A functional variant of the dimethylarginine dimethylaminohydrolase-2 gene is associated with insulin sensitivity.

PloS One
Francesco AndreozziGiorgio Sesti

Abstract

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of endothelial nitric oxide synthase, which was associated with insulin resistance. Dimethylarginine dimethylaminohydrolase (DDAH) is the major determinant of plasma ADMA. Examining data from the DIAGRAM+ (Diabetes Genetics Replication And Meta-analysis), we identified a variant (rs9267551) in the DDAH2 gene nominally associated with type 2 diabetes (P = 3 × 10(-5)). initially, we assessed the functional impact of rs9267551 in human endothelial cells (HUVECs), observing that the G allele had a lower transcriptional activity resulting in reduced expression of DDAH2 and decreased NO production in primary HUVECs naturally carrying it. We then proceeded to investigate whether this variant is associated with insulin sensitivity in vivo. To this end, two cohorts of nondiabetic subjects of European ancestry were studied. In sample 1 (n = 958) insulin sensitivity was determined by the insulin sensitivity index (ISI), while in sample 2 (n = 527) it was measured with a euglycemic-hyperinsulinemic clamp. In sample 1, carriers of the GG genotype had lower ISI than carriers of the C allele (67 ± 33 vs.79 ± 44; P = 0.003 after adjusting for age, gender, and BMI). ADMA levels were ...Continue Reading

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Citations

Mar 8, 2014·International Journal of Molecular Sciences·Jiunn-Ming SheenLi-Tung Huang
Oct 31, 2012·International Journal of Molecular Sciences·Luis Aldámiz-Echevarría, Fernando Andrade
Oct 31, 2015·Nephrology, Dialysis, Transplantation : Official Publication of the European Dialysis and Transplant Association - European Renal Association·Hitoshi MinakuchiHiroshi Itoh

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Methods Mentioned

BETA
transfection
genotyping
PCR

Software Mentioned

SPSS
DIAGRAM
Quanto

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