American Diabetes Association
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Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction

posted on 2020-05-04, 17:02 authored by Ada AdminAda Admin, Adam R. Wende, John C. Schell, Chae-Myeong Ha, Mark E. Pepin, Oleh Khalimonchuk, Hansjörg Schwertz, Renata O. Pereira, Manoja K. Brahma, Joseph Tuinei, Ariel Contreras-Ferrat, Li Wang, Chase A. Andrizzi, Curtis D. Olsen, Wayne E. Bradley, Louis J. Dell’Italia, Wolfgang H. Dillmann, Sheldon E. Litwin, E. Dale Abel
Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear if these changes are adaptive or maladaptive. To directly evaluate the relationship between glucose delivery and mitochondrial dysfunction in diabetic cardiomyopathy we generated transgenic mice with inducible cardiomyocyte-specific expression of the glucose transporter (GLUT4). We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in non-diabetic mice decreased mitochondrial ATP generation and was associated with echocardiographic evidence of diastolic dysfunction. Increasing myocardial glucose delivery after short-term diabetes onset, exacerbated mitochondrial oxidative dysfunction. Transcriptomic analysis revealed that the largest changes, driven by glucose and diabetes, were in genes involved in mitochondrial function. This glucose-dependent transcriptional repression was in part mediated by O-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct O-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins. These findings identify mitochondria as a major target of glucotoxicity. They also suggest reduced glucose utilization in diabetic cardiomyopathy might defend against glucotoxicity and caution that restoring glucose delivery to the heart in the context of diabetes could accelerate mitochondrial dysfunction by disrupting protective metabolic adaptations.


This work was supported by National Institutes of Health (NIH) grants R00 HL111322, R01 HL133011, and JDRF Advanced Postdoctoral Fellowship 10-2009-267 to A.R.W., M.E.P. was supported by an NIH grant F30 HL137240, R.O.P. and M.K.B. were both supported by postdoctoral fellowships from the American Heart Association (AHA), O.K. was supported by NIH grant R01 GM108975, and E.D.A. was supported by NIH grants R01 DK092065, R01 HL108379, U01 HL087947, and is an established investigator of the AHA.