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JCI Insight. 2016 Sep 22;1(15):e86976. doi: 10.1172/jci.insight.86976.

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

Author information

1
Department of Internal Medicine.
2
Department of Computational Medicine and Bioinformatics.
3
Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
4
Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, USA.
5
Department of Ophthalmology and Visual Sciences.
6
Department of Statistics, University of Michigan, Ann Arbor, Michigan, USA.
7
Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.
8
Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
9
Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
10
Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.
11
Institute of Metabolomic Medicine and Center for Renal Translational Medicine, Department of Medicine, University of California San Diego, and Veterans Administration San Diego Healthcare System, La Jolla, California, USA.
12
Department of Medicine.
13
Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, USA.
14
Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.

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 db/db 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.

PMID:
27699244
PMCID:
PMC5033761
DOI:
10.1172/jci.insight.86976
[Indexed for MEDLINE]
Free PMC Article

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