Evidence of a Causal Relationship Between Adiponectin Levels and Insulin Sensitivity
A Mendelian Randomization Study
- He Gao1,2,3,
- Tove Fall1,
- Rob M. van Dam2,3,
- Allan Flyvbjerg4,
- Björn Zethelius5,
- Erik Ingelsson1⇑ and
- Sara Hägg1
- 1Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- 2Saw Swee Hock School of Public Health, National University of Singapore, Singapore
- 3National University of Singapore Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore
- 4Medical Research Laboratories, Department of Clinical Medicine, Faculty of Health, Aarhus University, Aarhus, Denmark
- 5Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala and Medical Products Agency, Uppsala, Sweden.
- Corresponding author: Erik Ingelsson, .
E.I. and S.H. contributed equally to this 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 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 Pdifference ≥ 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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0935/-/DC1.
See accompanying commentary, p. 1007.
- Received July 13, 2012.
- Accepted October 27, 2012.
- © 2013 by the American Diabetes Association.
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