Metabolically Coupled Ion Channel Interactions in Islets

 描述(申请人提供)：2型糖尿病(T2 DM)患者第一时相胰岛素分泌减少，并扰乱胰岛素的搏动性。我们研究了Iset电生理、钙和葡萄糖代谢的振荡，它们介导了小鼠胰岛素的脉动性分泌，并开发了双振荡器模型(DOM)，该模型成功地预测了正常小鼠胰岛的许多特征，该模型基于磷酸果糖激酶-M(PFKM)引起的缓慢糖酵解振荡。然而，关于慢振荡的起源、调节和功能意义，仍然存在争议和异常。了解脉动性胰岛素分泌的意义在于，即使开发出增加糖尿病患者β细胞质量的治疗方法，恢复生理脉动性也将优化分泌的胰岛素在靶标上的功效，而不会使β细胞过度工作。我们的长期目标是了解T2 DM患者有缺陷的β细胞功能，以恢复搏动性分泌。在最后的支持期间，我们开发了新的工具来研究胰岛代谢和功能的动力学，并获得了关于DOM的新证据。在这一进展的基础上，我们将确定电振荡和代谢振荡之间的时相关系，测试代谢振荡是糖酵解还是线粒体，并阐明代谢、钙和β细胞分泌振荡之间的关系。我们将确定小鼠胰岛的振荡机制与人类的关系有多密切，T2 DM患者的胰岛是否改变了振荡，如果是，哪些方面受到了影响。我们将检验我们的新假设，即在β细胞中改变的ATP敏感性钾通道(KATP)运输设定了胰岛振荡的葡萄糖敏感性。将利用电生理学、[Ca~(2+)]成像、建模和新型光学探针来测量糖酵解活性、线粒体氧化还原电位(MRP)、ATP/ADP、细胞乳酸和胰岛素分泌，以研究野生型小鼠、缺乏KATP通道的小鼠以及正常和T2 DM人的胰岛。

 DESCRIPTION (provided by applicant): Patients with type 2 diabetes (T2DM) have reduced first phase insulin secretion and disrupted insulin pulsatility. We have studied oscillations in iset electrophysiology, calcium, and glucose metabolism that mediate pulsatile insulin secretion in mouse and developed the Dual Oscillator Model (DOM), which successfully predicts many features of normal mouse islets based on slow glycolytic oscillations due to phosphofructokinase-M (PFKM). However, controversies and anomalies remain concerning the origin, regulation and functional significance of slow oscillations. The significance of understanding pulsatile insulin secretion is that even if therapies are developed to increase beta cell mass in people with diabetes, restoring physiological pulsatility will optimize the efficacy o secreted insulin on its targets without overworking beta cells. Our long-term objective is to understand defective beta cell function in T2DM in order to restore pulsatile secretion. During the last period of support we developed new tools for studying the dynamics of islet metabolism and function and obtained new evidence for DOM. Building on this progress, we will determine the phase relationships between electrical and metabolic oscillations, test whether metabolic oscillations are glycolytic or mitochondrial, and clarify the relationship between metabolic, Ca and secretory oscillations in beta cells. We will determine how closely the oscillatory mechanisms of mouse islets pertain to human, whether islets from T2DM patients have altered oscillations and, if so, what aspects are affected. We will test our new hypothesis that altered ATP-sensitive potassium channel (KATP) trafficking in beta cells sets the glucose sensitivity of islet oscillations. Electrophysiology, [Ca2+] imaging, modeling, and novel optical probes to measure glycolytic activity, mitochondrial redox potential (MRP), ATP/ADP, cellular lactate and insulin secretion will be used to study the islets of wild type mice, mice lacking KATP channels, and islets from normal and T2DM humans.