., adiponectin levels; 2) the IVs are independent of confounders for the association between adiponectin and insulin sensitivity in observational studies; and 3) the IVs are independent of the outcome insulin sensitivity given adiponectin levels and the confounders. Moreover, we hypothesize that part of the effect of adiponectin on insulin sensitivity is mediated by adiposity, which is represented by BMI and waist circumference.