J Lipid Atheroscler.  2020 Jan;9(1):92-109. 10.12997/jla.2020.9.1.92.

Positioning Metabolism as a Central Player in the Diabetic Heart

• Mereweather LJ
• Montes Aparicio CN
• Heather LC

• KMID: 2470803
• DOI: http://doi.org/10.12997/jla.2020.9.1.92

Abstract

In type 2 diabetes (T2D), the leading cause of death is cardiovascular complications. One mechanism contributing to cardiac pathogenesis is alterations in metabolism, with the diabetic heart exhibiting increased fatty acid oxidation and reduced glucose utilisation. The processes classically thought to underlie this metabolic shift include the Randle cycle and changes to gene expression. More recently, alternative mechanisms have been proposed, most notably, changes in post-translational modification of mitochondrial proteins in the heart. This increased understanding of how metabolism is altered in the diabetic heart has highlighted new therapeutic targets, with an aim to improve cardiac function in T2D. This review focuses on metabolism in the healthy heart and how this is modified in T2D, providing evidence for the mechanisms underlying this shift. There will be emphasis on the current treatments for the heart in diabetes, alongside efforts for metabocentric pharmacological therapies.

Keyword

Type 2 diabetes; Cardiac metabolism; Cardiovascular complications; Mitochondrial acetylation

MeSH Terms

Cause of Death
Gene Expression
Glucose
Heart*
Metabolism*
Mitochondrial Proteins
Protein Processing, Post-Translational
Glucose
Mitochondrial Proteins

Figure

• 

  Fig. 1 Schematic representing glucose and fatty acid metabolism in the healthy heart. Glucose uptake into cardiomyocytes occurs via GLUTs, namely GLUT1 and GLUT4. Inside the cell, glucose is phosphorylated by HK to G-6-P, which is a central intermediate of metabolism and can enter many pathways. One such pathway is glycolysis, whereby glucose is broken down to pyruvate and a small amount of ATP is generated under anaerobic conditions. Pyruvate can then enter the mitochondria for oxidation or be reduced to lactate in the cytoplasm. Mitochondrial PDH catalyses the oxidative decarboxylation of pyruvate to acetyl-CoA, which can then enter the Krebs cycle to generate hydrogen carriers. In the case of FA, uptake across the sarcolemma occurs primarily by the transporter fatty acid translocase (FAT/CD36). Once within the cardiomyocyte, FA are esterified to LCFA-CoA, which enters mitochondria via CPT1 for β-oxidation, or is incorporated into the myocardial TAG pool. The Krebs cycle yields hydrogen carriers for ATP production at the electron transport chain. GLUT, glucose transporter; HK, hexokinase; G-6-P, glucose-6-phosphate; ATP, adenosine triphosphate; PDH, pyruvate dehydrogenase; FA, fatty acids; LCFA-CoA, long chain fatty acyl coenzyme A; CPT1, carnitine palmitoyl transferase 1; TAG, triglyceride.

• 

  Fig. 2 Cellular mechanisms that favour FA use within the diabetic cardiomyocyte. Intermediates from FA breakdown inhibit components of glucose metabolism. LCFA-CoA can inhibit HK, the primary enzyme involved in glucose breakdown. Acetyl-CoA from increased FA oxidation can also activate PDK, the inhibitor of PDH. This subsequently reduces PDH activity, reducing pyruvate metabolism. Citrate from the Krebs cycle generated by increased FA metabolism can also inhibit PFK in glycolysis. Overall, this reduces glycolytic flux in the cardiomyocyte. Increased LCFA-CoA leads to increased DAG accumulation, which contributes to altered signalling and increased storage of fats as triglycerides. DAG can activate PKCθ, which has been suggested as the enzyme driving lipid-induced insulin resistance. It has been proposed that PKCθ can phosphorylate serine residues on the insulin receptor and its adaptor protein, IRS1/2. This prevents tyrosine phosphorylation, which is necessary for signalling, reducing translocation of vesicles containing GLUT4 to the membrane, reducing insulin-stimulated glucose uptake. FA, fatty acids; LCFA-CoA, long chain fatty acyl coenzyme A; HK, hexokinase; PDK, pyruvate dehydrogenase kinase; PDH, pyruvate dehydrogenase; PFK, phosphofructokinase; DAG, diacylglycerol; PKCθ, protein kinase C theta; IRS1/2, insulin receptor substrates 1/2; GLUT, glucose transporter; G-6-P, glucose-6-phosphate.

• 

  Fig. 3 Schematic representing changes mediated by PPARα, which is upregulated in the diabetic heart. Upon FA binding, PPARα becomes activated and dimerises with the retinoic acid receptor. This heterodimer can then bind to the PPAR response element and activate a plethora of genes. This includes genes involved in FA uptake, mitochondrial FA uptake and β-oxidation, including fatty acid translocase (FAT/CD36) and CPT1. Furthermore, PPARα also promotes upregulation of PDK, inhibiting PDH and reducing glycolytic flux. PPAR, peroxisome proliferator-activated receptor; FA, fatty acids; CPT1, carnitine palmitoyl transferase 1; PDK, pyruvate dehydrogenase kinase; PDH, pyruvate dehydrogenase; HK, hexokinase; G-6-P, glucose-6-phosphate; ATP, adenosine triphosphate; LCFA-CoA, long chain fatty acyl coenzyme A.

• 

  Fig. 4 Schematic representing acetylation and deacetylation of mitochondrial proteins. Acetyltransferases mediate the transfer of an acetyl moiety from acetyl CoA onto lysine (K) residues of proteins in the mitochondria. SIRTs mediate deacetylation, which requires NAD+ as a cofactor, and removes the acetyl group from lysine residues. SIRT3 displays the most robust deacetylating capacity of the mitochondrial SIRTs. CoA, coenzyme A; SIRTs, sirtuins; Ac, acetylation.

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