Glutamate Signaling in Human Islets of Langerhans

描述(由申请人提供)： 关于啮齿动物胰岛的生理学信息很多，但朗格汉斯人的胰岛生物学仍然知之甚少。由于越来越多的证据表明，人类的胰岛在结构和细胞组成方面存在显著差异，人类的胰岛生物学需要重新评估。我们的长期目标是为了解人类胰岛生物学做出贡献。这项建议涉及人类胰岛功能的一个方面：调节胰高血糖素的释放。尽管它在预防低血糖和生存方面很重要，但胰岛调节胰升糖素分泌的机制仍然存在争议。血糖水平降低会刺激高血糖素的分泌。然而，当分离时，分泌胰高血糖素的阿尔法细胞会受到高葡萄糖水平的刺激。为了调和这些相互矛盾的观察，有人认为旁分泌或自分泌信号是调节α细胞活动和胰升糖素释放的主要调节机制。 谷氨酸是大脑中的一种主要神经递质，最近被认为是一种旁分泌信号分子，对啮齿类动物胰岛中的胰升糖素分泌提供负反馈。对啮齿动物胰岛的研究表明，α细胞释放谷氨酸，β细胞和α细胞分别表达离子型谷氨酸受体(IGluRs)和代谢型谷氨酸受体。与这些结果形成鲜明对比的是，我们对人和猴子胰岛的初步研究表明，谷氨酸仅在阿尔法细胞中诱导钙反应。谷氨酸强烈刺激胰高血糖素的释放，但不能促进胰岛素的释放。这些对谷氨酸的反应是由AMPA类型的iGluRs介导的。当AMPA受体被阻断时，葡萄糖水平下降时释放的胰高血糖素就会强烈减少。基于这些结果，我们假设谷氨酸信号提供了一个自分泌环路，这是阿尔法细胞对低血糖反应所必需的。这种正反馈允许胰岛内的胰升糖素反应的传播。三个具体目标将检验这一创新想法： 1)确定灵长类胰岛中的α细胞释放谷氨酸 2)确定灵长类阿尔法细胞表达功能性谷氨酸受体 3)确定灵长类胰岛中的谷氨酸自分泌环是胰升糖素反应所必需的 如果得到证实，这项研究将指导临床医生考虑激活AMPA受体的治疗方法，以防止接受胰岛素治疗的1型糖尿病患者再次发生低血糖。

DESCRIPTION (provided by applicant): There is a wealth of information about the physiology of rodent islets, but the biology of human islets of Langerhans remains poorly understood. Because there is growing evidence that human islets are strikingly different in terms of architecture and cellular composition, human islet biology needs to be reevaluated. Our long-term goal is to contribute to the understanding of human islet biology. This proposal addresses one aspect of human islet function: the regulation of glucagon release. Despite its importance to prevent hypoglycemia and therefore for survival, the mechanisms for the regulation of glucagon secretion by pancreatic islets are still controversial. Glucagon secretion is stimulated by decreasing plasma glucose levels. However, when isolated, glucagon-secreting alpha cells are stimulated by high glucose levels. To reconcile these contradictory observations, it has been suggested that paracrine or autocrine signaling is the primary regulatory mechanism governing alpha cell activity and glucagon release. Glutamate is a major neurotransmitter in the brain that has been recently proposed as a paracrine signaling molecule providing negative feedback on glucagon secretion in rodent islets. Studies on rodent islets have shown that alpha cells release glutamate and that beta cells and alpha cells express ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors, respectively. In striking contrast to these results, our preliminary studies on human and monkey islets show that glutamate induces Ca2+ responses exclusively in alpha cells. Glutamate strongly stimulates glucagon release but not insulin release. These responses to glutamate are mediated by iGluRs of the AMPA type. Glucagon release in response to decreasing glucose levels is strongly reduced when the AMPA receptors are blocked. Based on these results, we hypothesize that glutamate signaling provides an autocrine loop that is necessary for alpha cell responses to hypoglycemia. This positive feedback allows for propagation of glucagon responses throughout the islet. Three Specific Aims will test this innovative idea: 1) Determine that glutamate is released by alpha cells in primate islets 2) Determine that primate alpha cells express functional glutamate receptors 3) Determine that glutamate autocrine loops in primate islets are necessary for glucagon responses If validated, this research will direct clinicians to consider therapies that activate AMPA receptors to prevent recurrent hypoglycemia in type 1 diabetic patients treated with insulin.