Endothelial HSP72 is not reduced in type 2 diabetes nor is it a key determinant of endothelial insulin sensitivity.
Endothelial HSP72 is not reduced in type 2 diabetes nor is it a key determinant of endothelial insulin sensitivity.
复制标题
2 型糖尿病中内皮 HSP72 并未减少，也不是内皮胰岛素敏感性的关键决定因素。
DOI：
10.1152/ajpregu.00006.2022
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Padilla,Jaume
中科院分区：
文献类型：
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作者：
Pettit-Mee,RyanJ;Power,Gavin;Cabral-Amador,FranciscoJ;Ramirez-Perez,FranciscoI;Soares,RogerioN;Sharma,Neekun;Liu,Ying;Christou,DemetraD;Kanaley,JillA;Martinez-Lemus,LuisA;Manrique-Acevedo,Camila;Padilla,Jaume
内皮胰岛素信号传导受损和随后胰岛素诱导的血管舒张钝化是2型糖尿病（T2 D）的特征，其导致血管疾病和血糖失调。然而，内皮胰岛素抵抗的分子机制仍然知之甚少。在此，我们测试了T2 D中内皮胰岛素抵抗归因于热休克蛋白72（HSP 72）表达减少的假设。HSP 72是一种细胞保护性伴侣蛋白，其可以随着加热而上调，并且据报道部分通过抑制JNK活性来促进代谢活性组织中的胰岛素敏感性。因此，我们进一步假设，在患有T2 D的个体中，通过热水浸泡至腰部水平的7天被动热处理将改善腿部血流对口服葡萄糖负荷的反应（即，内源性胰岛素刺激）。相反，我们发现：1）T2 D小鼠和人的内皮胰岛素抵抗与动脉和静脉内皮细胞中HSP 72的减少无关：2）被动热处理后，对口服葡萄糖负荷的腿部血流反应的改善与内皮HSP 72的增加无关; HSP 72表达下调（通过小干扰RNA）或上调培养的内皮细胞中的HSP 72（通过加热）分别不损害或增强胰岛素信号传导，也不改变JNK活性。总的来说，这些发现不支持HSP 72减少是T2 D内皮胰岛素抵抗的关键驱动因素的假设，但提供了新的证据，证明下体加热可能是改善腿部血流对葡萄糖摄入诱导的高胰岛素血症反应的有效策略。
Impaired endothelial insulin signaling and consequent blunting of insulin-induced vasodilation is a feature of type 2 diabetes (T2D) that contributes to vascular disease and glycemic dysregulation. However, the molecular mechanisms underlying endothelial insulin resistance remain poorly known. Herein, we tested the hypothesis that endothelial insulin resistance in T2D is attributed to reduced expression of heat shock protein 72 (HSP72). HSP72 is a cytoprotective chaperone protein that can be upregulated with heating and is reported to promote insulin sensitivity in metabolically active tissues, in part via inhibition of JNK activity. Accordingly, we further hypothesized that, in individuals with T2D, 7 days of passive heat treatment via hot water immersion to waist level would improve leg blood flow responses to an oral glucose load (i.e., endogenous insulin stimulation) via induction of endothelial HSP72. In contrast, we found that:1) endothelial insulin resistance in T2D mice and humans was not associated with reduced HSP72 in aortas and venous endothelial cells, respectively;2) after passive heat treatment, improved leg blood flow responses to an oral glucose load did not parallel with increased endothelial HSP72; and3) downregulation of HSP72 (via small-interfering RNA) or upregulation of HSP72 (via heating) in cultured endothelial cells did not impair or enhance insulin signaling, respectively, nor was JNK activity altered. Collectively, these findings do not support the hypothesis that reduced HSP72 is a key driver of endothelial insulin resistance in T2D but provide novel evidence that lower-body heating may be an effective strategy for improving leg blood flow responses to glucose ingestion-induced hyperinsulinemia.