Secretion of insulin from pancreatic β-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by ATP-sensitive potassium (KATP) channel activity. Accordingly, loss-of-function mutations of the KATP channel Kir6.2 (KCNJ11) or SUR1 (ABCC8) subunit increase electrical excitability and secretion, resulting in congenital hyperinsulinism (CHI), whereas gain-of-function mutations cause underexcitability and undersecretion, resulting in neonatal diabetes mellitus (NDM). Thus, diazoxide, which activates KATP channels, and sulfonylureas, which inhibit KATP channels, have dramatically improved therapies for CHI and NDM, respectively. However, key findings do not fit within this simple paradigm: mice with complete absence of β-cell KATP activity are not hyperinsulinemic; instead, they are paradoxically glucose intolerant and prone to diabetes, as are older human CHI patients. Critically, despite these advances, there has been little insight into any role of KATP channel activity changes in the development of type 2 diabetes (T2D). Intriguingly, the CHI progression from hypersecretion to undersecretion actually mirrors the classical response to insulin resistance in the progression of T2D. In seeking to explain the progression of CHI, multiple lines of evidence lead us to propose that underlying mechanisms are also similar and that development of T2D may involve loss of KATP activity.

中文翻译：

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高胰岛素血症和 2 型糖尿病中的 ATP 敏感钾通道：难以忽视的悖论还是新范式？

胰腺 β 细胞分泌胰岛素的过程很复杂，但生理学葡萄糖依赖性分泌主要受电活动支配，而电活动又受 ATP 敏感钾 (KATP) 通道活动控制。因此，KATP 通道 Kir6.2 (KCNJ11) 或 SUR1 (ABCC8) 亚基的功能丧失突变会增加电兴奋性和分泌，导致先天性高胰岛素血症 (CHI)，而功能获得突变会导致兴奋性不足和分泌不足，导致新生儿糖尿病（NDM）。因此，激活 KATP 通道的二氮嗪和抑制 KATP 通道的磺酰脲类药物分别显着改善了 CHI 和 NDM 的治疗。然而，关键发现并不符合这个简单的范式：完全缺乏 β 细胞 KATP 活性的小鼠并不患有高胰岛素血症；相反，相反，他们与老年人类 CHI 患者一样，对葡萄糖不耐受，容易患糖尿病。重要的是，尽管取得了这些进展，但人们对 KATP 通道活性变化在 2 型糖尿病 (T2D) 发展中的作用知之甚少。有趣的是，CHI 从分泌过多到分泌不足的进展实际上反映了 T2D 进展中对胰岛素抵抗的经典反应。在试图解释 CHI 的进展过程中，多种证据使我们提出，潜在的机制也相似，并且 T2D 的发展可能涉及 KATP 活性的丧失。