@article{2b9941d81ad944f8916df566536bf854,
title = "Characterization of glycolytic enzymes and pyruvate kinase M2 in type 1 and 2 diabetic nephropathy",
abstract = "OBJECTIVE Elevated glycolytic enzymes in renal glomeruli correlated with preservation of renal function in the Medalist Study, individuals with ≥50 years of type 1 diabetes. Specifically, pyruvate kinase M2 (PKM2) activation protected insulin-deficient diabetic mice from hyperglycemia-induced glomerular pathology. This study aims to extend these findings in a separate cohort of individuals with type 1 and type 2 diabetes and discover new circulatory biomarkers for renal protection through proteomics and metabolomics of Medalists' plasma. We hypothesize that increased glycolytic flux and improved mitochondrial biogenesis will halt the progression of diabetic nephropathy. RESEARCH DESIGN AND METHODS Immunoblots analyzed selected glycolytic and mitochondrial enzymes in postmortemglomeruli of non-Medalists with type 1diabetes (n= 15), type 2diabetes (n= 19), and no diabetes (n = 5). Plasma proteomic (SOMAscan) (n = 180) and metabolomic screens (n = 214) of Medalists with and without stage 3b chronic kidney disease (CKD) were conducted and significant markers validated by ELISA. RESULTS Glycolytic (PKM1, PKM2, and ENO1) and mitochondrial (MTCO2) enzymes were significantly elevated in glomeruli of CKD2 versus CKD+ individuals with type 2 diabetes. Medalists' plasma PKM2 correlated with estimated glomerular filtration rate (r2 = 0.077; P = 0.0002). Several glucose and mitochondrial enzymes in circulation were upregulated with corresponding downregulation of toxic metabolites in CKD-protected Medalists. Amyloid precursor protein was also significantly upregulated, tumor necrosis factor receptors downregulated, and both confirmed by ELISA. CONCLUSIONS Elevation of enzymes involved in the metabolism of intracellular free glucose and its metabolites in renal glomeruli is connected to preserving kidney function in both type 1 and type 2 diabetes. The renal profile of elevated glycolytic enzymes and reduced toxic glucose metabolites is reflected in the circulation, supporting their use as biomarkers for endogenous renal protective factors in people with diabetes.",
author = "Daniel Gordin and Hetal Shah and Takanori Shinjo and Ronald St-Louis and Weier Qi and Kyoungmin Park and Paniagua, {Samantha M.} and Pober, {David M.} and Wu, {I. Hsien} and Vanessa Bahnam and Brissett, {Megan J.} and Tinsley, {Liane J.} and Dreyfuss, {Jonathan M.} and Hui Pan and Yutong Dong and Niewczas, {Monika A.} and Peter Amenta and Thorsten Sadowski and Aimo Kannt and Keenan, {Hillary A.} and King, {George L.}",
note = "Funding Information: Acknowledgments. The Medalist Study thanks the Clinical Research Center, Joslin Diabetes Center, Boston, MA, for assistance as well as the Medalists for participating in this study. The authors also thank Jialin Fu, Joslin Diabetes Center, Boston, MA, for technical help. Funding. The 50-Year Medalist Study is funded by the National Institute of Diabetes and Digestive and Kidney Diseases (P30-DK-036836, UL1-RR-025758-03, R24-283-DK-083957-01, DP3-DK-094333-01, and T32-DK-007260), JDRF (17-2013-310), the Tom Beatson, Jr 284 Foundation, and many Medalists. D.G. was supported by a Mary K. Iacocca Fellowship provided by the Iacocca Foundation and grants from the Wilhelm and Else Stockmann Foundation, The Medical Society of Finland (Finska L{\"a}kares{\"a}llskapet), the Finnish Medical Foundation, and the Biomedicum Helsinki Foundation. Duality of Interest. This study was also supported by a basic research grant from Sanofi Deutschland GmbH (Frankfurt am Main, Germany). W.Q. is an employee of AstraZeneca. T.Sa. and A.K. are employees of Sanofi. H.A.K. is an employee of Sanofi-Genzyme. No other potential conflicts of interest relevant to this article were reported. Author Contributions. D.G. and H.S. researched data, performed statistical analyses, and wrote the manuscript. T.Sh., R.S-L., and K.P. researched data, performed laboratory experiments, and contributed to the manuscript. W.Q., I-H.W., V.B., M.J.B., and L.J.T. recruited and managed the participant-level clinical data as well as the blood and tissue samples. S.M.P., D.M.P., J.M.D., and H.P. researched data, performed statistical analyses, and contributed to the manuscript. Y.D., T.Sa., A.K., and H.A.K. contributed to discussion and reviewed and edited the manuscript. M.A.N. supervised the TNF marker measurements and analyses. P.A. assessed all of the human kidney pathology. D.G., H.S., T.Sh., R.S-L., W.Q., K.P., S.M.P., D.M.P., I-H.W., V.B., M.J.B.,L.J.T.,J.M.D.,H.P.,Y.D.,M.A.N.,P.A.,T.Sa., A.K., H.A.K., and G.L.K. reviewed the manuscript. G.L.K. researched data and wrote the manuscript. G.L.K. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Prior Presentation. Parts of this study were presented at the 78th Scientific Sessions of the American Diabetes Association, Orlando, FL, 22– 26 June 2018. Publisher Copyright: {\textcopyright} 2019 by the American Diabetes Association.",
year = "2019",
doi = "10.2337/dc18-2585",
language = "English",
volume = "42",
pages = "1263--1273",
journal = "Diabetes care",
issn = "0149-5992",
publisher = "American Diabetes Association Inc.",
number = "7",
}
