Tissue-specific metabolic reprogramming drives nutrient flux in diabetic complications
Kelli M. Sas, … , Frank C. Brosius III, Subramaniam Pennathur
Kelli M. Sas, … , Frank C. Brosius III, Subramaniam Pennathur
Published September 22, 2016
Citation Information: JCI Insight. 2016;1(15):e86976. https://doi.org/10.1172/jci.insight.86976.
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Research Article Metabolism Nephrology

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 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.

Authors

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 III, Subramaniam Pennathur

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Figure 9

Schema of glucose and fatty acid metabolism in the diabetic proximal tubule cell.

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Schema of glucose and fatty acid metabolism in the diabetic proximal tub...
As the glucose concentration in plasma or urine increases, more glucose is transported into kidney proximal tubule cells. Glycolysis increases, resulting in increased pyruvate levels and TCA cycle activity in the mitochondria. Fatty acids are broken down into acyl-CoAs and transported across the mitochondrial membrane as acylcarnitines. β-Oxidation increases, resulting in increased TCA cycle activity. Although mitochondrial metabolism is elevated, there is a concurrent lack of increased ATP production through the electron transport chain (26). We propose that an uncoupling between mitochondrial metabolism and oxidative phosphorylation may underlie the metabolic phenotype of diabetic kidney disease. The increased TCA cycle metabolites can perturb normal cellular function. High levels of citrate can be used as a substrate for post-translational modifications (PTMs), such as acetylation (Ac), which can alter the activity of metabolic enzymes and localization of transcription factors. Succinate, through GPR91, can activate the renin-angiotensin system, and fumarate can induce HIF-1α. These perturbations can promote progression of DKD.