GABA对胰岛β细胞及糖代谢调节作用的机制研究

Loss of functional β-cells is the major cause of diabetes. Gamma amino-butyric acid (GABA) is a major neurotransmitter in the CNS, and it is also produced by fat, liver and pancreatic β-cells in large quantities. GABA was proved to have the function of promoting β-cell proliferation and regulating immunity. The β3 subunit was the most predominantly expressed GABAAR subunit in rodent and human β-cells. Our recent studies suggested a critical role for β3 subunit of GABAAR (GABAARβ3) in maintaining β-cell homeostasis. This is supported by its increased expression during β-cell regeneration, and its markedly decreased expression in T2D patients. Surprisingly, we found that β3 was translocated to the nucleus upon GABA activation, suggesting its critical role in mediating GABA’s effects in regulating gene transcription in the β-cells. We hypothesize that defects in GABAARβ3 signaling may cause β-cell dysfunction and hence impairing glucose homeostasis. The Overall objective of this project is to determine the role of GABA-GABAARβ3 in regulating the β-cells, to investigate the biological relevance of GABA-induced nuclear effects in the β-cells and the underlying mechanism. Notably, GABA does not cross blood brain barrier and can be administered orally in humans in large quantities. Our proposed work in identifying novel mechanisms of action will certainly advance the field of GABA biology. Furthermore, these studies are highly likely to lead to the development of novel therapies for Obesity-related diabetes and other metabolic disorders.

β细胞大量缺失是造成糖尿病的主要原因。γ-氨基丁酸(GABA)是神经递质，外周器官包括脂肪、肝脏和胰岛β细胞也大量表达和分泌。前期研究发现GABA有促进β细胞增殖和调节免疫的功能。GABAAR受体β3亚基（β3）是人和鼠胰岛表达最高的受体亚型。我们发现β3在β细胞再生过程中显著上调。相反，2型糖尿病患者胰岛中β3表达显著降低。我们还发现，GABA处理可诱导β3在β细胞核转位，提示GABA通过β3实施对基因转录的调控。这些结果表明β3在GABA调节β细胞功能中起着关键作用。我们假设β3的缺损是造成β细胞功能丧失和糖尿病发生的主要原因。本课题将探究GABA-GABAARβ3对β细胞功能的调节机理，阐明β细胞中GABAARβ3发生核转位的生物学意义。口服GABA不能透过血脑屏障，具有良好的安全性。本研究将揭示GABA对β细胞和机体糖代谢调节的分子靶点，推动其成为糖尿病治疗领域的新药物。

β细胞大量缺失是造成糖尿病的主要原因。γ-氨基丁酸(GABA)是神经递质，外周器官包括脂肪、肝脏和胰岛β细胞也大量表达和分泌。前期研究发现GABA有促进β细胞增殖和调节免疫的功能。GABAAR受体β3亚基（β3）是人和鼠胰岛表达最高的受体亚型。我们发现β3在β细胞再生过程中显著上调。相反，2型糖尿病患者胰岛中β3表达显著降低。我们还发现，GABA处理可诱导β3在β细胞核转位，提示GABA通过β3实施对基因转录的调控。这些结果表明β3在GABA调节β细胞功能中起着关键作用。我们体外构建了在胰岛β细胞中特异性敲除GABAAR受体β3亚基和GABABR受体B1亚基的小鼠，利用高脂喂养及胰腺大部分切除手术，我们发现受体敲除后，小鼠的葡萄糖耐量，β细胞增殖及胰岛素分泌显著受损，给予GABA不能改善上述损伤，证明GABA及GABA受体后信号在调控小鼠糖代谢中发挥重要作用。我们还发现GABA对胰岛β细胞的调控依赖于GLP-1受体，在胰岛内，β细胞分泌GABA，α细胞分泌GLP-1，基于转化应用目的，我们研究了GABA与GLP-1类药物联合使用对人胰岛及糖尿病小鼠的作用和机制，发现联合使用比单药使用产生更优越的治疗效果，这为GABA临床应用奠定理论基础。口服GABA不能透过血脑屏障，具有良好的安全性。本研究将揭示GABA对β细胞和机体糖代谢调节的分子靶点，推动其成为糖尿病治疗领域的新药物。