Targeted metabolomic analysis identifies increased serum levels of GABA and branched chain amino acids in canine diabetes

Abstract

Introduction: Dogs with naturally occurring diabetes mellitus represent a potential model for human type 1 diabetes, yet significant knowledge voids exist in terms of the pathogenic mechanisms underlying the canine disorder. Untargeted metabolomic studies from a limited number of diabetic dogs identified similarities to humans with the disease.

Objective: To expand and validate earlier metabolomic studies, identify metabolites that differ consistently between diabetic and healthy dogs, and address whether certain metabolites might serve as disease biomarkers.

Methods: Untargeted metabolomic analysis via liquid chromatography-mass spectrometry was performed on serum from diabetic (n = 15) and control (n = 15) dogs. Results were combined with those of our previously published studies using identical methods (12 diabetic and 12 control dogs) to identify metabolites consistently different between the groups in all 54 dogs. Thirty-two candidate biomarkers were quantified using targeted metabolomics. Biomarker concentrations were compared between the groups using multiple linear regression (corrected P < 0.0051 considered significant).

Results: Untargeted metabolomics identified multiple persistent differences in serum metabolites in diabetic dogs compared with previous studies. Targeted metabolomics showed increases in gamma amino butyric acid, valine, leucine, isoleucine, citramalate, and 2-hydroxyisobutyric acid in diabetic versus control dogs while indoxyl sulfate, N-acetyl-L-aspartic acid, kynurenine, anthranilic acid, tyrosine, glutamine, and tauroursodeoxycholic acid were decreased.

Conclusion: Several of these findings parallel metabolomic studies in both human diabetes and other animal models of this disease. Given recent studies on the role of GABA and branched chain amino acids in human diabetes, the increase in serum concentrations in canine diabetes warrants further study of these metabolites as potential biomarkers, and to identify similarity in mechanisms underlying this disease in humans and dogs.

Keywords: Animal model; Biomarkers; Canine; Diabetes; Dog(s); Metabolites; Metabolomics.