Metabolic remodelling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice.
Metabolic remodelling of glucose, fatty acid and redox pathways in the heart of type 2 diabetic mice.
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2 型糖尿病小鼠心脏中葡萄糖、脂肪酸和氧化还原途径的代谢重塑。
DOI：
10.1113/jp276824
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发表时间：
2020-04
期刊：
影响因子：
--
通讯作者：
Aon MA
中科院分区：
文献类型：
--
作者：
Cortassa S;Caceres V;Tocchetti CG;Bernier M;de Cabo R;Paolocci N;Sollott SJ;Aon MA
2型糖尿病（T2 DM）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聚是T2 DM心肌病的核心。先前的数据表明，棕榈酸酯（Palm）或谷胱甘肽在过量葡萄糖下保持心脏线粒体能量/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，随之而来的改善收缩性能的机制在很大程度上被忽视了。本文中，我们在正常血糖条件下，与非糖尿病对照组（+/+，WT）相比，在底物过量的完整心脏中，探索了与糖尿病db/db小鼠的心脏功能相关的代谢重塑，这些小鼠经受了由异丙肾上腺素和高葡萄糖刺激β-肾上腺素能给予的应激。当用Palm灌注时，与WT相比，T2 DM心脏表现出改善的收缩性/舒张性，伴随着广泛的代谢重构，如代谢组学-通量组学结合生物信息学和计算建模所证明的。2型糖尿病心脏代谢组显示，与葡萄糖、脂质和氧化还原代谢相关的代谢途径中的代谢物丰度存在显著差异。使用经验证的心脏中枢代谢计算模型（包括细胞质和线粒体区室中的葡萄糖和脂肪酸（FA）氧化），我们估计在所有研究条件下，T2 DM心脏中通过葡萄糖降解途径的通量比WT低约2倍。棕榈添加通过增强的β-氧化和降低的葡萄糖摄取来改善氧化还原状态，导致通量重定向远离氧化还原消耗途径（例如多元醇），同时维持通过氧化还原产生途径的通量以及氧化磷酸化的葡萄糖-FA“共享燃料”。因此，在高血压峰值和工作负荷增加期间，可用的FA（如Palm）可能有助于通过增强T2 DM心脏的氧化还原平衡来改善功能。
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.