Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, U.K.
Department of Physics, University of Oxford, Oxford, U.K.
Diabetes. 2021 May;70(5):1145-1156. doi: 10.2337/db20-0691. Epub 2021 Feb 10.
The ATP-sensitive K (K) channel controls blood glucose levels by coupling glucose metabolism to insulin secretion in pancreatic β-cells. E23K, a common polymorphism in the pore-forming K channel subunit () gene, has been linked to increased risk of type 2 diabetes. Understanding the risk-allele-specific pathogenesis has the potential to improve personalized diabetes treatment, but the underlying mechanism has remained elusive. Using a genetically engineered mouse model, we now show that the K23 variant impairs glucose-induced insulin secretion and increases diabetes risk when combined with a high-fat diet (HFD) and obesity. K-channels in β-cells with two K23 risk alleles (KK) showed decreased ATP inhibition, and the threshold for glucose-stimulated insulin secretion from KK islets was increased. Consequently, the insulin response to glucose and glycemic control was impaired in KK mice fed a standard diet. On an HFD, the effects of the KK genotype were exacerbated, accelerating diet-induced diabetes progression and causing β-cell failure. We conclude that the K23 variant increases diabetes risk by impairing insulin secretion at threshold glucose levels, thus accelerating loss of β-cell function in the early stages of diabetes progression.
ATP 敏感性钾 (K) 通道通过将葡萄糖代谢与胰岛 β 细胞中的胰岛素分泌偶联来控制血糖水平。在孔形成 K 通道亚基 () 基因中，E23K 是一种常见的多态性，与 2 型糖尿病风险增加有关。了解风险等位基因特异性发病机制有可能改善个性化糖尿病治疗，但潜在机制仍不清楚。使用基因工程小鼠模型，我们现在表明，当与高脂肪饮食 (HFD) 和肥胖相结合时，K23 变体可损害葡萄糖诱导的胰岛素分泌并增加糖尿病风险。具有两个 K23 风险等位基因 (KK) 的 β 细胞中的 K 通道显示出对 ATP 的抑制作用降低，并且 KK 胰岛的葡萄糖刺激胰岛素分泌的阈值增加。因此，在给予标准饮食的 KK 小鼠中，对葡萄糖的胰岛素反应和血糖控制受损。在 HFD 上，KK 基因型的作用加剧，加速了饮食诱导的糖尿病进展并导致 β 细胞衰竭。我们的结论是，K23 变体通过在阈值葡萄糖水平下损害胰岛素分泌来增加糖尿病风险，从而加速糖尿病进展早期 β 细胞功能的丧失。
