Molecular Physiology & Biophysics, Vanderbilt University Medical Centre, Nashville, TN 37232, USA.
J Physiol. 2011 Nov 15;589(Pt 22):5453-66. doi: 10.1113/jphysiol.2011.218909. Epub 2011 Sep 19.
Cell-cell communication in the islet of Langerhans is important for the regulation of insulin secretion. Gap-junctions coordinate oscillations in intracellular free-calcium (Ca(2+)) and insulin secretion in the islet following elevated glucose. Gap-junctions can also ensure that oscillatory Ca(2+) ceases when glucose is at a basal levels. We determine the roles of gap-junctions and other cell-cell communication pathways in the suppression of insulin secretion under basal conditions. Metabolic, electrical and insulin secretion levels were measured from islets lacking gap-junction coupling following deletion of connexion36 (Cx36(-/-)), and these results were compared to those obtained using fully isolated β-cells. K(ATP) loss-of-function islets provide a further experimental model to specifically study gap-junction mediated suppression of electrical activity. In isolated β-cells or Cx36(-/-) islets, elevations in Ca(2+) persisted in a subset of cells even at basal glucose. Isolated β-cells showed elevated insulin secretion at basal glucose; however, insulin secretion from Cx36(-/-) islets was minimally altered. Ca(2+) was further elevated under basal conditions, but insulin release still suppressed in K(ATP) loss-of-function islets. Forced elevation of cAMP led to PKA-mediated increases in insulin secretion from islets lacking gap-junctions, but not from islets expressing Cx36 gap junctions. We conclude there is a redundancy in how cell-cell communication in the islet suppresses insulin release. Gap junctions suppress cellular heterogeneity and spontaneous Ca(2+) signals, while other juxtacrine mechanisms, regulated by PKA and glucose, suppress more distal steps in exocytosis. Each mechanism is sufficiently robust to compensate for a loss of the other and still suppress basal insulin secretion.
胰岛细胞间的通讯对于胰岛素分泌的调节非常重要。缝隙连接协调葡萄糖升高后胰岛细胞内游离钙浓度(Ca(2+))的振荡和胰岛素分泌。缝隙连接还可以确保葡萄糖处于基础水平时，振荡的Ca(2+)停止。我们确定了缝隙连接和其他细胞间通讯途径在基础条件下抑制胰岛素分泌的作用。在Connexin36 (Cx36(-/-))缺失后，缺乏缝隙连接偶联的胰岛中测量代谢、电和胰岛素分泌水平，并将这些结果与使用完全分离的β细胞获得的结果进行比较。K(ATP)失活胰岛提供了一个进一步的实验模型，专门研究缝隙连接介导的电活动抑制。在分离的β细胞或 Cx36(-/-)胰岛中，即使在基础葡萄糖水平下，Ca(2+)的升高仍持续存在于一部分细胞中。分离的β细胞在基础葡萄糖下显示出升高的胰岛素分泌；然而，Cx36(-/-)胰岛的胰岛素分泌几乎没有改变。在基础条件下，Ca(2+)进一步升高，但在 K(ATP)失活胰岛中，胰岛素释放仍受到抑制。强制升高 cAMP 导致 PKA 介导的缺乏缝隙连接的胰岛中胰岛素分泌增加，但在表达 Cx36 缝隙连接的胰岛中则没有。我们得出结论，胰岛中细胞间通讯抑制胰岛素释放的方式存在冗余。缝隙连接抑制细胞异质性和自发的Ca(2+)信号，而其他旁分泌机制，受 PKA 和葡萄糖调节，抑制囊泡胞吐作用的更下游步骤。每种机制都足够强大，可以补偿另一种机制的丧失，并且仍然可以抑制基础胰岛素分泌。
