Yildirim Vehpi, Vadrevu Suryakiran, Thompson Benjamin, Satin Leslie S, Bertram Richard
Department of Mathematics, Florida State University, Tallahassee, FL, United States of America.
Brehm Diabetes Center, University of Michigan Medical School, Ann Arbor, MI, United States of America.
PLoS Comput Biol. 2017 Jul 27;13(7):e1005686. doi: 10.1371/journal.pcbi.1005686. eCollection 2017 Jul.
Plasma insulin oscillations are known to have physiological importance in the regulation of blood glucose. In insulin-secreting β-cells of pancreatic islets, K(ATP) channels play a key role in regulating glucose-dependent insulin secretion. In addition, they convey oscillations in cellular metabolism to the membrane by sensing adenine nucleotides, and are thus instrumental in mediating pulsatile insulin secretion. Blocking K(ATP) channels pharmacologically depolarizes the β-cell plasma membrane and terminates islet oscillations. Surprisingly, when K(ATP) channels are genetically knocked out, oscillations in islet activity persist, and relatively normal blood glucose levels are maintained. Compensation must therefore occur to overcome the loss of K(ATP) channels in K(ATP) knockout mice. In a companion study, we demonstrated a substantial increase in Kir2.1 protein occurs in β-cells lacking K(ATP) because of SUR1 deletion. In this report, we demonstrate that β-cells of SUR1 null islets have an upregulated inward rectifying K+ current that helps to compensate for the loss of K(ATP) channels. This current is likely due to the increased expression of Kir2.1 channels. We used mathematical modeling to determine whether an ionic current having the biophysical characteristics of Kir2.1 is capable of rescuing oscillations that are similar in period to those of wild-type islets. By experimentally testing a key model prediction we suggest that Kir2.1 current upregulation is a likely mechanism for rescuing the oscillations seen in islets from mice deficient in K(ATP) channels.
已知血浆胰岛素振荡在血糖调节中具有生理重要性。在胰岛分泌胰岛素的β细胞中，ATP敏感性钾通道（K(ATP)通道）在调节葡萄糖依赖性胰岛素分泌中起关键作用。此外，它们通过感知腺嘌呤核苷酸将细胞代谢的振荡传递到细胞膜，因此有助于介导脉冲式胰岛素分泌。通过药物阻断K(ATP)通道会使β细胞质膜去极化并终止胰岛振荡。令人惊讶的是，当K(ATP)通道被基因敲除时，胰岛活动的振荡仍然存在，并且血糖水平维持在相对正常的水平。因此，必须发生某种补偿机制来克服K(ATP)基因敲除小鼠中K(ATP)通道的缺失。在一项相关研究中，我们证明由于SUR1缺失，在缺乏K(ATP)的β细胞中Kir2.1蛋白大量增加。在本报告中，我们证明SUR1基因敲除胰岛的β细胞具有上调的内向整流钾电流，这有助于补偿K(ATP)通道的缺失。这种电流可能是由于Kir2.1通道表达增加所致。我们使用数学模型来确定具有Kir2.1生物物理特性的离子电流是否能够挽救与野生型胰岛周期相似的振荡。通过对一个关键模型预测进行实验测试，我们认为Kir2.1电流上调可能是挽救K(ATP)通道缺陷小鼠胰岛中所见振荡的一种机制。
