Diabetic cardiomyopathy (DCM) is a major contributor to mortality in diabetic patients, characterized by a multifaceted pathogenesis and limited therapeutic options. While lactate, a byproduct of glycolysis, is known to be significantly elevated in type 2 diabetes, its specific role in DCM remains uncertain. This study reveals an abnormal upregulation of monocarboxylate transporter 4 (MCT4) on the plasma membrane of cardiomyocytes in type 2 diabetes, leading to excessive lactate efflux from these cells. The disruption in lactate transport homeostasis perturbs the intracellular lactate-pyruvate balance in cardiomyocytes, resulting in oxidative stress and inflammatory responses that exacerbate myocardial damage. Additionally, our findings suggest increased lactate efflux augments histone H4K12 lactylation in macrophages, facilitating inflammatory infiltration within the microenvironment. In vivo experiments have demonstrated that inhibiting MCT4 effectively alleviates myocardial oxidative stress and pathological damage, reduces inflammatory macrophage infiltration, and enhances cardiac function in type 2 diabetic mice. Furthermore, a clinical prediction model has been established, demonstrating a notable association between peripheral blood lactate levels and diastolic dysfunction in individuals with type 2 diabetes. This underscores the potential of lactate as a prognostic biomarker for DCM. Ultimately, our findings highlight the pivotal involvement of MCT4 in the dysregulation of cardiac energy metabolism and macrophage-mediated inflammation in type 2 diabetes. These insights offer novel perspectives on the pathogenesis of DCM and pave the way for the development of targeted therapeutic strategies against this debilitating condition.

中文翻译：

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MCT4依赖性乳酸转运：2型糖尿病心脏能量代谢损伤和炎症的新机制

糖尿病心肌病（DCM）是糖尿病患者死亡的主要原因，其特点是发病机制多方面且治疗选择有限。虽然已知乳酸（糖酵解的副产物）在 2 型糖尿病中显着升高，但其在 DCM 中的具体作用仍不确定。这项研究揭示了 2 型糖尿病患者心肌细胞质膜上单羧酸转运蛋白 4 (MCT4) 的异常上调，导致这些细胞中乳酸外流过多。乳酸转运稳态的破坏会扰乱心肌细胞内的乳酸-丙酮酸平衡，导致氧化应激和炎症反应，从而加剧心肌损伤。此外，我们的研究结果表明，乳酸外流的增加会增强巨噬细胞中的组蛋白 H4K12 乳酸化，促进微环境内的炎症浸润。体内实验证明，抑制MCT4可有效缓解2型糖尿病小鼠心肌氧化应激和病理损伤，减少炎症巨噬细胞浸润，增强心功能。此外，还建立了临床预测模型，证明 2 型糖尿病患者外周血乳酸水平与舒张功能障碍之间存在显着关联。这强调了乳酸作为 DCM 预后生物标志物的潜力。最终，我们的研究结果强调了 MCT4 在 2 型糖尿病心脏能量代谢失调和巨噬细胞介导的炎症中的关键参与。这些见解为 DCM 的发病机制提供了新的视角，并为开发针对这种使人衰弱的疾病的靶向治疗策略铺平了道路。