GABA-B Receptors as Regulators of Islet Biology

描述(由申请人提供)： 郎格汉斯胰岛不能提供足够的胰岛素以维持血糖在生理范围内，这是1型(胰岛素依赖型)和2型(胰岛素非依赖型)糖尿病的基础。尽管自从胰岛素和胰岛素受体的发现以来，糖尿病的治疗已经取得了长足的进步，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于分泌胰岛素的β细胞数量的减少而诱发和/或加重的，开发促进β细胞增殖的方法可能会导致为全球约2亿糖尿病患者开发新的治疗方法。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物(如葡萄糖、氨基酸)，这表明从β细胞释放的因子可能作为胰岛功能的反馈调节因子。我们的初步研究表明，β-氨基丁酸(GAGA)就是这样一个因素，长期以来人们知道它是由β细胞合成、储存和分泌的。我们证明GABA对胰岛的作用是通过代谢性GABAB受体介导的。与GABA作为一种快速抑制性神经递质的名声不同，它对胰岛的增殖作用相当缓慢(需要数小时)；此外，GABA似乎与胰岛素协同工作来刺激胰岛增殖，因为它的作用被胰岛素受体信号传递的抑制剂所阻断。这类研究预测，从长远来看，GABA可以增强胰腺的胰岛素释放能力。我们进一步证明，自相矛盾的是，GABA也对胰岛起快速作用(几秒到几分钟)，抑制胰岛β细胞的胰岛素分泌。因此，我们认为GABA是胰岛功能的内源性双相调节因子。这种双重调节的一个可能的生理基础是，GABA可能在短期接触葡萄糖时起到限制胰岛增殖的作用，而在葡萄糖频繁或持续升高的情况下则起到促进作用。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它们两种作用下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机制是利用它们开发新的糖尿病治疗策略的先决条件。

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.