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Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications.

Citation
Sas, K. M., et al. “Tissue-Specific Metabolic Reprogramming Drives Nutrient Flux In Diabetic Complications.”. Jci Insight, p. e86976.
Center University of Michigan
Featured
Author Kelli M Sas, Pradeep Kayampilly, Jaeman Byun, Viji Nair, Lucy M Hinder, Junguk Hur, Hongyu Zhang, Chengmao Lin, Nathan R Qi, George Michailidis, Per-Henrik Groop, Robert G Nelson, Manjula Darshi, Kumar Sharma, Jeffrey R Schelling, John R Sedor, Rodica Pop-Busui, Joel M Weinberg, Scott A Soleimanpour, Steven F Abcouwer, Thomas W Gardner, Charles F Burant, Eva L Feldman, Matthias Kretzler, Frank C Brosius, Subramaniam Pennathur
Abstract

Diabetes is associated with altered cellular metabolism, but how altered metabolism contributes to the development of diabetic complications is unknown. We used the BKS diabetic mouse model to investigate changes in carbohydrate and lipid metabolism in kidney cortex, peripheral nerve, and retina. A systems approach using transcriptomics, metabolomics, and metabolic flux analysis identified tissue-specific differences, with increased glucose and fatty acid metabolism in the kidney, a moderate increase in the retina, and a decrease in the nerve. In the kidney, increased metabolism was associated with enhanced protein acetylation and mitochondrial dysfunction. To confirm these findings in human disease, we analyzed diabetic kidney transcriptomic data and urinary metabolites from a cohort of Southwestern American Indians. The urinary findings were replicated in 2 independent patient cohorts, the Finnish Diabetic Nephropathy and the Family Investigation of Nephropathy and Diabetes studies. Increased concentrations of TCA cycle metabolites in urine, but not in plasma, predicted progression of diabetic kidney disease, and there was an enrichment of pathways involved in glycolysis and fatty acid and amino acid metabolism. Our findings highlight tissue-specific changes in metabolism in complication-prone tissues in diabetes and suggest that urinary TCA cycle intermediates are potential prognostic biomarkers of diabetic kidney disease progression.

Year of Publication
2016
Journal
JCI insight
Volume
1
Issue
15
Number of Pages
e86976
Date Published
12/2016
ISSN Number
2379-3708
DOI
10.1172/jci.insight.86976
Alternate Journal
JCI Insight
PMID
27699244
PMCID
PMC5033761
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