Changes in arginine are inversely associated with type 2 diabetes: A case-cohort study in the PREDIMED trial

The associations between arginine‐based metabolites and incident type 2 diabetes (T2D) are unknown. We employed a case‐cohort design, nested within the PREDIMED trial, to examine six plasma metabolites (arginine, citrulline, ornithine, asymmetric dimethylarginine [ADMA], symmetric dimethylarginine [SDMA] and N‐monomethyl‐l‐arginine [NMMA]) among 892 individuals (251 cases) for associations with incident T2D and insulin resistance. Weighted Cox models with robust variance were used. The 1‐year changes in arginine (adjusted hazard ratio [HR] per SD 0.68, 95% confidence interval [CI] 0.49, 0.95; Q4 vs. Q1 0.46, 95% CI 0.21, 1.04; P trend = 0.02) and arginine/ADMA ratio (adjusted HR per SD 0.73, 95% CI 0.51, 1.04; Q4 vs. Q1 0.52, 95% CI 0.22, 1.25; P trend = 0.04) were associated with a lower risk of T2D. Positive changes of citrulline and ornithine, and negative changes in SDMA and arginine/(ornithine + citrulline) were associated with concurrent 1‐year changes in homeostatic model assessment of insulin resistance. Individuals in the low‐fat‐diet group had a higher risk of T2D for 1‐year changes in NMMA than individuals in Mediterranean‐diet groups (P interaction = 0.02). We conclude that arginine bioavailability is important in T2D pathophysiology.This study was funded by the National Institutes of Health (R01DK102896, F31DK114938), the Spanish Ministry of Health (Instituto de Salud Carlos III), the Ministerio de Economía y Competitividad‐Fondo Europeo de Desarrollo Regional (Projects CNIC‐06/2007, RTIC G03/140, CIBER 06/03, PI06‐1326, PI07‐0954, PI11/02505, RTIC RD06/0045, SAF2009‐12304 and AGL2010‐22319‐C03‐03) and by the Generalitat Valenciana (ACOMP2010‐181, AP111/10, AP‐042/11, ACOM2011/145, ACOMP/2012/190, ACOMP/2013/159 and ACOMP/213/165). M.G.‐F. is supported by the American Diabetes Association (#1‐18‐PMF‐029)