Forkhead box protein O1 (FOXO1), a nuclear transcription factor, is preferably activated in the myocardium of diabetic mice. However, its role and mechanism in the development of diabetic cardiomyopathy in non‐obese insulin‐deficient diabetes are unclear. We hypothesized that cardiac FOXO1 over‐activation was attributable to the imbalanced myocardial oxidative metabolism and mitochondrial and cardiac dysfunction in type 1 diabetes. FOXO1‐selective inhibitor AS1842856 was administered to streptozotocin‐induced diabetic (D) rats, and cardiac functions, mitochondrial enzymes PDK4 and CPT1 and mitochondrial function were assessed. Primary cardiomyocytes isolated from non‐diabetic control (C) and D rats were treated with or without 1 µM AS1842856 and underwent Seahorse experiment to determine the effects of glucose, palmitate and pyruvate on cardiomyocyte bioenergetics. The results showed diabetic hearts displayed elevated FOXO1 nuclear translocation, concomitant with cardiac and mitochondrial dysfunction (manifested as elevated mtROS level and reduced mitochondrial membrane potential) and increased cell apoptosis (all P  < .05, D vs C). Diabetic myocardium showed impaired glycolysis, glucose oxidation and elevated fatty acid oxidation and enhanced PDK4 and CPT1 expression. AS1842856 attenuated or prevented all these changes except for glycolysis. We concluded that FOXO1 activation, through stimulating PDK4 and CPT1, shifts substrate selection from glucose to fatty acid and causes mitochondrial and cardiac dysfunction.

中文翻译：

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FOXO1通过诱导1型糖尿病的氧化代谢失衡而促进糖尿病性心肌病。

前额箱蛋白O1（FOXO1）是一种核转录因子，优选在糖尿病小鼠的心肌中被激活。但是，其在非肥胖胰岛素缺乏型糖尿病糖尿病性心肌病发展中的作用和机制尚不清楚。我们假设心脏FOXO1过度活化是由于1型糖尿病的心肌氧化代谢不平衡以及线粒体和心脏功能障碍所致。对链脲佐菌素诱发的糖尿病（D）大鼠使用FOXO1选择抑制剂AS1842856，并评估其心脏功能，线粒体酶PDK4和CPT1以及线粒体功能。将从非糖尿病对照（C）和D大鼠中分离出的原代心肌细胞用或不用1 µM AS1842856进行处理，然后进行海马实验以确定葡萄糖的作用，棕榈酸酯和丙酮酸对心肌细胞生物能的影响。结果显示，糖尿病心脏显示出FOXO1核易位升高，并伴有心脏和线粒体功能障碍（表现为mtROS水平升高和线粒体膜电位降低）和细胞凋亡增加（所有P  <.05，D vs C）。糖尿病心肌显示糖酵解受损，葡萄糖氧化和脂肪酸氧化升高以及PDK4和CPT1表达增强。AS1842856减弱或阻止了除糖酵解以外的所有这些变化。我们得出的结论是，通过刺激PDK4和CPT1，FOXO1激活将底物选择从葡萄糖转变为脂肪酸，并导致线粒体和心脏功能障碍。