Untargeted metabolomic analysis in naturally occurring canine diabetes mellitus identifies similarities to human Type 1 Diabetes

Abstract

While predominant as a disease entity, knowledge voids exist regarding the pathogenesis of canine diabetes. To test the hypothesis that diabetic dogs have similar metabolomic perturbations to humans with type 1 diabetes (T1D), we analyzed serum metabolomic profiles of breed- and body weight-matched, diabetic (n=6) and healthy (n=6) dogs by liquid chromatography-mass spectrometry (LC-MS) profiling. We report distinct clustering of diabetic and control groups based on heat map analysis of known and unknown metabolites. Random forest classification identified 5/6 dogs per group correctly with overall out of bag error rate=16.7%. Diabetic dogs demonstrated significant upregulation of glycolysis/gluconeogenesis intermediates (e.g., glucose/fructose, C₆H₁₂O₆, keto-hexose, deoxy-hexose, (P<0.01)), with significant downregulation of tryptophan metabolism metabolites (e.g., picolinic acid, indoxyl sulfate, anthranilate, (P<0.01)). Multiple amino acids (AA), AA metabolites, and bile acids were also significantly lower in diabetic versus healthy dogs (P<0.05) with the exception of the branched chain AA valine, which was elevated in diabetic animals (P<0.05). Metabolomic profiles in diabetic versus healthy dogs shared similarities with those reported in human T1D (e.g., alterations in glycolysis/gluconeogensis metabolites, bile acids, and elevated branched chain AA). Further studies are warranted to evaluate the utility of canine diabetes to provide novel mechanistic insights to the human disorder.