Characterization of glycolytic enzymes and pyruvate kinase M2 in type 1 and 2 diabetic nephropathy

Daniel Gordin, Hetal Shah, Takanori Shinjo, Ronald St-Louis, Weier Qi, Kyoungmin Park, Samantha M. Paniagua, David M. Pober, I. Hsien Wu, Vanessa Bahnam, Megan J. Brissett, Liane J. Tinsley, Jonathan M. Dreyfuss, Hui Pan, Yutong Dong, Monika A. Niewczas, Peter Amenta, Thorsten Sadowski, Aimo Kannt, Hillary A. KeenanGeorge L. King

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1263-1273
Number of pages11
JournalDiabetes care
Volume42
Issue number7
DOIs
Publication statusPublished - Jan 1 2019
Externally publishedYes

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Pyruvate Kinase
Diabetic Nephropathies
Kidney
Enzymes
Type 1 Diabetes Mellitus
Chronic Renal Insufficiency
Type 2 Diabetes Mellitus
Metabolomics
Poisons
Glucose
Proteomics
Down-Regulation
Biomarkers
Enzyme-Linked Immunosorbent Assay
Amyloid beta-Protein Precursor
Tumor Necrosis Factor Receptors
Organelle Biogenesis
Glomerular Filtration Rate
Hyperglycemia
Insulin

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Advanced and Specialised Nursing

Cite this

Characterization of glycolytic enzymes and pyruvate kinase M2 in type 1 and 2 diabetic nephropathy. / Gordin, Daniel; Shah, Hetal; Shinjo, Takanori; St-Louis, Ronald; Qi, Weier; Park, Kyoungmin; Paniagua, Samantha M.; Pober, David M.; Wu, I. Hsien; Bahnam, Vanessa; Brissett, Megan J.; Tinsley, Liane J.; Dreyfuss, Jonathan M.; Pan, Hui; Dong, Yutong; Niewczas, Monika A.; Amenta, Peter; Sadowski, Thorsten; Kannt, Aimo; Keenan, Hillary A.; King, George L.

In: Diabetes care, Vol. 42, No. 7, 01.01.2019, p. 1263-1273.

Research output: Contribution to journalArticle

Gordin, D, Shah, H, Shinjo, T, St-Louis, R, Qi, W, Park, K, Paniagua, SM, Pober, DM, Wu, IH, Bahnam, V, Brissett, MJ, Tinsley, LJ, Dreyfuss, JM, Pan, H, Dong, Y, Niewczas, MA, Amenta, P, Sadowski, T, Kannt, A, Keenan, HA & King, GL 2019, 'Characterization of glycolytic enzymes and pyruvate kinase M2 in type 1 and 2 diabetic nephropathy', Diabetes care, vol. 42, no. 7, pp. 1263-1273. https://doi.org/10.2337/dc18-2585
Gordin, Daniel ; Shah, Hetal ; Shinjo, Takanori ; St-Louis, Ronald ; Qi, Weier ; Park, Kyoungmin ; Paniagua, Samantha M. ; Pober, David M. ; Wu, I. Hsien ; Bahnam, Vanessa ; Brissett, Megan J. ; Tinsley, Liane J. ; Dreyfuss, Jonathan M. ; Pan, Hui ; Dong, Yutong ; Niewczas, Monika A. ; Amenta, Peter ; Sadowski, Thorsten ; Kannt, Aimo ; Keenan, Hillary A. ; King, George L. / Characterization of glycolytic enzymes and pyruvate kinase M2 in type 1 and 2 diabetic nephropathy. In: Diabetes care. 2019 ; Vol. 42, No. 7. pp. 1263-1273.
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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.",
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T1 - Characterization of glycolytic enzymes and pyruvate kinase M2 in type 1 and 2 diabetic nephropathy

AU - Gordin, Daniel

AU - Shah, Hetal

AU - Shinjo, Takanori

AU - St-Louis, Ronald

AU - Qi, Weier

AU - Park, Kyoungmin

AU - Paniagua, Samantha M.

AU - Pober, David M.

AU - Wu, I. Hsien

AU - Bahnam, Vanessa

AU - Brissett, Megan J.

AU - Tinsley, Liane J.

AU - Dreyfuss, Jonathan M.

AU - Pan, Hui

AU - Dong, Yutong

AU - Niewczas, Monika A.

AU - Amenta, Peter

AU - Sadowski, Thorsten

AU - Kannt, Aimo

AU - Keenan, Hillary A.

AU - King, George L.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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