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Metabolic dysfunction in diabetic cardiomyopathy

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Abstract

Diabetic cardiomyopathy (DCM) is defined as cardiac disease independent of vascular complications during diabetes. The number of new cases of DCM is rising at epidemic rates in proportion to newly diagnosed cases of diabetes mellitus (DM) throughout the world. DCM is a heart failure syndrome found in diabetic patients that is characterized by left ventricular hypertrophy and reduced diastolic function, with or without concurrent systolic dysfunction, occurring in the absence of hypertension and coronary artery disease. DCM and other diabetic complications are caused in part by elevations in blood glucose and lipids, characteristic of DM. Although there are pathological consequences to hyperglycemia and hyperlipidemia, the combination of the two metabolic abnormalities potentiates the severity of diabetic complications. A natural competition exists between glucose and fatty acid metabolism in the heart that is regulated by allosteric and feedback control and transcriptional modulation of key limiting enzymes. Inhibition of these glycolytic enzymes not only controls flux of substrate through the glycolytic pathway, but also leads to the diversion of glycolytic intermediate substrate through pathological pathways, which mediate the onset of diabetic complications. The present review describes the limiting steps involved in the development of these pathological pathways and the factors involved in the regulation of these limiting steps. Additionally, therapeutic options with demonstrated or postulated effects on DCM are described.

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Abbreviations

ACEI:

Angiotensin-converting enzyme inhibitor

ADP:

Adenosine diphosphate

AGES:

Advanced glycation end products

AMP:

Adenosine monophosphate

ARB:

Angiotensin receptor blockers

ATP:

Adenosine triphosphate

BMI:

Body mass index

CASQ2:

Calsequestrin

CCB:

Calcium channel blockers

CHF:

Congestive heart failure

COX:

Cytochrome oxidase

CPT-1:

Carnitine palmitoyltransferase-1

CVD:

Cardiovascular disease

DCM:

Diabetic cardiomyopathy

DM:

Diabetes mellitus

FAT:

Fatty acid translocase

FKBP:

FK 506 binding protein

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

GLP-1:

Glucagon-like peptide-1

GLUT:

Glucose transporter

GSH/GSSG:

Glutathione redox ratio

HMG-COA:

3-hydroxy-3-methylglutaryl coenzyme A

LV:

Left ventricle

LVDD:

Left ventricular diastolic dysfunction

LVH:

Left ventricular hypertrophy

NADPH:

Nicotinamide adenine dinucleotide phosphate

NCX:

Na+/Ca2+ exchanger

O-GlcNAC:

O-linked N-acetylglucosamine

PDH:

Pyruvate dehydrogenase complex

PFK:

Phosphofructokinase

PKC:

Protein kinase C

PPAR:

Peroxisome proliferation-activated receptor

RAAS:

Renin–angiotensin aldosterone system

ROS:

Reactive oxygen species

SERCA2A:

Sarco(endo)plasmic reticulum calcium ATPase

SR:

Sarcoplasmic reticulum

STZ:

Streptozotocin

TFAM:

Mitochondrial transcription factor A

TZD:

Thiazolidinediones

T1D:

Type 1 diabetes mellitus

T2D:

Type 2 diabetes mellitus

ZFR:

Zucker fatty rats

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Conflict of interest

Mr. Isfort and Drs. Stevens, Schaffer, Jong, and Wold declare that they have no conflicts of interest or financial ties to disclose.

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Authors and Affiliations

  1. The Ohio State University College of Medicine, Columbus, OH, USA

    Michael Isfort

  2. Center for Cardiovascular and Pulmonary Research, The Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA

    Michael Isfort, Sarah C. W. Stevens & Loren E. Wold

  3. Department of Pharmacology, University of South Alabama, Mobile, AL, USA

    Stephen Schaffer & Chian Ju Jong

  4. Department of Pediatrics, The Ohio State University, 575 Children’s Crossroad, WB4135, Columbus, OH, 43215, USA

    Loren E. Wold

  5. Department of Physiology and Cell Biology, The Ohio State University, Columbus, OH, USA

    Loren E. Wold

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  1. Michael Isfort
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  2. Sarah C. W. Stevens
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  3. Stephen Schaffer
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  4. Chian Ju Jong
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  5. Loren E. Wold
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Correspondence to Loren E. Wold.

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Michael Isfort, Sarah C. W. Stevens equally contributed to this manuscript.

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Isfort, M., Stevens, S.C.W., Schaffer, S. et al. Metabolic dysfunction in diabetic cardiomyopathy. Heart Fail Rev 19, 35–48 (2014). https://doi.org/10.1007/s10741-013-9377-8

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