Barker Christopher J, Leibiger Ingo B, Berggren Per-Olof
The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, 171 76 Stockholm, Sweden.
Adv Biol Regul. 2013 Jan;53(1):156-63. doi: 10.1016/j.jbior.2012.09.011. Epub 2012 Sep 28.
Over the last two decades we have focused on beta cell signal transduction, bringing many new insights, especially in the context of insulin signal transduction, the role of inositol polyphosphates and the regulation of cytoplasmic free Ca(2+) concentration. However, there has been a growing awareness that the beta cell, which is mandatory for insulin secretion, has a unique context within the micro-organ of the pancreatic Islet of Langerhans. In this environment the beta cell both mediates and receives paracrine regulation, critical for the control of blood glucose homeostasis. Failure of an appropriate beta cell function leads to the development of diabetes mellitus. In our quest to understand the molecular events maintaining beta cell function we have faced two key challenges. Firstly, whilst there are many similarities between signal transduction in pancreatic islets between the much used rodent models and humans there are some notable differences. Critical distinctions between rodent and primate can be made in the structure of the islet, including the arrangement of the islet cells, the innervation pattern and the microcirculation. This means that important signaling interactions between islets cells, mediated through for example insulin, glucagon, GABA, glutamate and ATP, will have a unique human framework. The second challenge was to be able to take the discoveries we have made using in vitro systems and examine them in an in vivo context. Advances in in vivo imaging achieved by utilizing the anterior chamber of the eye as a transplantation site for pancreatic islets make it possible for non-invasive, longitudinal studies at single cell resolution in real time of islet cell physiology and pathology. Thus it is becoming possible to study the insulin secreting pancreatic beta cell within the framework of the unique micro-organ, the Islet of Langerhans, for the first time in a physiological context, i.e. when being innervated and connected to the blood supply.
在过去的二十年里，我们专注于β细胞信号转导，获得了许多新见解，尤其是在胰岛素信号转导、肌醇多磷酸的作用以及细胞质游离钙（Ca2+）浓度调节方面。然而，人们越来越意识到，胰岛素分泌所必需的β细胞在胰岛这个微小器官中具有独特的环境。在这种环境中，β细胞既介导又接受旁分泌调节，这对血糖稳态的控制至关重要。β细胞功能异常会导致糖尿病的发生。在我们试图理解维持β细胞功能的分子事件的过程中，我们面临两个关键挑战。首先，尽管常用的啮齿动物模型和人类的胰岛信号转导有许多相似之处，但也存在一些显著差异。啮齿动物和灵长类动物在胰岛结构上存在关键区别，包括胰岛细胞的排列、神经支配模式和微循环。这意味着胰岛细胞之间通过例如胰岛素、胰高血糖素、γ-氨基丁酸、谷氨酸和三磷酸腺苷介导的重要信号相互作用将具有独特的人类框架。第二个挑战是能够将我们在体外系统中取得的发现应用于体内研究。通过利用眼前房作为胰岛移植部位实现的体内成像技术的进步，使得以单细胞分辨率实时对胰岛细胞生理和病理进行非侵入性纵向研究成为可能。因此，首次有可能在生理环境下，即在有神经支配并与血液供应相连的情况下，在独特的微小器官胰岛的框架内研究分泌胰岛素的胰腺β细胞。
