Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO.
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO.
Diabetes. 2022 Mar 1;71(3):367-375. doi: 10.2337/db21-0755.
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.
胰腺β细胞的胰岛素分泌过程较为复杂，但生理性葡萄糖依赖性分泌主要受电活动的控制，而电活动又受到三磷酸腺苷（ATP）敏感性钾（KATP）通道活性的控制。因此，KATP 通道 Kir6.2（KCNJ11）或 SUR1（ABCC8）亚单位的功能丧失性突变会增加电兴奋性和分泌，导致先天性高胰岛素血症（CHI），而功能获得性突变会导致兴奋性降低和分泌不足，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著改善了 CHI 和 NDM 的治疗效果。然而，关键发现并不符合这一简单的模式：β细胞中完全缺乏 KATP 活性的小鼠不会发生高胰岛素血症；相反，它们表现出葡萄糖不耐受和易患糖尿病的现象，这与老年 CHI 患者的情况类似。关键的是，尽管取得了这些进展，但对于 KATP 通道活性变化在 2 型糖尿病（T2D）发展中的任何作用，仍几乎没有深入了解。有趣的是，CHI 从过度分泌到分泌不足的进展实际上反映了 T2D 中胰岛素抵抗进展的经典反应。为了解释 CHI 的进展，多条证据线索促使我们提出，潜在的机制也相似，而 T2D 的发展可能涉及 KATP 活性的丧失。
