PKA activation enhances insulin secretion to improve glucose homeostacis in aging

描述(由申请人提供)：这项提案的总体目标是更好地了解在老年人口中增加？细胞PKA活性以增强？细胞功能和改善葡萄糖稳态的潜力。在老年人中，β-细胞功能的普遍下降通常是突出的，典型的表现为胰岛素分泌的障碍。最近，旨在通过提高细胞内cAMP水平来促进细胞胰岛素分泌的新的治疗药物已经出现。蛋白激酶A(PKA)是细胞内cAMP升高激活的两条途径之一，在促进葡萄糖刺激的胰岛素分泌中起着基础性作用。β-细胞PKA信号的独有作用及其对生理性血糖稳态的影响尚不清楚。我们已经建立了一种新的转基因小鼠模型，在？-细胞中含有结构性活性的PKA，表现出胰岛素分泌增加三倍，葡萄糖清除改善。这项拟议的研究将：[1]确定细胞内PKA活性增加在整个衰老过程中改善细胞功能、血糖控制和胰岛素敏感性的可持续性和有效性，以及[2]确定即使在老年人和2型糖尿病患者中观察到的葡萄糖耐量增加的情况下，更严格的血糖控制是否能导致维持更好的胰岛素敏感性。将被检验的假设是：？-细胞PKA活性增加将[1]增强第一时相胰岛素的分泌，并在整个衰老过程中改善葡萄糖清除，并保持对老年人的疗效，这将导致[2]随年龄增长的外周敏感性提高。将被检验的第二组假设是：[1]PKA活性的诱导将延缓和/或阻止高脂饮食诱导的胰岛素抵抗的进展，这是由于改善了葡萄糖稳态和更好地维持了细胞质量；以及[2]在胰岛素抵抗建立后，PKA的激活将导致葡萄糖耐量的恢复。实验技术使用生理学研究，包括喂养和空腹血糖和胰岛素的测量，腹膜糖耐量试验，高血糖和高胰岛素-正常血糖钳夹研究，以及免疫组织化学。高脂肪饮食将被用来加剧胰岛素抵抗。这项工作的结果将提供？细胞PKA信号的基础知识，以及它作为治疗手段改善老年人b细胞功能的潜力。 公共卫生相关性：老年人易患糖尿病，因为他们的胰腺细胞分泌足够胰岛素的能力下降。这项拟议的研究将确定，在老年人口中，细胞内PKA信号的增加是否会改善细胞功能和胰岛素分泌能力。

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.