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

描述（由申请人提供）：朗格汉斯胰岛通过葡萄糖调节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β细胞上。然而，最近胰高血糖素(由？-细胞)已被证明对糖尿病的病理生理有显著贡献。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。因此，理解潜在的机制？-细胞功能和胰高血糖素分泌是糖尿病管理新治疗策略发展的重要途径。结合目前的治疗方法，基于新？-细胞靶标将通过解决高血糖的多种原因，使1型和2型糖尿病患者受益。尽管胰高血糖素的重要生理作用，调节其分泌的机制仍然知之甚少。活塞实验室最近公布的数据表明，GIGS并不是宇宙的内在特征。-细胞，抑制胰高血糖素分泌是独立于Ca2+内流。我们的数据显示，与糖尿病患者相似，纯人群的分类？-细胞在低糖时胰高血糖素分泌增加，葡萄糖分泌抑制（GIGS）丧失。此外，细胞内[Ca2+]升高，以响应葡萄糖的增加，抑制胰高血糖素的分泌。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来解释，因为分选的细胞不再对旁分泌抑制剂（胰岛素和生长抑素）敏感。

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).