PKA activation enhances insulin secretion to improve glucose homeostacis in aging

描述（由申请人提供）：本提案的总体目标是更好地了解增加的潜力？-细胞PKA活性增强？-老年人的细胞功能和改善葡萄糖稳态。在老年人中，？-细胞功能往往突出，典型表现为胰岛素分泌障碍。最近，新的治疗药物旨在增强？？通过增加细胞内cAMP水平来分泌胰岛素。蛋白激酶A （PKA）是由？-细胞内cAMP，并在-细胞中增强葡萄糖刺激的胰岛素分泌中起基本作用。的独家角色？-细胞PKA信号传导及其对生理葡萄糖稳态的影响尚不清楚。我们创造了一种新的转基因小鼠模型，在？-胰岛素分泌增加三倍并改善葡萄糖清除的细胞。拟议的研究将：b[1]定义增加的可持续性和有效性？-细胞PKA活性改善？-细胞功能、葡萄糖控制和整个衰老过程中的胰岛素敏感性，以及[2]决定了在老年人和T2DM患者中观察到的糖耐受性增高的环境中，更严格的葡萄糖控制是否能维持更好的胰岛素敏感性。将要测试的假设是：增加？-细胞PKA活性将[1]在整个衰老过程中增强第一阶段胰岛素分泌，改善葡萄糖清除，并在老年人中保持功效，这将导致[1]随着年龄的增长而改善外周敏感性。第二组将被测试的假设是：[1]诱导PKA活性将延迟和/或阻止向高脂肪饮食诱导的胰岛素抵抗的进展，这是由于改善葡萄糖稳态和更好地维持？？细胞质量;b[2]认为PKA的激活，在胰岛素抵抗建立后，会导致葡萄糖耐量的恢复。实验技术使用生理学研究，包括喂养和空腹葡萄糖和胰岛素测量，腹腔葡萄糖耐量试验，高血糖和高胰岛素-正糖钳研究，免疫组织化学。高脂肪饮食会加剧胰岛素抵抗。这项工作的结果将提供关于？？-细胞PKA信号传导及其作为改善老年人b细胞功能的治疗潜力。

DESCRIPTION (provided by applicant): The overall goal of this proposal is to better understand the potential for increasing ?-cell PKA activity to enhance ?-cell function and improve glucose homeostasis in an aged population. In the elderly, a general decline in ?-cell function is often prominent and is typically manifested in an impairment in insulin secretion. Recently, new therapeutic agents aimed at enhancing??-cell insulin secretion by increasing intracellular cAMP levels have emerged. Protein kinase A (PKA) is one of two pathways that is activated by increases in ?-cell intracellular cAMP, and has a fundamental role in potentiating glucose stimulated insulin secretion in the ?-cell. The exclusive role of ?-cell PKA signaling and its effects on physiological glucose homeostasis remains unknown. We have created a novel transgenic mouse model harboring a constitutively active PKA in ?-cells that displays a three-fold enhancement in insulin secretion and improved glucose clearance. The proposed research will: [1] define the sustainability and efficacy of increased ?-cell PKA activity for improving ?-cell function, glucose control, and insulin sensitivity throughout aging, and [2] determine whether tighter glucose control leads to the maintenance of better insulin sensitivity even in an environment when glucose intolerance is heighted as observed in aged individuals and individuals with T2DM. The hypotheses that will be tested are: increased ?-cell PKA activity will [1] enhance first phase insulin secretion and improve glucose clearance throughout aging and maintain efficacy in aged individuals, and this will lead to [2] improved peripheral sensitivity with age. The second set of hypotheses that will be tested are: [1] induction of PKA activity will delay and/or prevent the progression towards high fat diet induced insulin resistance due to improved glucose homeostasis and better maintenance of??-cell mass; and [2] that PKA activation, after the establishment of insulin resistance, will lead to a recovery of glucose tolerance. Experimental techniques use physiological studies including fed and fasting glucose and insulin measurements, intraperitoneal glucose tolerance test, hyperglycemic and hyperinsulinemic-euglycemic clamp studies, and immunohistochemistry. A high-fat diet will be used to exacerbate insulin resistance. The results of this work will provide fundamental knowledge of??-cell PKA signaling and its potential as a therapeutic to improve b-cell function in the elderly. PUBLIC HEALTH RELEVANCE: Older individuals are predisposed to develop diabetes due to a decrease in the capacity of their pancreatic ?- cells to secrete sufficient insulin. The proposed studies will determine whether increased PKA signaling in ?- cells will improve ?-cell function and insulin secretory capacity in an aged population.