Laboratory of Cardiovascular Science, National Institute on Aging/NIH, Baltimore, MD, 21224, USA.
Division of Cardiology, Department of Medicine, The Johns Hopkins University, Baltimore, MD, 21205, USA.
J Physiol. 2020 Apr;598(7):1393-1415. doi: 10.1113/JP276824. Epub 2018 Dec 30.
Hearts from type 2 diabetic animals display perturbations in excitation-contraction coupling, impairing myocyte contractility and delaying relaxation, along with altered substrate consumption patterns. Under high glucose and β-adrenergic stimulation conditions, palmitate can, at least in part, offset left ventricle (LV) dysfunction in hearts from diabetic mice, improving contractility and relaxation while restoring coronary perfusion pressure. Fluxome calculations of central catabolism in diabetic hearts show that, in the presence of palmitate, there is a metabolic remodelling involving tricarboxylic acid cycle, polyol and pentose phosphate pathways, leading to improved redox balance in cytoplasmic and mitochondrial compartments. Under high glucose and increased energy demand, the metabolic/fluxomic redirection leading to restored redox balance imparted by palmitate helps explain maintained LV function and may contribute to designing novel therapeutic approaches to prevent cardiac dysfunction in diabetic patients.
Type-2 diabetes (T2DM) leads to reduced myocardial performance, and eventually heart failure. Excessive accumulation of lipids and glucose is central to T2DM cardiomyopathy. Previous data showed that palmitate (Palm) or glutathione preserved heart mitochondrial energy/redox balance under excess glucose, rescuing β-adrenergic-stimulated cardiac excitation-contraction coupling. However, the mechanisms underlying the accompanying improved contractile performance have been largely ignored. Herein we explore in intact heart under substrate excess the metabolic remodelling associated with cardiac function in diabetic db/db mice subjected to stress given by β-adrenergic stimulation with isoproterenol and high glucose compared to their non-diabetic controls (+/+, WT) under euglycaemic conditions. When perfused with Palm, T2DM hearts exhibited improved contractility/relaxation compared to WT, accompanied by extensive metabolic remodelling as demonstrated by metabolomics-fluxomics combined with bioinformatics and computational modelling. The T2DM heart metabolome showed significant differences in the abundance of metabolites in pathways related to glucose, lipids and redox metabolism. Using a validated computational model of heart's central catabolism, comprising glucose and fatty acid (FA) oxidation in cytoplasmic and mitochondrial compartments, we estimated that fluxes through glucose degradation pathways are ∼2-fold lower in heart from T2DM vs. WT under all conditions studied. Palm addition elicits improvement of the redox status via enhanced β-oxidation and decreased glucose uptake, leading to flux-redirection away from redox-consuming pathways (e.g. polyol) while maintaining the flux through redox-generating pathways together with glucose-FA 'shared fuelling' of oxidative phosphorylation. Thus, available FAs such as Palm may help improve function via enhanced redox balance in T2DM hearts during peaks of hyperglycaemia and increased workload.
2 型糖尿病动物的心脏表现出兴奋-收缩偶联的紊乱，损害心肌收缩力并延迟舒张，并伴有底物消耗模式的改变。在高葡萄糖和β-肾上腺素刺激条件下，棕榈酸至少部分可以抵消糖尿病小鼠心脏的左心室（LV）功能障碍，改善收缩力和舒张功能，同时恢复冠状动脉灌注压。在糖尿病心脏中进行的中心分解代谢通量计算表明，在棕榈酸存在的情况下，存在涉及三羧酸循环、多元醇和戊糖磷酸途径的代谢重塑，导致细胞质和线粒体区室中氧化还原平衡得到改善。在高葡萄糖和能量需求增加的情况下，由棕榈酸引起的代谢/通量重定向导致的氧化还原平衡的恢复有助于解释 LV 功能的维持，并可能有助于设计预防糖尿病患者心脏功能障碍的新治疗方法。
2 型糖尿病（T2DM）导致心肌性能降低，最终导致心力衰竭。脂质和葡萄糖的过度积累是 T2DM 心肌病的核心。先前的数据表明，棕榈酸（Palm）或谷胱甘肽在高葡萄糖存在下维持心脏线粒体的能量/氧化还原平衡，挽救β-肾上腺素刺激的心脏兴奋-收缩偶联。然而，伴随改善的收缩性能的相关机制在很大程度上被忽视了。在此，我们在完整心脏中，在底物过剩的情况下，研究了与β-肾上腺素刺激异丙肾上腺素和高葡萄糖引起的糖尿病 db/db 小鼠心脏功能相关的代谢重塑，与正常血糖条件下的非糖尿病对照（+/+，WT）相比。当用棕榈酸灌注时，与 WT 相比，T2DM 心脏的收缩/松弛能力得到改善，同时通过代谢组学-通量组学结合生物信息学和计算建模证实了广泛的代谢重塑。T2DM 心脏的代谢组学显示与葡萄糖、脂质和氧化还原代谢相关途径的代谢物丰度存在显著差异。使用包括细胞质和线粒体区室中葡萄糖和脂肪酸（FA）氧化的心脏中央分解代谢的验证计算模型，我们估计在所有研究条件下，T2DM 心脏中葡萄糖降解途径的通量比 WT 低约 2 倍。棕榈酸的添加通过增强β-氧化和减少葡萄糖摄取来改善氧化还原状态，导致从消耗氧化还原的途径（例如多元醇）的通量重定向，同时维持与葡萄糖-FA“共享供能”氧化磷酸化相关的氧化还原生成途径的通量。因此，在高血糖和工作量增加的高峰期，可用的 FA （如棕榈酸）可能有助于通过改善 T2DM 心脏的氧化还原平衡来改善功能。
