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Mendelian Randomization Studies Do Not Support a Causal Role for Reduced Circulating Adiponectin Levels in Insulin Resistance and Type 2 Diabetes.

Authors :
Yaghootkar, Hanieh
Lamina, Claudia
Scott, Robert A.
Dastani, Zari
Hivert, Marie-France
Warren, Liling L.
Stancáková, Alena
Buxbaum, Sarah G.
Lyytikäinen, Leo-Pekka
Henneman, Peter
Ying Wu
Cheung, Chloe Y. Y.
Pankow, James S.
Jackson, Anne U.
Gustafsson, Stefan
Jing Hua Zhao
Ballantyne, Christie M.
Weijia Xie
Bergman, Richard N.
Boehnke, Michael
Source :
Diabetes; Oct2013, Vol. 62 Issue 10, p3589-3598, 10p, 6 Charts, 2 Graphs
Publication Year :
2013

Abstract

Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics--based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI 20.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00121797
Volume :
62
Issue :
10
Database :
Complementary Index
Journal :
Diabetes
Publication Type :
Academic Journal
Accession number :
90405226
Full Text :
https://doi.org/10.2337/db13-0128