1Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC 27710, USA.
Sci Signal. 2010 Mar 16;3(113):ra19. doi: 10.1126/scisignal.2000771.
Parasympathetic stimulation of pancreatic islets augments glucose-stimulated insulin secretion by inducing inositol trisphosphate receptor (IP(3)R)-mediated calcium ion (Ca2+) release. Ankyrin-B binds to the IP(3)R and is enriched in pancreatic beta cells. We found that ankyrin-B-deficient islets displayed impaired potentiation of insulin secretion by the muscarinic agonist carbachol, blunted carbachol-mediated intracellular Ca2+ release, and reduced the abundance of IP3R. Ankyrin-B-haploinsufficient mice exhibited hyperglycemia after oral ingestion but not after intraperitoneal injection of glucose, consistent with impaired parasympathetic potentiation of glucose-stimulated insulin secretion. The R1788W mutation of ankyrin-B impaired its function in pancreatic islets and is associated with type 2 diabetes in Caucasians and Hispanics. Thus, defective glycemic regulation through loss of ankyrin-B-dependent stabilization of IP3R is a potential risk factor for type 2 diabetes.
胰岛的副交感神经刺激通过诱导三磷酸肌醇受体 (IP(3)R) 介导的钙离子 (Ca2+) 释放来增强葡萄糖刺激的胰岛素分泌。锚蛋白-B 与 IP(3)R 结合，在胰腺 β 细胞中丰富。我们发现，锚蛋白-B 缺陷的胰岛显示出对毒蕈碱激动剂卡巴胆碱诱导的胰岛素分泌的增强作用受损，卡巴胆碱介导的细胞内 Ca2+释放减弱，IP3R 的丰度降低。锚蛋白-B 单倍不足的小鼠在口服摄入葡萄糖后表现出高血糖，但在腹腔内注射葡萄糖后则没有，这与副交感神经增强葡萄糖刺激的胰岛素分泌受损一致。锚蛋白-B 的 R1788W 突变损害了其在胰岛中的功能，与白种人和西班牙裔人群的 2 型糖尿病有关。因此，通过锚蛋白-B 依赖性 IP3R 稳定的丧失导致的血糖调节缺陷是 2 型糖尿病的一个潜在危险因素。
