title: Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications.
abstract: Diabetes is associated with altered cellular metabolism, but how altered metabolism contributes to the development of diabetic complications is unknown. We used the BKSdb/dbdiabetic 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.
authors.affiliation: Department of Internal Medicine.
authors.forename: Kelli M
authors.initials: KM
authors.lastname: Sas
authors.affiliation: Department of Internal Medicine.
authors.forename: Pradeep
authors.initials: P
authors.lastname: Kayampilly
authors.affiliation: Department of Internal Medicine.
authors.forename: Jaeman
authors.initials: J
authors.lastname: Byun
authors.affiliation: Department of Internal Medicine.|Department of Computational Medicine and Bioinformatics.
authors.forename: Viji
authors.initials: V
authors.lastname: Nair
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Lucy M
authors.initials: LM
authors.lastname: Hinder
authors.affiliation: Department of Biomedical Sciences, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, USA.
authors.forename: Junguk
authors.initials: J
authors.lastname: Hur
authors.affiliation: Department of Internal Medicine.
authors.forename: Hongyu
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Chengmao
authors.initials: C
authors.lastname: Lin
authors.affiliation: Department of Internal Medicine.
authors.forename: Nathan R
authors.initials: NR
authors.lastname: Qi
authors.affiliation: Department of Statistics, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: George
authors.initials: G
authors.lastname: Michailidis
authors.affiliation: Folkhälsan Institute of Genetics, Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.|Abdominal Center Nephrology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.|Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Per-Henrik
authors.initials: PH
authors.lastname: Groop
authors.affiliation: Diabetes Epidemiology and Clinical Research Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Nelson
authors.affiliation: 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.
authors.forename: Manjula
authors.initials: M
authors.lastname: Darshi
authors.affiliation: 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.
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Department of Medicine.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Schelling
authors.affiliation: Department of Medicine.|Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, Ohio, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Sedor
authors.affiliation: Department of Internal Medicine.
authors.forename: Rodica
authors.initials: R
authors.lastname: Pop-Busui
authors.affiliation: Department of Internal Medicine.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Weinberg
authors.affiliation: Department of Internal Medicine.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Soleimanpour
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Steven F
authors.initials: SF
authors.lastname: Abcouwer
authors.affiliation: Department of Ophthalmology and Visual Sciences.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Gardner
authors.affiliation: Department of Internal Medicine.|Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Charles F
authors.initials: CF
authors.lastname: Burant
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Eva L
authors.initials: EL
authors.lastname: Feldman
authors.affiliation: Department of Internal Medicine.|Department of Computational Medicine and Bioinformatics.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.affiliation: Department of Internal Medicine.|Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan, USA.
authors.forename: Frank C
authors.initials: FC
authors.lastname: Brosius
authors.affiliation: Department of Internal Medicine.
authors.forename: Subramaniam
authors.initials: S
authors.lastname: Pennathur
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers; D050260:Carbohydrate Metabolism; D002952:Citric Acid Cycle; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000378:metabolism; D003928:Diabetic Nephropathies / Q000378:metabolism / Q000503:physiopathology*; D005260:Female; D006801:Humans; D007198:Indians, North American; D007668:Kidney; D050356:Lipid Metabolism; D008297:Male; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic; D059467:Transcriptome
chemical_list: D015415:Biomarkers