Formation of the integrated insulin secretion system and its failure

1) β细胞分化过程中胰岛素分泌功能是如何获得的？(1)我们已经通过细胞谱系追踪直接证明了胰腺腺泡细胞可以在体外转分化为胰岛素分泌细胞。钙粘蛋白介导的细胞-细胞粘附的破坏和重塑对转分化很重要，而pi3激酶的激活是这些过程所必需的。(2)我们发现Kir6.2G132S转基因小鼠胰腺β-细胞可以自发再生，胰岛内标记的细胞可能代表β-细胞的祖细胞。(3)我们发现了一种新的转录因子，Mgx-1 (Isx)，它在肠道中特异性表达。肠源性细胞表达Pdx1和胰岛素需要Isx失活2.2)胰岛素分泌的信号成分是如何在空间和时间上整合在β细胞中的？(1)葡萄糖诱导的第1期和第2期融合事件主要涉及新招募的颗粒，更多的颗粒在没有对接的情况下立即融合到质膜上（不安的新来者）。(2) cAMP信号的激活明显增强了葡萄糖诱导的融合事件的两个阶段。所有负责这种增强作用的颗粒都是不安的新来者。我们发现Epac2/Rap1信号在cAMP增强胰岛素颗粒胞外分泌中是必不可少的，主要是在cAMP增强胞外分泌的第一阶段，通过增加不安的新来者的数量。(3)我们提出含有epac2的cAMP分室与含有pka的分室不同。3) b细胞如何与其他器官（如大脑和胃肠道）相互作用？(1)虽然K_<ATP>通道缺陷小鼠缺乏葡萄糖诱导的胰岛素分泌，但我们发现胃肠道激素肠促胰岛素（如GLP-1和GIP）通过食物摄入释放，并赋予Kir6.2^<-/-> β-细胞葡萄糖反应性。(2)通过研究分泌相关分子Noc2缺失小鼠，我们发现Noc2对G_<i/o>介导的胰岛素分泌抑制有抑制作用。4)系统缺陷引起的病理生理(1)我们产生了转录因子Otx3 （Dmbxl）缺乏的小鼠，我们之前在胰岛素瘤细胞系中发现了这种转录因子。通过与肥胖和糖尿病遗传小鼠模型agouti yellow （Ay）小鼠杂交，我们发现Dmbx1对Ay小鼠的肥胖和糖尿病的发生至关重要。(2) 1型糖尿病在非kdp遗传背景下重构，大鼠MHC-RT1u和Cblb突变为2个主要易感基因。通过对日本2型糖尿病患者胰腺β细胞功能相关变异的关联研究，发现了SUR1（ABCC8）变异的显著相关性。少

1) How is insulin secretory function acquired during β-cell differentiation? (1) We have demonstrated directly by cell lineage tracing that pancreatic acinar cells can transdifferentiate into insulin-secreting cells in vitro. Destruction and remodeling of cadherin-mediated cell-cell adhesion was found to be important for the transdifferentiation, and activation of PI3-kinase was required for these processes. (2) We have shown that pancreatic β-cells of Kir6.2G132S transgenic mice were spontaneously regenerated, and that intraislet DBA-labeled cells may represent progenitors for the β-cells. (3) We have identified a novel transcriptional factor, Mgx-1 (Isx), which is expressed specifically in gut. Isx inactivation is required for the gut-derived cell to express Pdx1 and Insulin2.2) How are the signaling components in insulin secretion spatially and temporally integrated in β-cells? (1) Both 1st and 2nd phases of glucose-induced fusion event involved mostly granules that are newly recrui … More ted and immediately fused to the plasma membrane without docking (restless newcomer). (2) Activation of cAMP signaling clearly potentiated both phases of glucose-induced fusion events. All granules responsible for this potentiation were restless newcomer. We have found that Epac2/Rap1 signaling is essential in the potentiation of insulin granule exocytosis by cAMP, primarily in the first phase of cAMP-potentiated exocytosis, by increasing the number of restless newcomer. (3) We have proposed that Epac2-containing cAMP compartment is distinct from PKA-containing compartment.3) How do B-cells interact functionally with other organs such as the brain and gastrointestine? (1) Although K_<ATP> channel-deficient mice lack glucose-induced insulin secretion, we found that gastrointestinal hormone incretin (such as GLP-1 and GIP) is released by food ingestion and endows Kir6.2^<-/-> β-cells with glucose responsiveness. (2) By studying the mice deficient in an exocytosis-related molecule Noc2, we found that Noc2 elicits an inhibitory effect on G_<i/o> mediated suppression of insulin secretion.4) Pathophysiology due to defects in the system (1) We have generated mice deficient in transcription factor Otx3 (Dmbxl), which we previously identified in insulinoma cell lines. By cross-breeding with agouti yellow (Ay) mice, a hereditary mouse model of obesity and diabetes, we found that Dmbx1 is essential for developing obesity and diabetes of Ay mice. (2) Type 1 diabetes was reconstituted on a non-KDP genetic background with the two major susceptibility genes, MHC-RT1u and Cblb mutation, in the rat. By association study of variants involved in pancreatic β-cell function in Japanese type 2 diabetes, a significant association of a variant in SUR1(ABCC8) was found. Less