The role of EphA-ephrin-A signaling in glucose-inhibition of glucagon secretion

描述（由申请方提供）：胰岛通过葡萄糖调节的剂量依赖性激素分泌在血糖稳态中发挥核心作用。胰岛素治疗的成功使得大多数糖尿病研究都集中在？细胞然而，最近，胰高血糖素（由？细胞）已显示对糖尿病的病理生理学有显著贡献。在1型和2型糖尿病中，胰高血糖素分泌不适当地升高和失调，进一步加剧高血糖症。因此，了解潜在的机制？细胞功能和胰高血糖素分泌代表了开发糖尿病管理的新治疗策略的重要途径。结合目前的治疗方法，治疗的基础上，新的？- 细胞靶点将通过解决高血糖症的多种原因使1型和2型糖尿病患者受益。尽管胰高血糖素具有重要的生理作用，但对其分泌的调节机制仍知之甚少。活塞实验室最近发表的数据表明，GIGS不是固有的？胰高血糖素分泌的抑制不依赖于Ca ~（2+）内流。我们的数据表明，类似于糖尿病患者，纯人群的排序？- 细胞在低葡萄糖下胰高血糖素分泌增加，并且胰高血糖素分泌的葡萄糖抑制（GIGS）丧失。此外，细胞内[Ca 2 +]在γ-细胞中升高，以响应抑制胰高血糖素分泌的葡萄糖增加。胰岛内环境对适当胰高血糖素分泌的必要性不能仅仅通过旁分泌信号传导来解释，因为分选的胰岛细胞不再对提议的旁分泌抑制剂（胰岛素和生长抑素）敏感。 在这里，我们提出了一个新的GIGS的阿曲他克林信号依赖模型，调节胰高血糖素分泌下游的Ca 2+流入。通过EphA-ephrin-A信号传导途径的Juxtacrine信号传导已被证明在胰岛β细胞的基础和葡萄糖依赖性激素分泌中起重要作用。细胞自从？-细胞与？细胞，我们推测类似的机制在基础胰高血糖素分泌和GIGS中起作用。有趣的是，人类和老鼠？细胞仅表达单一Eph受体EphA 4。在抑制EphA 4受体信号传导的初步研究中，胰高血糖素分泌在基础葡萄糖下升高，并且分泌被不适当地刺激响应葡萄糖。这两个发现反映了在两种分类的？细胞和糖尿病患者，表明EphA 4受体信号传导在基础和升高的葡萄糖下介导胰高血糖素分泌的重要性。我们假设EphA 4受体信号在？在基础葡萄糖下适当抑制胰高血糖素分泌和GIGS需要细胞。此外，我们假设EphA 4受体信号传导允许额外的旁分泌抑制信号（胰岛素和/或生长抑素）。

DESCRIPTION (provided by applicant): The islets of Langerhans play a central role in blood glucose homeostasis through glucose regulated dose-dependent hormone secretion. The therapeutic success of insulin has led most diabetes research to be focused on ?-cells. Recently however, glucagon (secreted by ?-cells) has been shown to significantly contribute to the pathophysiology of diabetes. In both type 1 and type 2 diabetes, glucagon secretion is inappropriately elevated and dysregulated, further exacerbating hyperglycemia. Thus, understanding the mechanisms underlying ?-cell function and glucagon secretion represents an important avenue in the development of new therapeutic strategies for diabetes management. In combination with current treatments, therapeutics based on novel ? -cell targets will benefit patients with type 1 and type 2 diabetes by addressing multiple causes of hyperglycemia. Despite the important physiologic role of glucagon, the mechanisms regulating its secretion remain poorly understood. The Piston lab has recently published data suggesting that GIGS is not intrinsic to ? -cells, and that the inhibition of glucagon secretion is independent of Ca2+ influx. Our data show that similar to diabetic patients, pure populations of sorted ? -cells displa an increase in glucagon secretion at low glucose and a loss of glucose-inhibition of glucagon secretion (GIGS). Additionally, intracellular [Ca2+] is elevated in ¿-cells in response to increase in glucose that inhibit glucagon secretion. The necessity of the intraislet environment for appropriate glucagon secretion cannot be explained solely through paracrine signaling, as sorted ¿-cells are no longer sensitive to proposed paracrine inhibitors (insulin and somatostatin). Here, we propose a new juxtacrine signaling dependent model of GIGS that regulates glucagon secretion downstream of Ca2+ influx. Juxtacrine signaling through the EphA-ephrin-A signaling pathways has been shown to play an important role in both the basal and glucose dependent hormone secretion from islet ?-cells. Since the ?-cell is closely related to the ?-cell, we speculate that a similar mechanism plays a role in basal glucagon secretion and GIGS. Interestingly, both human and mouse ?-cells only express a single Eph receptor, EphA4. In preliminary studies pharmacologically inhibiting EphA4 receptor signaling, glucagon secretion was elevated at basal glucose and secretion was inappropriately stimulated response to glucose. These two findings mirror the glucagon secretion patterns observed in both sorted ?-cells and diabetic patients, indicating the importance of EphA4 receptor signaling in mediating glucagon secretion at basal and elevated glucose. We hypothesize that EphA4 receptor signaling in ?-cells is required for the appropriate suppression of glucagon secretion at basal glucose and for GIGS. Additionally, we hypothesize EphA4 receptor signaling is permissive for additional paracrine inhibitory signals (insulin and/or somatostatin).