Type 2 diabetics have impaired insulin secretion. We hypothesize that abnormal pancreatic islet electrical activity contributes to this impairment by causing dysfunctional [Ca2+]i signaling. Islets are a syncytium of electrically-coupled endocrine cells. In response to elevated plasma [glucose], islets exhibit rhythmical electrical activity, termed bursting, which consists of 10-60 second plateau depolarizations with rapid spikes. This activity mediates the cyclic Ca uptake required for normal insulin secretion. While previous studies have increased our understanding of islet ion channels and Ca2+ signaling mechanisms, it is unclear how these channels interact with one another and with cell metabolism, or how coupled cells within the islet interact to mediate bursting in controls or diabetics. Studies carried out in the previous period of support showed that while single beta-cells burst, their burst period is typically faster (less than or equal to 5 s) than that of whole islets. A new model was developed which accounts for medium bursting resulting from an interaction between intrinsically fast and intrinsically slow beta-cell processes (Phantom Burster Model). Fast bursting is hypothesized to result from Ca channel inactivation or the activation of a novel, Ca-activated K channel. Slow bursting may be mediated by metabolic oscillations in ATP/ADP driving KATP channel oscillations, novel insulin activation of KATP, or oscillations in KCa driven by changes in endoplasmic reticulum (ER) [Ca2+]i levels. Dynamic clamp, simultaneous recordings of membrane potential or current with [Ca2+]i, patch clamping whole islets, and single cell insulin secretion assays will be used with mathematical modeling to develop a comprehensive understanding of mouse islet bursting, the behavior of single beta-cells, and the significance of gap junctional coupling. In addition, we will identify the crucial beta-cell ion channels which determine the electrophysiology of and may lead to novel pharmacologic approaches for treating diabetes based on manipulating these ion channels.
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