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Characterization of Glycolytic Enzymes and Pyruvate Kinase M2 in Type 1 and 2 Diabetic Nephropathy
- Source :
- Diabetes Care
- Publication Year :
- 2019
- Publisher :
- American Diabetes Association, 2019.
-
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 postmortem glomeruli of non-Medalists with type 1 diabetes (n = 15), type 2 diabetes (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 CKD− 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.
- Subjects :
- Male
Proteomics
Endocrinology, Diabetes and Metabolism
Kidney Glomerulus
Type 2 diabetes
urologic and male genital diseases
Kidney
Cohort Studies
Diabetic nephropathy
0302 clinical medicine
Diabetic Nephropathies
030212 general & internal medicine
Aged, 80 and over
Middle Aged
Enzymes
Mitochondria
medicine.anatomical_structure
Disease Progression
Female
Autopsy
Metabolic Networks and Pathways
Glomerular Filtration Rate
medicine.medical_specialty
Pyruvate Kinase
030209 endocrinology & metabolism
PKM2
03 medical and health sciences
Downregulation and upregulation
Internal medicine
Diabetes mellitus
Internal Medicine
medicine
Humans
Metabolomics
Renal Insufficiency, Chronic
Pathophysiology/Complications
Aged
Advanced and Specialized Nursing
business.industry
Kidney metabolism
medicine.disease
Diabetes Mellitus, Type 1
Glucose
Endocrinology
Diabetes Mellitus, Type 2
Mitochondrial biogenesis
Case-Control Studies
business
Biomarkers
Subjects
Details
- ISSN :
- 19355548 and 01495992
- Volume :
- 42
- Database :
- OpenAIRE
- Journal :
- Diabetes Care
- Accession number :
- edsair.doi.dedup.....6638a6132a3c581bca05ec2d0bd71588