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: Joshua K Salabei, Pawel K Lorkiewicz, Parul Mehra, Andrew A Gibb, Petra Haberzettl, Kyung U Hong, Xiaoli Wei, Xiang Zhang, Qianhong Li, Marcin Wysoczynski, Roberto Bolli, Aruni Bhatnagar, Bradford G Hill
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 291 Issue 26 Pg. 13634-48 (Jun 24 2016) ISSN: 1083-351X [Electronic] United States
• PMID: 27151219 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• PFKFB3 protein, mouse
• Phosphofructokinase-2
• Glucose

Topics

• Animals
• Diabetes Mellitus, Experimental (genetics, metabolism, pathology)
• Diabetes Mellitus, Type 2 (genetics, metabolism, pathology)
• Gene Expression Regulation, Enzymologic
• Glucose (genetics, metabolism)
• Glycolysis
• Male
• Mice
• Myoblasts, Cardiac (metabolism, pathology)
• Phosphofructokinase-2 (biosynthesis, genetics)
• Up-Regulation