Formation of the integrated insulin secretion system and its failure

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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