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  • American Diabetes Association  (3)
  • FAUZI, MUHAMMAD  (3)
  • 1
    Online Resource
    Online Resource
    2150-P: Single Cell RNA-Sequencing Dissects Proliferation of Pancreatic Beta Cells
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Background: The decreasing pancreatic beta cell mass in patients with type 2 diabetes mellitus is a critical problem and increasing the beta cell mass would be one of the strategies for its treatment. However, little is known about the mechanism of beta cell proliferation in adult. In addition, since pancreatic beta cells are heterogeneous and proliferating beta cells are in a small population, the analysis using bulk pancreatic islets has limitations. To clarify the further molecular mechanism of beta cell proliferation, we addressed the gene regulation of proliferating beta cells at single cell level. Methods: Young (8 weeks) and old (1 year) C57BL/6 mice were performed partial pancreatectomy (PPTx), and conducted 3 analyses; 1) immunohistochemistry for proliferating beta cells with BrdU staining, 2) conventional bulk RNA-sequencing (bulk RNA-seq) of isolated pancreatic islets from young or old mice with PPTx or without PPTx (control) to examine the impact of aging and stimulation by resection, 3) single cell RNA-seq to highlight gene expression profiles of proliferating beta cells. Results: In young mice, the proliferation of beta cells was highly induced by PPTx. On the contrary, the proliferation in old PPTx mice was much less than young PPTx. The bulk RNA-seq followed by gene ontology analysis demonstrated that genes related to DNA replication and cell cycle regulation were specifically up-regulated in young PPTx. The scRNA-seq could sort beta cells with Ins1 and Ins2 expression from the other endocrine cells like alpha, delta and PP cells, and identified the cells with high expressions of Pcna and Ccnb1 in the beta cells. By the motif analysis, we further identified candidate transcription factors that activate genes specific for the proliferating cells. Conclusion: We found genes specific for proliferating beta cells and identified candidate regulators to activate the proliferation of beta cells. Disclosure H. Tatsuoka: None. D. Yabe: Advisory Panel; Self; Abbott. Research Support; Self; Astellas Pharma Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. S. Sakamoto: None. A. Watanabe: None. R. Usui: None. S. Tokumoto: None. A. Botagarova: None. D. Ootani: None. H. Goto: None. M. Fauzi: None. M. Ogura: Research Support; Self; Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kyowa Hakko Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited. N. Inagaki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Japan Tobacco Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-2150-P
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
    detail.hit.zdb_id: 1501252-9
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  • 2
    Online Resource
    Online Resource
    110-OR: Generation of a Novel Mouse Model to Study ß-Cell Proliferation
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Background and Aims: The induction of β-cell proliferation could relieve the progression of diabetes. Many factors have been claimed to be potential β-cell mitogens, but their impacts on β-cell replication have been poorly reproduced and validated due to unstandardized β-cell proliferation assay and lack of alternative methods. In this study, we aimed to generate a novel mouse model that enables more accurate quantification of β-cell proliferation by using a cell cycle monitoring biosensor (Fucci2a). imaging of the pancreas from this mouse model. Next, 3D images of optically cleared pancreas samples were obtained for the analysis of replicating β-cell number and morphometric data per islet following the mitogenic intervention of insulin receptor antagonist (S961). Moreover, in order to examine whether glucose mediates S961-induced β-cell proliferation, we compared the β-cell proliferation rate between the hyperglycemic S961 monotherapy group and the normoglycemic S961 group with coadministration of SGLT2i (S961 + SGLT2i group). vivo Materials and Methods: We established a novel mouse line in which the Fucci2a reporter is specifically expressed in β-cells (RIP-Cre; Fucci2aR). We performed real-time 3D in Results: We succeeded in real-time visualization of cell cycle progression of β-cells. A strong correlation between replicating β-cell number per islet and islet size was found in both S961 (r = 0.87, p & lt;0.01) and vehicle groups (r = 0.77, p & lt;0.01). While hyperglycemia induced by S961 treatment was normalized in the S961 + SGLT2i group, there was no significant difference in β-cell proliferation rate between the S961 monotherapy and S961 + SGLT2i groups. Conclusion: Here we present the first in vivo 4D images of cell cycle phase transition of β-cells. The strong correlation between islet size and its proliferative capacity suggests stochastic replication of β-cells. S961-induced β-cell replication was not mediated by glucose. Thus, this novel mouse could be a powerful tool for β-cell proliferation assessment. Disclosure S. Tokumoto: None. D. Yabe: Advisory Panel; Self; Abbott. Research Support; Self; Astellas Pharma Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. H. Tatsuoka: None. R. Usui: None. M. Fauzi: None. H. Goto: None. M. Ogura: Research Support; Self; Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kyowa Hakko Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited. N. Inagaki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Japan Tobacco Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-110-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
    detail.hit.zdb_id: 1501252-9
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  • 3
    Online Resource
    Online Resource
    41-OR: Store-Operated Ca2+ Entry Activated by STIM1 Plays an Essential Role in GPR40-Mediated GIIS Potentiation
    American Diabetes Association ; 2019
    In:  Diabetes Vol. 68, No. Supplement_1 ( 2019-06-01)
    Details
    In: Diabetes, American Diabetes Association, Vol. 68, No. Supplement_1 ( 2019-06-01)
    Abstract: Background: Store-operated Ca2+ entry (SOCE) is activated by endoplasmic reticulum (ER) Ca2+ sensor STIM1 which senses depletion of Ca2+ from the ER, and induces extracellular Ca2+ influx through Orai1 to the cytosol to maintain intracellular Ca2+ homeostasis in various cell types, however the role of SOCE in pancreatic β-cells remains largely unknown. GPR40 plays an important role in potentiation of glucose-induced insulin secretion (GIIS) by long-chain fatty acids and its activation enhances Ca2+-release from ER by activating inositol 1,4,5-triphosphate (IP3) receptor. Therefore, we hypothesized that SOCE contributed to GPR40-mediated GIIS potentiation. To test the hypothesis, we examined the role of SOCE modulator, STIM1 in MIN6 cells and β-cell specific STIM1-deficient mice (βSTIM1 cKO). Methods: Fasiglifam(fas) was used for GPR40 agonist. STIM1 or Orai1 knockdowned (KD) MIN6 cells were analyzed for insulin secretion or intracellular Ca2+-dynamics. MIN6 cells were also transfected with pEX-SP-YFP-STIM1(23-685) and Orai1-CFP to analyze intracellular trafficking of STIM1 in response to fas. Insulin secretion from βSTIM1 cKO islets and OGTT was also analyzed to reveal physiological role of STIM1. Results: STIM1 or Orai1 KD MIN6 cells and islets from βSTIM1 cKO similarly abolished fas-mediated potentiation of GIIS and fas-induced elevation of intracellular Ca2+ levels, while there was little effect on GIIS itself. STIM1-YFP was rapidly translocated from the ER to the plasma membrane and merged with Orai1-CFP in response to fas which was cancelled by pretreatment of IP3 receptor antagonist, xestospongin C. In OGTT, blood glucose levels were similar in control mice and βSTIM1 cKO without fas administration, however fas-mediated glucose lowering and insulin increasing effect were significantly lower compared with control. Conclusion: GPR40 signal activates STIM1 and SOCE activated by STIM1 is essential for GPR40-mediated potentiation of GIIS. Disclosure R. Usui: None. D. Yabe: Advisory Panel; Self; Abbott. Research Support; Self; Astellas Pharma Inc. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Eli Lilly and Company, Merck Sharp & Dohme Corp., Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi K.K., Taisho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Company Limited. M. Fauzi: None. A. Botagarova: None. H. Goto: None. S. Tokumoto: None. H. Tatsuoka: None. Y. Tahara: None. S. Kobayashi: None. T. Manabe: None. Y. Baba: None. T. Kurosaki: None. M. Ogura: Research Support; Self; Takeda Pharmaceutical Company Limited. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Daiichi Sankyo Company, Limited, Eli Lilly and Company, Kyowa Hakko Kirin Co., Ltd., Merck & Co., Inc., Mitsubishi Tanabe Pharma Corporation, Novo Nordisk Inc., Ono Pharmaceutical Co., Ltd., Sanofi, Takeda Pharmaceutical Company Limited. K. Nagashima: None. N. Inagaki: Research Support; Self; Astellas Pharma Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo Company, Limited, Japan Tobacco Inc., Kyowa Hakko Kirin Co., Ltd., Merck Sharp & Dohme Corp., Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Ono Pharmaceutical Co., Ltd., Sanofi, Sumitomo Dainippon Pharma Co., Ltd., Takeda Pharmaceutical Company Limited. Funding Japan Society for the Promotion of Science; Japan Association for Diabetes Education and Care
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db19-41-OR
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2019
    detail.hit.zdb_id: 1501252-9
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