Zhang Min, Fendler Bernard, Peercy Bradford, Goel Pranay, Bertram Richard, Sherman Arthur, Satin Leslie
Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, Virginia 23298-0524, USA.
Biophys J. 2008 Nov 15;95(10):4676-88. doi: 10.1529/biophysj.107.125088. Epub 2008 Aug 15.
Individual mouse pancreatic islets exhibit oscillations in Ca(2+) and insulin secretion in response to glucose in vitro, but how the oscillations of a million islets are coordinated within the human pancreas in vivo is unclear. Islet to islet synchronization is necessary, however, for the pancreas to produce regular pulses of insulin. To determine whether neurohormone release within the pancreas might play a role in coordinating islet activity, Ca(2+) changes in 4-6 isolated mouse islets were simultaneously monitored before and after a transient pulse of a putative synchronizing agent. The degree of synchronicity was quantified using a novel analytical approach that yields a parameter that we call the "Synchronization Index". Individual islets exhibited Ca(2+) oscillations with periods of 3-6 min, but were not synchronized under control conditions. However, raising islet Ca(2+) with a brief application of the cholinergic agonist carbachol (25 microM) or elevated KCl in glucose-containing saline rapidly synchronized islet Ca(2+) oscillations for >/=30 min, long after the synchronizing agent was removed. In contrast, the adrenergic agonists clonidine or norepinephrine, and the K(ATP) channel inhibitor tolbutamide, failed to synchronize islets. Partial synchronization was observed, however, with the K(ATP) channel opener diazoxide. The synchronizing action of carbachol depended on the glucose concentration used, suggesting that glucose metabolism was necessary for synchronization to occur. To understand how transiently perturbing islet Ca(2+) produced sustained synchronization, we used a mathematical model of islet oscillations in which complex oscillatory behavior results from the interaction between a fast electrical subsystem and a slower metabolic oscillator. Transient synchronization simulated by the model was mediated by resetting of the islet oscillators to a similar initial phase followed by transient "ringing" behavior, during which the model islets oscillated with a similar frequency. These results suggest that neurohormone release from intrapancreatic neurons could help synchronize islets in situ. Defects in this coordinating mechanism could contribute to the disrupted insulin secretion observed in Type 2 diabetes.
单个小鼠胰岛在体外对葡萄糖的反应中表现出胞内钙离子浓度（Ca(2+)）振荡和胰岛素分泌，但尚不清楚在体内人胰腺中数百万个胰岛的振荡是如何协调的。然而，胰岛间同步对于胰腺产生规律的胰岛素脉冲是必要的。为了确定胰腺内神经激素释放是否可能在协调胰岛活动中发挥作用，在施加假定同步剂的短暂脉冲前后，同时监测4 - 6个分离的小鼠胰岛中的Ca(2+)变化。使用一种新颖的分析方法对同步程度进行量化，该方法产生一个我们称为“同步指数”的参数。单个胰岛表现出周期为3 - 6分钟的Ca(2+)振荡，但在对照条件下未同步。然而，通过短暂应用胆碱能激动剂卡巴胆碱（25 microM）或在含葡萄糖的盐水中升高氯化钾，可使胰岛Ca(2+)振荡迅速同步≥30分钟，即使在同步剂去除后很长时间也是如此。相比之下，肾上腺素能激动剂可乐定或去甲肾上腺素以及K(ATP)通道抑制剂甲苯磺丁脲未能使胰岛同步。然而，使用K(ATP)通道开放剂二氮嗪观察到了部分同步。卡巴胆碱的同步作用取决于所用的葡萄糖浓度，这表明葡萄糖代谢是同步发生所必需的。为了理解短暂扰动胰岛Ca(2+)如何产生持续同步，我们使用了一个胰岛振荡的数学模型，其中复杂的振荡行为源于快速电学子系统和较慢代谢振荡器之间的相互作用。该模型模拟的短暂同步是通过将胰岛振荡器重置到相似的初始相位，随后是短暂的“振铃”行为来介导的，在此期间模型胰岛以相似的频率振荡。这些结果表明胰腺内神经元释放的神经激素可能有助于原位同步胰岛。这种协调机制的缺陷可能导致2型糖尿病中观察到的胰岛素分泌紊乱。
