Hypoglycemia triggers autonomic and endocrine counter-regulatory responses to restore glucose homeostasis, a response that is impaired in patients with diabetes and its long-term complication hypoglycemia-associated autonomic failure (HAAF). We show that insulin-evoked hypoglycemia is severely aggravated in mice lacking the cation channel proteins TRPC1, TRPC4, TRPC5, and TRPC6, which cannot be explained by alterations in glucagon or glucocorticoid action. By using various TRPC compound knockout mouse lines, we pinpointed the failure in sympathetic counter-regulation to the lack of the TRPC5 channel subtype in adrenal chromaffin cells, which prevents proper adrenaline rise in blood plasma. Using electrophysiological analyses, we delineate a previously unknown signaling pathway in which stimulation of PAC1 or muscarinic receptors activates TRPC5 channels in a phospholipase-C-dependent manner to induce sustained adrenaline secretion as a crucial step in the sympathetic counter response to insulin-induced hypoglycemia. By comparing metabolites in the plasma, we identified reduced taurine levels after hypoglycemia induction as a commonality in TRPC5-deficient mice and HAAF patients.

中文翻译：

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TRPC5 控制肾上腺素介导的低血糖反调节。


低血糖触发自主神经和内分泌反调节反应以恢复葡萄糖稳态，这种反应在糖尿病及其长期并发症低血糖相关自主神经衰竭 （HAAF） 患者中受损。我们表明，在缺乏阳离子通道蛋白 TRPC1 、 TRPC4 、 TRPC5 和 TRPC6 的小鼠中，胰岛素诱发的低血糖症严重加重，这不能用胰高血糖素或糖皮质激素作用的改变来解释。通过使用各种 TRPC 化合物敲除小鼠品系，我们确定了肾上腺嗜铬细胞中缺乏 TRPC5 通道亚型的交感神经反调节失败，这阻止了血浆中肾上腺素的正常上升。使用电生理学分析，我们描绘了一个以前未知的信号通路，其中 PAC1 或毒蕈碱受体的刺激以磷脂酶 C 依赖性方式激活 TRPC5 通道，以诱导持续的肾上腺素分泌，这是交感神经对胰岛素诱导的低血糖反应的关键步骤。通过比较血浆中的代谢物，我们确定了低血糖诱导后牛磺酸水平降低是 TRPC5 缺陷小鼠和 HAAF 患者的共同点。