烟酸及其G-蛋白偶联受体PUMA-G通路在脂肪代谢及血脂调控中具有重要作用，本研究组发现PUMA-G在小鼠胰岛Beta细胞高表达并影响胰岛素分泌。我们推测PUMA-G通路可能通过Beta-抑制蛋白抑制NF-kB在胰岛Beta细胞中的核转位，从而抑制胰岛Beta细胞的凋亡。因此，本研究拟用转座子技术建立稳定表达PUMA-G和NF-kB报告基因的胰岛Beta细胞株NIT-1，观察该信号通路在炎症因子、毒素、高糖及高脂刺激下对NIT-1细胞的保护作用，及其调节机制：即对Beta-抑制蛋白的激活和对NF-kB及其下游炎症因子的抑制作用等；用基因沉默等技术在体外进一步验证该信号通路对NF-kB的抑制作用和对胰岛Beta细胞的保护作用；检测PUMA-G在2型糖尿病db/db模型小鼠胰岛中的表达情况，探索烟酸给药对db/db小鼠胰岛的影响，为2型糖尿病的防治提供新的途经。

The signal transduction pathway through the G-protein-coupled nicotinic acid receptor PUMA-G plays an important role in lipid metabolism and the regulation of dyslipidemia. The results from our study for the first time found the expression of PUMA-G in murine islet beta cells and its role in the regulation of insulin secretion. In this proposal, we hypothesize that PUMA-G pathway could inhibit the nuclear translocation of NF-κB via activation of beta-arrestin, and thus protect islet beta cell from apoptosis which is an important cause for the development of type 2 diabetes. Therefore, this research project will first generate an islet beta cell line NIT-1 which stably expresses a transgenic PUMA-G construct and the NF-κB reporter by using the transposon techqique, measure the activation of beta-arrestin and inhibition of NF-κB activation and its downstream target genes, and investigate the protective effect of PUMA-G pathway against inflammatory cytokines, cytotoxins, and glucolipocytoxicity. Secendly, we will use RNAi technique to further investigate in vitro the NF-kB inhibitory and Beta-cell protective effects of PUMA-G pathway. Lastly, PUMA-G expression will be determined in the type 2 diabetic db/db model mice, and nicotinic acid will be administered into db/db mice for protection of islet beta-cells. This study may provide a new approach to the prevention and/or treatment of type 2 diabetes.