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.
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Data availability
The datasets generated during and/or analyzed during the current study are available at the NIH Common Fund’s National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org (Study ID ST001754, ST001742, and PR000396).
Change history
19 December 2021
A Correction to this paper has been published: https://doi.org/10.1007/s11306-021-01865-5
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Acknowledgements
The authors sincerely thank Dr. Amanda Posgai and Dr. Sara Williams (University of Florida) for editorial assistance and Dr. Rhonda Bacher (University of Florida) for her statistical expertise and advice.
Funding
This research was supported by Zomedica Inc. and the National Institute of Diabetes and Digestive and Kidney Disease of the National Institutes of Health (AO – K08DK116735). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
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ALO conceived of and designed the study, acquired the samples, analyzed and interpreted the data, and wrote the manuscript; CW conceived of the study, interpreted the data, and reviewed/edited the manuscript; JGC analyzed the samples, analyzed the data, and contributed to the manuscript; BMWR performed data analysis and contributed to the manuscript; MAA conceived of the study and reviewed/edited the manuscript; TJG designed the study, analyzed the samples, analyzed and interpreted the data, and reviewed/edited the manuscript. Allison O’Kell is the guarantor of this work, had full access to all of the data in the study, and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.
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Zomedica Inc. provided financial support for the study, but had no influence on study design, data analysis, or the decision to publish. No other potential conflicts of interest relevant to this article were reported.
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O’Kell, A.L., Wasserfall, C., Guingab-Cagmat, J. et al. Targeted metabolomic analysis identifies increased serum levels of GABA and branched chain amino acids in canine diabetes. Metabolomics 17, 100 (2021). https://doi.org/10.1007/s11306-021-01850-y
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DOI: https://doi.org/10.1007/s11306-021-01850-y