Charles Perkins Centre, The University of Sydney, Camperdown, Australia; School of Medical Sciences, The University of Sydney, Camperdown, Australia.
Charles Perkins Centre, The University of Sydney, Camperdown, Australia; School of Life and Environmental Sciences, Camperdown, The University of Sydney, Australia.
J Mol Cell Cardiol. 2022 Mar;164:92-109. doi: 10.1016/j.yjmcc.2021.11.009. Epub 2021 Nov 24.
The incidence of type 2 diabetes (T2D) is increasing globally, with long-term implications for human health and longevity. Heart disease is the leading cause of death in T2D patients, who display an elevated risk of an acute cardiovascular event and worse outcomes following such an insult. The underlying mechanisms that predispose the diabetic heart to this poor prognosis remain to be defined. This study developed a pre-clinical model (Rattus norvegicus) that complemented caloric excess from a high-fat diet (HFD) and pancreatic β-cell dysfunction from streptozotocin (STZ) to produce hyperglycaemia, peripheral insulin resistance, hyperlipidaemia and elevated fat mass to mimic the clinical features of T2D. Ex vivo cardiac function was assessed using Langendorff perfusion with systolic and diastolic contractile depression observed in T2D hearts. Cohorts representing untreated, individual HFD- or STZ-treatments and the combined HFD + STZ approach were used to generate ventricular samples (n = 9 per cohort) for sequential and integrated analysis of the proteome, lipidome and metabolome by liquid chromatography-tandem mass spectrometry. This study found that in T2D hearts, HFD treatment primed the metabolome, while STZ treatment was the major driver for changes in the proteome. Both treatments equally impacted the lipidome. Our data suggest that increases in β-oxidation and early TCA cycle intermediates promoted rerouting via 2-oxaloacetate to glutamate, γ-aminobutyric acid and glutathione. Furthermore, we suggest that the T2D heart activates networks to redistribute excess acetyl-CoA towards ketogenesis and incomplete β-oxidation through the formation of short-chain acylcarnitine species. Multi-omics provided a global and comprehensive molecular view of the diabetic heart, which distributes substrates and products from excess β-oxidation, reduces metabolic flexibility and impairs capacity to restore high energy reservoirs needed to respond to and prevent subsequent acute cardiovascular events.
2 型糖尿病（T2D）的发病率在全球范围内不断上升，对人类健康和长寿有着长期的影响。心脏病是 T2D 患者的主要死亡原因，他们在急性心血管事件后发生风险增加，预后更差。导致糖尿病心脏预后不良的潜在机制仍有待确定。本研究建立了一个临床前模型（挪威褐鼠），该模型补充了高脂肪饮食（HFD）引起的热量过剩和链脲佐菌素（STZ）引起的胰岛β细胞功能障碍，以产生高血糖、外周胰岛素抵抗、高脂血症和脂肪量增加，模拟 T2D 的临床特征。使用 Langendorff 灌注法评估离体心脏功能，观察到 T2D 心脏的收缩和舒张收缩功能下降。使用未经处理、单独 HFD 或 STZ 处理以及 HFD+STZ 联合处理的队列，生成心室样本（每个队列 9 个样本），通过液相色谱-串联质谱法进行蛋白质组、脂质组和代谢组的顺序和综合分析。本研究发现，在 T2D 心脏中，HFD 处理使代谢组发生变化，而 STZ 处理是导致蛋白质组变化的主要驱动因素。两种处理方法均同等影响脂质组。我们的数据表明，β-氧化和早期 TCA 循环中间体的增加通过 2-氧代戊二酸促进了谷氨酸、γ-氨基丁酸和谷胱甘肽的重排。此外，我们认为 T2D 心脏通过形成短链酰基辅酶 A 物质，激活网络将多余的乙酰辅酶 A 重新分配到酮体生成和不完全的β-氧化途径。多组学提供了糖尿病心脏的全局和综合分子视图，该视图分配了来自多余β-氧化的底物和产物，降低了代谢灵活性，并损害了恢复应对和预防随后急性心血管事件所需的高能储备的能力。
