Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, 171 76 Stockholm, Sweden.
Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Research Center, 3rd Floor, 118 83 Stockholm, Sweden.
J Diabetes Res. 2017;2017:5131785. doi: 10.1155/2017/5131785. Epub 2017 Oct 2.
Pancreatic -cells express several ion channels of the transient receptor potential family, which play important roles in mediating the stimulus-secretion coupling. One of these channels, the TRPM4 is a Ca-activated monovalent cation channel. This channel is inhibited by 9-phenanthrol, which also inhibits the TMEM16a Cl channel, and activates the Ca-activated K channel, K3.1. The net effects of ion-channel modulation by 9-phenantherol on the insulin secretion remain unclear. We tested the effects of 9-phenanthrol on glucose- and GLP-1-induced insulin secretion from isolated rat islets in static incubations. When applied to the islets in the presence of 3.3 mM glucose, 9-phenanthrol caused a small increase in insulin secretion (~7% of the insulin secretion stimulated by 10 mM glucose). 10 M 9-phenanthrol did not inhibit glucose- or GLP-1-induced insulin secretion. 20 M and 30 M 9-phenanthrol inhibited glucose-induced insulin secretion by ~80% and ~85%, respectively. Inhibition of the GLP-1-induced insulin secretion by 20 M and 30 M 9-phenanthrol was 65% and 94%, respectively. Our study shows that the major effect of 9-phenanthrol on the islets is a strong inhibition of insulin secretion, and we speculate that compounds related to 9-phenanthrol may be potentially useful in treating the pancreatogenous hyperinsulinemic hypoglycemia syndromes.
胰岛细胞表达几种瞬时受体电位家族的离子通道，这些通道在介导刺激-分泌偶联中发挥重要作用。这些通道之一，TRPM4 是一种 Ca2+激活的单价阳离子通道。该通道被 9-菲咯啉抑制，9-菲咯啉还抑制 TMEM16a Cl-通道，并激活 Ca2+激活的 K 通道 K3.1。9-菲咯啉对离子通道调节的净效应对胰岛素分泌仍不清楚。我们在静态孵育中测试了 9-菲咯啉对分离的大鼠胰岛中葡萄糖和 GLP-1 诱导的胰岛素分泌的影响。当在 3.3mM 葡萄糖存在的情况下将 9-菲咯啉应用于胰岛时，它会导致胰岛素分泌略有增加（约为 10mM 葡萄糖刺激的胰岛素分泌的 7%）。10μM 9-菲咯啉不会抑制葡萄糖或 GLP-1 诱导的胰岛素分泌。20μM 和 30μM 9-菲咯啉分别抑制葡萄糖诱导的胰岛素分泌约 80%和 85%。20μM 和 30μM 9-菲咯啉对 GLP-1 诱导的胰岛素分泌的抑制作用分别为 65%和 94%。我们的研究表明，9-菲咯啉对胰岛的主要作用是强烈抑制胰岛素分泌，我们推测与 9-菲咯啉相关的化合物可能在治疗胰源性高胰岛素血症性低血糖综合征方面具有潜在的用途。
