title: Nardilysin Is Required for Maintaining Pancreatic β-Cell Function.
abstract: Type 2 diabetes (T2D) is associated with pancreatic β-cell dysfunction, manifested by reduced glucose-stimulated insulin secretion (GSIS). Several transcription factors enriched in β-cells, such as MafA, control β-cell function by organizing genes involved in GSIS. Here we demonstrate that nardilysin (N-arginine dibasic convertase; Nrd1 and NRDc) critically regulates β-cell function through MafA. Nrd1(-/-) mice showed glucose intolerance and severely decreased GSIS. Islets isolated from Nrd1(-/-) mice exhibited reduced insulin content and impaired GSIS in vitro. Moreover, β-cell-specific NRDc-deficient (Nrd1(delβ)) mice showed a diabetic phenotype with markedly reduced GSIS. MafA was specifically downregulated in islets from Nrd1(delβ) mice, whereas overexpression of NRDc upregulated MafA and insulin expression in INS832/13 cells. Chromatin immunoprecipitation assay revealed that NRDc is associated with Islet-1 in the enhancer region of MafA, where NRDc controls the recruitment of Islet-1 and MafA transcription. Our findings demonstrate that NRDc controls β-cell function via regulation of the Islet-1-MafA pathway.
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Nishi
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sato
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Mikiko
authors.initials: M
authors.lastname: Ohno
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan Division of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Chuo-ku, Kobe, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hiraoka
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Saijo
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Jiro
authors.initials: J
authors.lastname: Sakamoto
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Po-Min
authors.initials: PM
authors.lastname: Chen
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Morita
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Matsuda
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Kanako
authors.initials: K
authors.lastname: Iwasaki
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Kazu
authors.initials: K
authors.lastname: Sugizaki
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Harada
authors.affiliation: Genetic Engineering Team, RIKEN Center for Life Science Technologies, Chuo-ku, Kobe, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Mukumoto
authors.affiliation: Genetic Engineering Team, RIKEN Center for Life Science Technologies, Chuo-ku, Kobe, Japan Animal Resource Development Unit, RIKEN Center for Life Science Technologies, Chuo-ku, Kobe, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kiyonari
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Furuyama
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan Department of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Kawaguchi
authors.affiliation: Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Uemoto
authors.affiliation: Kobe City Medical Center General Hospital, Chuo-ku, Kobe, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kita
authors.affiliation: Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Nobuya
authors.initials: N
authors.lastname: Inagaki
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kimura
authors.affiliation: Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan nishi@kuhp.kyoto-u.ac.jp.
authors.forename: Eiichiro
authors.initials: E
authors.lastname: Nishi
mesh_terms: D000818:Animals; D047369:Chromatin Immunoprecipitation; D005947:Glucose / Q000494:pharmacology; D018149:Glucose Intolerance / Q000235:genetics / Q000503:physiopathology; D007328:Insulin / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051473:Maf Transcription Factors, Large / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding
chemical_list: D007328:Insulin; D051473:Maf Transcription Factors, Large; D008666:Metalloendopeptidases; C087976:nardilysin; D005947:Glucose