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E-Book 3rd Congress

  • The Central Mechanism of Pyruvate Dehydrogenase Inhibition in Diabetic Cardiomyopathy
  • Farnaz seifi,1,* Tahoura nazemi,2 Mobina gharibi,3
    1. Tehran Medical Sciences, Islamic Azad University
    2. Tehran Medical Sciences, Islamic Azad University
    3. Tehran Medical Sciences, Islamic Azad University


  • Introduction: Diabetic cardiomyopathy, a complex disease characterized by profound structural and functional alterations in the myocardium, poses a significant burden on the health of individuals with diabetes. While the intricate mechanisms underlying this disease are not fully elucidated, a constellation of factors, including oxidative stress, endoplasmic reticulum stress, microvascular dysfunction, cardiomyocyte apoptosis, cardiac lipotoxicity, and alterations in cardiac energetics, have been implicated in its pathogenesis.
  • Methods: To thoroughly explore the central mechanism of pyruvate dehydrogenase (PDH) inhibition in diabetic cardiomyopathy, a comprehensive literature search was conducted across PubMed, Google Scholar, and NCBI databases. This search yielded 22 relevant articles, which were carefully reviewed and analyzed to gain a deeper understanding of this topic.
  • Results: Among these metabolic perturbations, a robust impairment in glucose oxidation stands out as a hallmark feature of the diabetic heart. This decline in glucose utilization is attributed to a multifaceted interplay of factors, including enhanced fatty acid oxidation, mitochondrial dysfunction, and increased expression of pyruvate dehydrogenase kinase 4 (PDK4), an enzyme that inhibits PDH, the central regulatory enzyme of glucose oxidation. PDH: A Pivotal Player in Cardiac Metabolism: PDH catalyzes the oxidative decarboxylation of pyruvate, a key intermediate in glucose metabolism, to Acetyl-CoA and NADH, crucial energy substrates for cellular processes. Its regulation is a delicate balance of allosteric and posttranslational mechanisms, ensuring efficient energy production in response to metabolic demands. Inhibition of PDH: A Catalyst for Diabetic Cardiomyopathy: Studies in mice fed high-fat diets, a model of obesity and diabetes, have revealed rapid PDH inhibition in the myocardium. This inhibition, driven by increased PDK4 activity, disrupts the delicate balance of pyruvate metabolism and shifts the heart's reliance towards fatty acid oxidation, a process associated with enhanced mitochondrial pro-oxidant production. Pathophysiological Consequences of PDH Inhibition: The metabolic shift induced by PDH inhibition has profound consequences for cardiac function. First, it compromises the heart's ability to generate energy from glucose, a primary fuel for cardiac muscle contraction. Second, it promotes oxidative stress, a hallmark of diabetic cardiomyopathy, through increased mitochondrial reactive oxygen species (ROS) production. Evidence from Humans with Diabetes: Data from individuals with type 2 diabetes substantiate the role of impaired PDH activity in the progression of diabetic cardiomyopathy. Studies employing noninvasive hyperpolarized 13C magnetic resonance imaging (MRI) have shown diminished pyruvate oxidation in the hearts of type 2 diabetic individuals with normal systolic function. This metabolic alteration is accompanied by a concomitant decline in myocardial energy levels and diastolic dysfunction, further compromising cardiac performance. Therapeutic Interventions Targeting PDH: Several therapeutic approaches have emerged as potential strategies to counteract PDH inhibition and ameliorate diabetic cardiomyopathy. These interventions include: 1. PDK4 Inhibition: PDK4 inhibitors have demonstrated efficacy in enhancing glucose oxidation in animal models of diabetes. 2. PDP Activation: PDH phosphatases (PDPs) are enzymes that reverse PDH inhibition by dephosphorylating the enzyme. Activation of PDPs has also been shown to improve glucose oxidation in animal models of diabetes. 3. IRS-2 Enhancement: Insulin receptor substrate-2 (IRS-2) is a protein involved in the signaling pathway that promotes PDP activation. Increasing the expression of IRS-2 may also be beneficial in improving glucose oxidation in diabetic cardiomyopathy.
  • Conclusion: Inhibition of pyruvate dehydrogenase (PDH) plays a pivotal role in the development of diabetic cardiomyopathy. This inhibition disrupts glucose oxidation, promotes oxidative stress, and hinders myocardial function. Several therapeutic approaches targeting PDH hold promise for improving glucose utilization, mitigating oxidative stress, and ameliorating the detrimental effects of diabetic cardiomyopathy. Further research is warranted to optimize these interventions and their translation into clinical practice.
  • Keywords: Pyruvate dehydrogenase, Diabetic cardiomyopathy, Oxidative stress