Diabetes severity is reflected by changes in a cardiac gene expression signature characterized by metabolism and cell death processes

We tested the impact of a graded reduction in insulin on cardiac gene expression with particular focus on metabolism and energy homeostasis. Wistar rats were made diabetic with a single dose of either 55 (D55) or 100 (D100) mg/kg streptozotocin (STZ). Although both D55 and D100 were equally hyperglycemic compared to control, D100 showed markedly lower plasma insulin and robust increases in plasma FA and TG. D100 demonstrated more significant transcriptomic changes than D55 with enrichment for metabolic processes that direct the heart to use FA, when glucose use is obstructed. Analysis of a protein-protein interaction network identified functional networks in D100 that describe mitochondrial overload, incomplete fatty acid oxidation, and loss of cardiomyocytes. Our data suggests that the differential reduction of insulin produced a dramatic change in cardiac gene expression largely enriched for substrate metabolism functions as well as a gene expression program supporting cell death.本研究探讨了胰岛素梯度降低对心脏基因表达的影响，重点聚焦代谢与能量稳态。通过单次注射55（D55）或100（D100）mg/kg链脲佐菌素（streptozotocin, STZ）构建Wistar大鼠糖尿病模型。尽管D55与D100两组大鼠的血糖升高程度与对照组无显著差异，但D100组的血浆胰岛素水平显著更低，血浆脂肪酸（fatty acid, FA）与甘油三酯（triglyceride, TG）水平则显著升高。相较于D55组，D100组的转录组变化更为显著，且富集于葡萄糖利用受阻时引导心脏利用脂肪酸的代谢过程。通过蛋白质相互作用网络（protein-protein interaction network）分析，在D100组中鉴定出与线粒体负荷过载、脂肪酸氧化不全以及心肌细胞丢失相关的功能网络。本研究数据表明，胰岛素的差异化降低会引发心脏基因表达的显著改变，这些改变主要富集于底物代谢相关功能，同时也伴随支持细胞死亡的基因表达程序。