Diabetes Metab J.  2017 Feb;41(1):1-9. 10.4093/dmj.2017.41.1.1.

My Sweetheart Is Broken: Role of Glucose in Diabetic Cardiomyopathy

Affiliations
  • 1Division of Molecular and Cellular Pathology, Department of Pathology, The University of Alabama at Birmingham, Birmingham, AL, USA. adamwende@uabmc.edu
  • 2Department of Biomedical Engineering, The University of Alabama at Birmingham, Birmingham, AL, USA.

Abstract

Despite overall reductions in heart disease prevalence, the risk of developing heart failure has remained 2-fold greater among people with diabetes. Growing evidence has supported that fluctuations in glucose level and uptake contribute to cardiovascular disease (CVD) by modifying proteins, DNA, and gene expression. In the case of glucose, clinical studies have shown that increased dietary sugars for healthy individuals or poor glycemic control in diabetic patients further increased CVD risk. Furthermore, even after decades of maintaining tight glycemic control, susceptibility to disease progression can persist following a period of poor glycemic control through a process termed "glycemic memory." In response to chronically elevated glucose levels, a number of studies have identified molecular targets of the glucose-mediated protein posttranslational modification by the addition of an O-linked N-acetylglucosamine to impair contractility, calcium sensitivity, and mitochondrial protein function. Additionally, elevated glucose contributes to dysfunction in coupling glycolysis to glucose oxidation, pentose phosphate pathway, and polyol pathway. Therefore, in the "sweetened" environment associated with hyperglycemia, there are a number of pathways contributing to increased susceptibly to "breaking" the heart of diabetics. In this review we will discuss the unique contribution of glucose to heart disease and recent advances in defining mechanisms of action.

Keyword

Cardiomyopathies; Diabetes; Glucose; Metabolism

MeSH Terms

Calcium
Cardiomyopathies
Cardiovascular Diseases
Diabetic Cardiomyopathies*
Dietary Sucrose
Disease Progression
DNA
Gene Expression
Glucose*
Glycolysis
Heart
Heart Diseases
Heart Failure
Humans
Hyperglycemia
Metabolism
Mitochondrial Proteins
Pentose Phosphate Pathway
Prevalence
Protein Processing, Post-Translational
Calcium
DNA
Dietary Sucrose
Glucose
Mitochondrial Proteins

Figure

  • Fig. 1 Schematic depiction of impact “on” and impact “of” myocardial glucose metabolism during the initiation and progression of cardiomyopathy. During diabetes overall glucose utilization is blunted (down arrows) at the level of glucose uptake, glycolysis, and glucose oxidation. Partially through regulation of the glucose transporters (GLUT1 and 4) although other cardiac expressed family members may play a role (GLUT8, 3, 10, 11, and 12). Fatty acids are known to have negative effect on glucose transport via myocardial insulin resistance and on glucose oxidation by inhibiting the pyruvate dehydrogenase (PDH) complex activity. Non-oxidative pathways (up arrows) of glucose metabolism such as polyol pathway, advanced glycation end product (AGE) pathway, and protein kinase C pathway to produce excess reactive oxygen species (ROS) leading to oxidative stress. Induction of O-linked N-acetylglucosamine (O-GlcNAc) modification of via increased hexosamine biosynthesis flux disrupts cardiac protein contractility, calcium sensitivity, calcium cycling, and mitochondrial function. Also, modification of nuclear transcription factors (TFs) and histones (e.g., H3) may contribute to gene expression changes in diabetic cardiomyopathy. Brown arrows indicate glucose metabolite flux and its regulation by diabetes. Black arrows illustrate fatty acid-mediated pathways altering glucose utilization. Blue arrows indicate pathways induced by non-adenosine triphosphate (ATP) producing pathways of glucose metabolism owing to reduced glycolysis and glucose oxidation. PFK, phosphofructokinase; STIM1, stromal interaction molecule 1; SERCA2a, sarco/endoplasmic reticulum Ca2+ ATPase; PDK, pyruvate dehydrogenase kinase; FA, fatty acids.


Cited by  1 articles

The Potential Role of MicroRNA in Diabetic Cardiomyopathy
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Diabetes Metab J. 2020;44(1):54-55.    doi: 10.4093/dmj.2020.0019.


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