Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy
Accelerates Mitochondrial Dysfunction.
Authors Wende AR, Schell JC, Ha CM, Pepin ME, Khalimonchuk O, Schwertz H, Pereira RO,
Brahma MK, Tuinei J, Contreras-Ferrat A, Wang L, Andrizzi CA, Olsen CD, Bradley
WE, Dell'Italia LJ, Dillmann WH, Litwin SE, Abel ED
Submitted By Submitted Externally on 6/8/2020
Status Published
Journal Diabetes
Year 2020
Date Published 5/1/2020
Volume : Pages Not Specified : Not Specified
PubMed Reference 32366681
Abstract 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.

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