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

• Published in: Diabetes (New York, N.Y.) Vol. 62; no. 10; pp. 3589 - 3598
• Main 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, Wu, Ying, Cheung, Chloe Y.Y., Pankow, James S., Jackson, Anne U., Gustafsson, Stefan, Zhao, Jing Hua, Ballantyne, Christie M., Xie, Weijia, Bergman, Richard N., Boehnke, Michael, el Bouazzaoui, Fatiha, Collins, Francis S., Dunn, Sandra H., Dupuis, Josee, Forouhi, Nita G., Gillson, Christopher, Hattersley, Andrew T., Hong, Jaeyoung, Kähönen, Mika, Kuusisto, Johanna, Kedenko, Lyudmyla, Kronenberg, Florian, Doria, Alessandro, Assimes, Themistocles L., Ferrannini, Ele, Hansen, Torben, Hao, Ke, Häring, Hans, Knowles, Joshua W., Lindgren, Cecilia M., Nolan, John J., Paananen, Jussi, Pedersen, Oluf, Quertermous, Thomas, Smith, Ulf, Lehtimäki, Terho, Liu, Ching-Ti, Loos, Ruth J.F., McCarthy, Mark I., Morris, Andrew D., Vasan, Ramachandran S., Spector, Tim D., Teslovich, Tanya M., Tuomilehto, Jaakko, van Dijk, Ko Willems, Viikari, Jorma S., Zhu, Na, Langenberg, Claudia, Ingelsson, Erik, Semple, Robert K., Sinaiko, Alan R., Palmer, Colin N.A., Walker, Mark, Lam, Karen S.L., Paulweber, Bernhard, Mohlke, Karen L., van Duijn, Cornelia, Raitakari, Olli T., Bidulescu, Aurelian, Wareham, Nick J., Laakso, Markku, Waterworth, Dawn M., Lawlor, Debbie A., Meigs, James B., Richards, J. Brent, Frayling, Timothy M.
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.10.2013
• Subjects: Adiponectin; Adiponectin - blood; Adiponectin - genetics; Biological and medical sciences; blood; Blood Glucose; Blood Glucose - metabolism; Causality; Diabetes; Diabetes Mellitus; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Diabetes therapy; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinology and Diabetes; Endocrinopathies; Endokrinologi och diabetes; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Experiments; Female; Genes; Genetic Predisposition to Disease; Genetic Variation; genetics; Health aspects; Humans; Insulin Resistance; Insulin Resistance - genetics; Male; Medical sciences; Mendelian Randomization Analysis; metabolism; Odds Ratio; Original Research; Polymorphism; Polymorphism, Single Nucleotide; Proteins; Regression Analysis; Risk factors; Sensitivity analysis; Single Nucleotide; Type 2; Type 2 diabetes; Massachusetts; Minnesota; Finland; Endocrinopathy; Type 2 diabetes; Target tissue resistance; Support; Metabolic diseases; Insulin resistance; Adipokine; Adiponectin
• ISSN: 0012-1797; 1939-327X; 1939-327X
• DOI: 10.2337/db13-0128

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 −0.07 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.