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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

Lookup NU author(s): Professor Mark Walker

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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 -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.


Publication metadata

Author(s): Yaghootkar H, Lamina C, Scott RA, Dastani Z, Hivert MF, Warren LL, Stancakova A, Buxbaum SG, Lyytikaeinen LP, Henneman P, Wu Y, Cheung CYY, Pankow JS, Jackson AU, Gustafsson S, Zhao JH, Ballantyne CM, Xie WJ, Bergman RN, Boehnke M, el Bouazzaoui F, Collins FS, Dunn SH, Dupuis J, Forouhi NG, Gillson C, Hattersley AT, Hong JY, Kaehoenen M, Kuusisto J, Kedenko L, Kronenberg F, Doria A, Assimes TL, Ferrannini E, Hansen T, Hao K, Haering H, Knowles JW, Lindgren CM, Nolan JJ, Paananen J, Pedersen O, Quertermous T, Smith U, Lehtimaeki T, Liu CT, Loos RJF, McCarthy MI, Morris AD, Vasan RS, Spector TD, Teslovich TM, Tuomilehto J, van Dijk KW, Viikari JS, Zhu N, Langenberg C, Ingelsson E, Semple RK, Sinaiko AR, Palmer CNA, Walker M, Lam KSL, Paulweber B, Mohlke KL, van Duijn C, Raitakari OT, Bidulescu A, Wareham NJ, Laakso M, Waterworth DM, Lawlor DA, Meigs JB, Richards JB, Frayling TM, GENESIS Consortium, RISC Consortium

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2013

Volume: 62

Issue: 10

Pages: 3589-3598

Print publication date: 01/10/2013

Online publication date: 08/07/2013

Acceptance date: 25/06/2013

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Assocation

URL: http://dx.doi.org/10.2337/db13-0128

DOI: 10.2337/db13-0128


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Funding

Funder referenceFunder name
Canadian Institutes of Health Research
Intramural NIH HHS
Wellcome Trust
100574Wellcome Trust
090532Wellcome Trust
098498Wellcome Trust
1Z01 HG000024NHGRI NIH HHS
DK062370NIDDK NIH HHS
DK56350NIDDK NIH HHS
DK072193NIDDK NIH HHS
DK078150NIDDK NIH HHS
DK36836-25NIDDK NIH HHS
G0600705Medical Research Council
ES10126NIEHS NIH HHS
G0500070Medical Research Council
G20234Biotechnology and Biological Sciences Research Council
HL085144NHLBI NIH HHS
HL52851NHLBI NIH HHS
K24 DK080140NIDDK NIH HHS
MC_U106179471Medical Research Council
MC_UP_A100_1003Medical Research Council
MC_UU_12013/5Medical Research Council
MC_U106188470Medical Research Council
MO1-RR-00400NCRR NIH HHS
N01-HC-55019NHLBI NIH HHS
N01-HC-55021NHLBI NIH HHS
N01-HC-95170NHLBI NIH HHS
N01-HC-95172NHLBI NIH HHS
N01-HG-65403NHGRI NIH HHS
N01-HC-25195NHLBI NIH HHS
N01-HC-55015NHLBI NIH HHS
N01-HC-55016NHLBI NIH HHS
N01-HC-55018NHLBI NIH HHS
N01-HC-55020NHLBI NIH HHS
N01-HC-55022NHLBI NIH HHS
N01-HC-95171NHLBI NIH HHS
R01 DK072193NIDDK NIH HHS
R01 DK078616NIDDK NIH HHS
R01 DK093757NIDDK NIH HHS
R01 HL105756NHLBI NIH HHS
R01HL59367NHLBI NIH HHS
RC2 HL102419NHLBI NIH HHS
P20 MD006899NIMHD NIH HHS
P30 DK020572NIDDK NIH HHS
U01HG004402NHGRI NIH HHS
UL1 RR025008NCRR NIH HHS
UL1 TR000454NCATS NIH HHS
R01DK056918NIDDK NIH HHS
R01HL086694NHLBI NIH HHS
R01HL087641NHLBI NIH HHS
RR20649NCRR NIH HHS
T32 NR009759NINR NIH HHS
TW05596FIC NIH HHS
UH1 HL073461NHLBI NIH HHS
UL1RR025005NCRR NIH HHS

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