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 weightmatched, 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, C 6 H 12 O 6 , 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.Type 1 diabetes (T1D) is characterized by insulin deficiency and resulting dysglycemia 1 . Recently, metabolomic analyses have been used to study metabolic changes in T1D patients prior to autoantibody (AAb) development 2 , associated with AAb seroconversion 3 , as well as with symptomatic T1D and glycemic control 4-6 . Specifically, metabolomic alterations documented prior to AAb development in children that later developed T1D include decreased succinic acid, phosphatidylcholine, and citric acid at birth alongside increased pro-inflammatory lysophosphatidylcholine months prior to seroconversion 2 . AAb positivity is associated with low methionine and hydroxyproline, with high odd-chain triglycerides and polyunsaturated fatty acids (FA) containing phospholipids 3 . Beyond this, T1D patients with poor glycemic control demonstrate decreased glycolytic metabolites and elevated carbohydrate metabolites, branched chain amino acids (AA), short chain FA, and ketoacids 4 . Interestingly, many of these metabolic perturbations are also present in T1D patients with good glycemic control 4 .Canine diabetes has multiple parallels to human T1D, including a requirement for lifelong insulin therapy in most cases, the development of ketoacidosis at diagnosis or during therapy 7 , and a suspected role for autoimmunity 7,8 . Increased levels of glucose, triglycerides, non-esterified FA, cholesterol, ketones, acetate, and β-hydroxybutyrate have been reported in diabetic dogs 9 . Further research is required to determine the potent...

Metabolome of canine and human saliva: a non-targeted metabolomics study

“…Since saliva is rich in small molecules and given its role as “a mirror of the body”, there is a growing interest towards saliva usage as a non-invasive sample material for monitoring health trajectories to aid diagnosis or reveal the molecular mechanisms of disease pathologies. The same applies to domestic dogs which suffer from similar diseases to humans such as metabolic diseases, chronic inflammation, and cancers, manifested as diabetes (O'Kell et al 2017 ), inflammatory bowel disease (Minamoto et al 2015 ) and leukemia (Breen and Modiano 2008 ), respectively. Physiological similarity with humans and the large size of the canine have been reasons for the rise of these animals to one of the biomedical models alongside the rodents, for example in the study of genomics (Hytonen and Lohi 2016 ; van Steenbeek et al 2016 ) and behavior (Puurunen et al 2018 ).…”

Natural biased signaling of hydroxycarboxylic acid receptor 3 and G protein-coupled receptor 84

“…3hydroxy derivatives of MCFAs are derived from endogenous and exogenous sources. Although basal plasma concentrations of 3-hydroxyoctanoic acid (3HO) and 3-hydroxydecanoic acid (3HDec) rarely exceed 0.4 μM, they are both increased in patients undergoing a ketogenic diet and in patients with diabetic ketoacidosis or defects of mitochondrial β-fatty acid oxidation [5,11,18,19]. 3-hydroxy fatty acids of 10-14 carbon chain lengths are also components of lipopolysaccharides (LPS) of Gram-negative bacteria and have been used as endotoxin markers in clinical and environmental samples [20][21][22][23].…”

Metabolomics in the study of spontaneous animal diseases

“…Similarly, a 2017 study identified similar serum metabolites in canine diabetes mellitus and human type I diabetes, including changes in glycolytic intermediates and elevated levels of branch-chain amino acids. 51 Reflecting the increasingly recognized importance of the microbiome, multiple studies explored the relationship between host health and the gastrointestinal microbiota. 22,44 As an example, dogs with acute diarrhea were found to have decreased fecal concentrations of Faecalibacterium spp.…”