GABA-B Receptors as Regulators of Islet Biology

GABA-B 受体作为胰岛生物学的调节剂

• 批准号: 6574939
• 负责人: Kathleen Dunlap
• 金额: $ 40.5万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6574939
• 关键词: G protein; GABA receptor; NOD mouse; biological signal transduction; cell line; cell proliferation; diabetes mellitus; electrophysiology; gamma aminobutyrate; gene targeting; genetically modified animals; insulin; insulin receptor; laboratory mouse; molecular cloning; neuropharmacology; neurotransmitter agonist; neurotransmitter antagonist; neurotransmitter transport; pancreatic islet function; polymerase chain reaction; protein isoforms; protein structure function; receptor coupling; receptor expression; synaptic vesicles

DESCRIPTION (provided by applicant): The failure of pancreatic islets of Langerhans to supply insulin in sufficient quantities to maintain blood glucose within physiological limits underlies Type 1 (insulin-dependent) and Type 2 (insulin-independent) diabetes mellitus. Although great strides have been made in the treatment of diabetes since the discoveries of insulin and the insulin receptor, the clinical management of these disorders remains a challenge even under the best of circumstances. As most forms of diabetes are precipitated and/or exacerbated by a reduction in numbers of insulin-secreting beta cells, developing methods that promote beta cell proliferation may lead to the development of new therapies for the estimated 200 million individuals world-wide who live with diabetes. A number of islet growth factors have been reported; many of these are known islet secretagogues as well (e.g., glucose, amino acids), suggesting the possibility that factors released from beta cells act as feedback regulators of islet function. Our preliminary studies suggest that ?-aminobutyric acid (GAGA), long known to be synthesized, stored, and secreted by beta cells, is such a factor. We demonstrate that GABA's effects on islets are mediated through metabotropic GABAB receptors. In contrast to GABA's reputation as a fast inhibitory neurotransmitter, its proliferative action on islets is rather slow (requiring hours); further, GABA appears to work in concert with insulin to stimulate islet proliferation, as its effects are blocked by inhibitors of insulin receptor signaling. Such studies predict that, in the long term, GABA enhances the insulin-releasing capacity of the pancreas. We further demonstrate that, paradoxically, GABA also acts rapidly (seconds to minutes) on islets to inhibit insulin secretion from beta cells. Thus, we suggest the hypothesis that GABA is an endogenous biphasic regulator of islet function. A putative physiological rationale for such dual regulation is that GABA may serve to limit islet proliferation during short exposure to glucose and to encourage it under conditions of frequent or persistent elevations in glucose. Experiments outlined in three Aims will explore this novel hypothesis by defining which GABAB receptor isoforms are expressed in islets and characterizing the signaling pathways underlying their two actions. Understanding the natural biological mechanisms by which islets are regulated is prerequisite to harnessing them for the development of new treatment strategies for diabetes.

描述（由申请人提供）： 胰岛不能提供足够量的胰岛素以将血糖维持在生理限度内是1型（胰岛素依赖性）和2型（胰岛素非依赖性）糖尿病的基础。尽管自从发现胰岛素和胰岛素受体以来，糖尿病的治疗已经取得了很大的进步，但即使在最好的情况下，这些疾病的临床管理仍然是一个挑战。由于大多数形式的糖尿病是由胰岛素分泌β细胞数量的减少而促成和/或加剧的，因此开发促进β细胞增殖的方法可能导致为全世界估计2亿患有糖尿病的个体开发新的疗法。已经报道了许多胰岛生长因子;其中许多也是已知的胰岛促分泌素（例如，葡萄糖，氨基酸），这表明β细胞释放的因子可能作为胰岛功能的反馈调节剂。我们的初步研究表明？-氨基丁酸（GAGA），长期以来已知由β细胞合成，储存和分泌，就是这样一种因子。我们证明GABA对胰岛的作用是通过代谢型GABAB受体介导的。与GABA作为快速抑制性神经递质的声誉相反，其对胰岛的增殖作用相当缓慢（需要数小时）;此外，GABA似乎与胰岛素协同作用以刺激胰岛增殖，因为其作用被胰岛素受体信号传导的抑制剂阻断。这些研究预测，从长远来看，GABA增强了胰腺的胰岛素释放能力。我们进一步证明，自相矛盾的是，GABA也迅速（秒至分钟）作用于胰岛，抑制β细胞分泌胰岛素。因此，我们提出的假设，GABA是一个内源性的双相调节胰岛功能。这种双重调节的一个假定的生理学原理是，GABA可能有助于在短期暴露于葡萄糖期间限制胰岛增殖，并在葡萄糖频繁或持续升高的条件下促进胰岛增殖。在三个目标中概述的实验将通过定义哪些GABAB受体亚型在胰岛中表达并表征其两种作用背后的信号通路来探索这一新的假设。了解调节胰岛的自然生物学机制是利用它们开发糖尿病新治疗策略的先决条件。