Tissue-specific metabolic reprogramming drives nutrient flux in diabetic
Authors Sas KM, Kayampilly P, Byun J, Nair V, Hinder LM, Hur J, Zhang H, Lin C, Qi NR,
Michailidis G, Groop PH, Nelson RG, Darshi M, Sharma K, Schelling JR, Sedor JR,
Pop-Busui R, Weinberg JM, Soleimanpour SA, Abcouwer SF, Gardner TW, Burant CF,
Feldman EL, Kretzler M, Brosius FC, Pennathur S
Submitted By Steven Abcouwer on 10/27/2016
Status Published
Journal JCI insight
Year 2016
Date Published
Volume : Pages 1 : e86976
PubMed Reference 27699244
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.

Investigators with authorship
Steven AbcouwerUniversity of Michigan-Ann Arbor
Frank BrosiusUniversity of Arizona
Eva FeldmanUniversity of Michigan
Matthias KretzlerUniversity of Michigan
Kumar SharmaUniversity of California San Diego