Journal article
Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction
Diabetes (New York, N.Y.), Vol.69(10), pp.2094-2111
10/2020
DOI: 10.2337/db19-1057
PMCID: PMC7506832
PMID: 32366681
Abstract
Cardiac glucose uptake and oxidation are reduced in diabetes despite hyperglycemia. Mitochondrial dysfunction contributes to heart failure in diabetes. It is unclear whether 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 GLUT4. We examined mice rendered hyperglycemic following low-dose streptozotocin prior to increasing cardiomyocyte glucose uptake by transgene induction. Enhanced myocardial glucose in nondiabetic 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\n-GlcNAcylation of the transcription factor Sp1. Increased glucose uptake induced direct\n-GlcNAcylation of many electron transport chain subunits and other mitochondrial proteins. These findings identify mitochondria as a major target of glucotoxicity. They also suggest that 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.
Details
- Title: Subtitle
- Maintaining Myocardial Glucose Utilization in Diabetic Cardiomyopathy Accelerates Mitochondrial Dysfunction
- Creators
- Adam R Wende - Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, ALJohn C Schell - Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, UTChae-Myeong Ha - Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, ALMark E Pepin - Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, ALOleh Khalimonchuk - Department of Biochemistry and Nebraska Redox Biology Center, University of Nebraska, Lincoln, NEHansjörg Schwertz - Division of Occupational Medicine, Molecular Medicine Program, and Rocky Mountain Center for Occupational and Environmental Health, University of Utah, Salt Lake City, UTRenata O Pereira - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IAManoja K Brahma - Division of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, ALJoseph Tuinei - Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, UTAriel Contreras-Ferrat - Advanced Center for Chronic Diseases, Facultad de Ciencias Químicas y Farmacéuticas & Facultad de Medicina, Universidad de Chile, Santiago, ChileLi Wang - Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, UTChase A Andrizzi - Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, UTCurtis D Olsen - Division of Endocrinology, Metabolism, and Diabetes, University of Utah School of Medicine, Salt Lake City, UTWayne E Bradley - Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, ALLouis J Dell'Italia - Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, ALWolfgang H Dillmann - Department of Medicine, University of California, San Diego, La Jolla, CASheldon E Litwin - Division of Cardiology, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SCE Dale Abel - Fraternal Order of Eagles Diabetes Research Center and Division of Endocrinology and Metabolism, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.69(10), pp.2094-2111
- DOI
- 10.2337/db19-1057
- PMID
- 32366681
- PMCID
- PMC7506832
- NLM abbreviation
- Diabetes
- ISSN
- 0012-1797
- eISSN
- 1939-327X
- Publisher
- United States
- Grant note
- R01 HL133011 / NHLBI NIH HHS\nF30 HL137240 / NHLBI NIH HHS\nR00 HL111322 / NHLBI NIH HHS\nR01 GM108975 / NIGMS NIH HHS\nR01 HL108379 / NHLBI NIH HHS\nR01 DK092065 / NIDDK NIH HHS\nU01 HL087947 / NHLBI NIH HHS\nR35 GM131701 / NIGMS NIH HHS\nP30 DK056336 / NIDDK NIH HHS
- Language
- English
- Date published
- 10/2020
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology; Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984066343302771
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