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被认为是重要的转分化，和PI 3-激酶的激活需要这些过程。(2)我们已经证明Kir6.2G132S转基因小鼠的胰腺β细胞自发再生，并且胰岛内DBA标记的细胞可能代表β细胞的祖细胞。(3)我们已经确定了一个新的转录因子，Mgx-1（Isx），这是在肠道特异性表达。Isx失活是肠源性细胞表达Pdx 1和胰岛素所必需的。2）胰岛素分泌中的信号成分如何在β细胞中时空整合？(1)葡萄糖诱导的融合事件的第一和第二阶段主要涉及新募集的颗粒 ...更多信息 ted并立即融合到质膜上而没有对接（不安分的新来者）。(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分的新来者。我们已经发现Epac 2/Rap 1信号传导在cAMP增强胰岛素颗粒胞吐作用中是必不可少的，主要是在cAMP增强的胞吐作用的第一阶段，通过增加不安分的新来者的数量。(3)我们提出Epac 2的cAMP区室不同于PKA区室。3）B细胞如何与其他器官如脑和胃肠功能性相互作用？(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）通过食物摄取而释放，并赋予Kir6.2^&lt;-/-&gt; β细胞葡萄糖反应性。(2)通过研究胞吐相关分子Noc 2缺陷的小鼠，我们发现Noc 2对G_&lt;i/o&gt;介导的胰岛素分泌抑制具有抑制作用。4）由于系统缺陷导致的病理生理（1）我们已经产生了转录因子Otx 3（Dmbxl）缺陷的小鼠，该转录因子Otx 3（Dmbxl）是我们先前在胰岛素瘤细胞系中发现的。通过与遗传性肥胖和糖尿病小鼠模型Agglutinyellow（Ay）小鼠杂交，我们发现Dmbx 1是Ay小鼠发生肥胖和糖尿病所必需的。(2)1型糖尿病是在非KDP遗传背景下重建的，在大鼠中具有两个主要易感基因MHC-RT 1u和Cblb突变。通过对日本2型糖尿病患者胰腺β细胞功能相关变异体的关联研究，发现SUR 1（ABCC 8）变异体的显著关联。

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