Acyl ethanolamides in Diabetes and Diabetic Nephropathy: Novel targets from untargeted plasma metabolomic profiles of South Asian Indian men

Authors : Devi S, Nongkhlaw B, Limesh M, Pasanna RM, Thomas T, Kuriyan R, Kurpad AV, Mukhopadhyay A

Publication Year : 2019

Abstract :

The pathophysiology of diabetic nephropathy (DN) in type 2 diabetes (T2D) patients is minimally understood. We compared untargeted high-resolution accurate mass (HRAM) orbitrap-based plasma metabolomic profiles of 31 T2D-DN (with estimated glomerular filtration rate less than or equal to 80 mL/min/1.73 m2), 29 T2D and 30 normal glucose tolerance (NGT) Indian men. Of the 939 plasma metabolites that were differentially abundant amongst the NGT, T2D and T2D-DN (ANOVA, False Discovery Rate - FDR adjusted p-value less than 0.05), 48 were associated with T2D irrespective of the renal function of the subjects. Acyl ethanolamides and acetylcholine were decreased while monoacylglycerols (MAGs) and cortisol were elevated in both T2D and T2D-DN. Sixteen metabolites, including amino acid metabolites Imidazolelactate and N-Acetylornithine, changed significantly between NGT, T2D and T2D-DN. 192 metabolites were specifically dysregulated in T2D-DN (ratio greater than or equal to 2 or less than or equal to 0.5 between T2D-DN and T2D, similar abundance in NGT and T2D). These included increased levels of multiple acylcarnitine and amino acid metabolites. We observed a significant dysregulation of amino acid and fatty acid metabolism in South Asian Indian male T2D-DN subjects. Unique to this study, we report a reduction in acyl ethanolamide levels in both T2D and T2D-DN males. Those with dysregulation in acyl ethanolamides, which are endogenous agonists of GPR119, are likely to exhibit improved glycemic control with GPR119 agonists.