title: Clock Gene Dysregulation Induced by Chronic ER Stress Disrupts β-cell Function.
abstract: In Wfs1-/-Ay/a islets, in association with endoplasmic reticulum (ER) stress, D-site-binding protein (Dbp) expression decreased and Nuclear Factor IL-3 (Nfil3)/E4 Promoter-binding protein 4 (E4bp4) expression increased, leading to reduced DBP transcriptional activity. Similar alterations were observed with chemically-induced ER stress. Transgenic mice expressing E4BP4 under the control of the mouse insulin I gene promoter (MIP), in which E4BP4 in β-cells is expected to compete with DBP for D-box, displayed remarkable glucose intolerance with severely impaired insulin secretion. Basal ATP/ADP ratios in MIP-E4BP4 islets were elevated without the circadian oscillations observed in wild-type islets. Neither elevation of the ATP/ADP ratio nor an intracellular Ca2+ response was observed after glucose stimulation. RNA expressions of genes involved in insulin secretion gradually increase in wild-type islets early in the feeding period. In MIP-E4BP4 islets, however, these increases were not observed. Thus, molecular clock output DBP transcriptional activity, susceptible to ER stress, plays pivotal roles in β-cell priming for insulin release by regulating β-cell metabolism and gene expressions. Because ER stress is also involved in the β-cell failure in more common Type-2 diabetes, understanding the currently identified ER stress-associated mechanisms warrants novel therapeutic and preventive strategies for both rare form and common diabetes.
authors.affiliation: Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi 755-8505, Japan; Department of Diabetes Research, Yamaguchi University, School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi 755-8505, Japan. Electronic address: yohta@yamaguchi-u.ac.jp.
authors.forename: Yasuharu
authors.initials: Y
authors.lastname: Ohta
authors.affiliation: Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Akihiko
authors.initials: A
authors.lastname: Taguchi
authors.affiliation: Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Takuro
authors.initials: T
authors.lastname: Matsumura
authors.affiliation: Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Nakabayashi
authors.affiliation: Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Masaru
authors.initials: M
authors.lastname: Akiyama
authors.affiliation: Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Ruriko
authors.initials: R
authors.lastname: Fujimoto
authors.affiliation: Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Risa
authors.initials: R
authors.lastname: Suetomi
authors.affiliation: Department of Neuroanatomy, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Akie
authors.initials: A
authors.lastname: Yanai
authors.affiliation: Department of Neuroanatomy, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi 755-8505, Japan.
authors.forename: Koh
authors.initials: K
authors.lastname: Shinoda
authors.affiliation: Department of Endocrinology, Metabolism, Hematological Science and Therapeutics, Yamaguchi University, Graduate School of Medicine, 1-1-1, Minami Kogushi, Ube, Yamaguchi 755-8505, Japan. Electronic address: tanizawa@yamaguchi-u.ac.jp.
authors.forename: Yukio
authors.initials: Y
authors.lastname: Tanizawa
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D056926:CLOCK Proteins / Q000235:genetics* / Q000378:metabolism; D002118:Calcium / Q000032:analysis; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005951:Glucose Tolerance Test; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; C063898:DBP protein, human; D004268:DNA-Binding Proteins; C514817:Ins1 protein, mouse; D007328:Insulin; D008565:Membrane Proteins; C497440:NFIL3 protein, human; D014157:Transcription Factors; C114987:wolframin protein; D056926:CLOCK Proteins; C538943:CLOCK protein, human; D002118:Calcium
keywords: Clock out-put gene; Diabetes mellitus; Endoplasmic reticulum stress; Insulin secretion; Pancreatic islet β-cell