title: Type 2 Diabetes Dysregulates Glucose Metabolism in Cardiac Progenitor Cells.
abstract: Type 2 diabetes is associated with increased mortality and progression to heart failure. Recent studies suggest that diabetes also impairs reparative responses after cell therapy. In this study, we examined potential mechanisms by which diabetes affects cardiac progenitor cells (CPCs). CPCs isolated from the diabetic heart showed diminished proliferation, a propensity for cell death, and a pro-adipogenic phenotype. The diabetic CPCs were insulin-resistant, and they showed higher energetic reliance on glycolysis, which was associated with up-regulation of the pro-glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3). In WT CPCs, expression of a mutant form of PFKFB, which mimics PFKFB3 activity and increases glycolytic rate, was sufficient to phenocopy the mitochondrial and proliferative deficiencies found in diabetic cells. Consistent with activation of phosphofructokinase in diabetic cells, stable isotope carbon tracing in diabetic CPCs showed dysregulation of the pentose phosphate and glycero(phospho)lipid synthesis pathways. We describe diabetes-induced dysregulation of carbon partitioning using stable isotope metabolomics-based coupling quotients, which relate relative flux values between metabolic pathways. These findings suggest that diabetes causes an imbalance in glucose carbon allocation by uncoupling biosynthetic pathway activity, which could diminish the efficacy of CPCs for myocardial repair.
authors.affiliation: From the Institute of Molecular Cardiology, Diabetes and Obesity Center.
authors.forename: Joshua K
authors.initials: JK
authors.lastname: Salabei
authors.affiliation: From the Institute of Molecular Cardiology, Diabetes and Obesity Center.
authors.forename: Pawel K
authors.initials: PK
authors.lastname: Lorkiewicz
authors.affiliation: From the Institute of Molecular Cardiology, Diabetes and Obesity Center.
authors.forename: Parul
authors.initials: P
authors.lastname: Mehra
authors.affiliation: From the Institute of Molecular Cardiology, Diabetes and Obesity Center, Physiology.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Gibb
authors.affiliation: From the Institute of Molecular Cardiology, Diabetes and Obesity Center.
authors.forename: Petra
authors.initials: P
authors.lastname: Haberzettl
authors.affiliation: From the Institute of Molecular Cardiology, Diabetes and Obesity Center.
authors.forename: Kyung U
authors.initials: KU
authors.lastname: Hong
authors.affiliation: Chemistry, the Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, Kentucky 40202.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Wei
authors.affiliation: Chemistry, the Center for Regulatory and Environmental Analytical Metabolomics, University of Louisville, Louisville, Kentucky 40202 Pharmacology and Toxicology, and.
authors.forename: Xiang
authors.initials: X
authors.lastname: Zhang
authors.affiliation: From the Institute of Molecular Cardiology.
authors.forename: Qianhong
authors.initials: Q
authors.lastname: Li
authors.affiliation: From the Institute of Molecular Cardiology, Diabetes and Obesity Center.
authors.forename: Marcin
authors.initials: M
authors.lastname: Wysoczynski
authors.affiliation: From the Institute of Molecular Cardiology, Diabetes and Obesity Center, Physiology.
authors.forename: Roberto
authors.initials: R
authors.lastname: Bolli
authors.affiliation: From the Institute of Molecular Cardiology, Diabetes and Obesity Center, Physiology, the Departments of Biochemistry and Molecular Genetics.
authors.forename: Aruni
authors.initials: A
authors.lastname: Bhatnagar
authors.affiliation: From the Institute of Molecular Cardiology, Diabetes and Obesity Center, Physiology, the Departments of Biochemistry and Molecular Genetics, bradford.hill@louisville.edu.
authors.forename: Bradford G
authors.initials: BG
authors.lastname: Hill
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D005947:Glucose / Q000235:genetics / Q000378:metabolism*; D006019:Glycolysis; D008297:Male; D051379:Mice; D032386:Myoblasts, Cardiac / Q000378:metabolism* / Q000473:pathology; D025481:Phosphofructokinase-2 / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation
chemical_list: C000595376:PFKFB3 protein, mouse; D025481:Phosphofructokinase-2; D005947:Glucose
keywords: cell therapy; diabetes; glycolysis; heart failure; isotope; metabolomics; mitochondria; stable isotope