title: Regulation of Pancreatic β Cell Mass by Cross-Interaction between CCAAT Enhancer Binding Protein β Induced by Endoplasmic Reticulum Stress and AMP-Activated Protein Kinase Activity.
abstract: During the development of type 2 diabetes, endoplasmic reticulum (ER) stress leads to not only insulin resistance but also to pancreatic beta cell failure. Conversely, cell function under various stressed conditions can be restored by reducing ER stress by activating AMP-activated protein kinase (AMPK). However, the details of this mechanism are still obscure. Therefore, the current study aims to elucidate the role of AMPK activity during ER stress-associated pancreatic beta cell failure. MIN6 cells were loaded with 5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide (AICAR) and metformin to assess the relationship between AMPK activity and CCAAT enhancer binding protein β (C/EBPβ) expression levels. The effect of C/EBPβ phosphorylation on expression levels was also investigated. Vildagliptin and metformin were administered to pancreatic beta cell-specific C/EBPβ transgenic mice to investigate the relationship between C/EBPβ expression levels and AMPK activity in the pancreatic islets. When pancreatic beta cells are exposed to ER stress, the accumulation of the transcription factor C/EBPβ lowers the AMP/ATP ratio, thereby decreasing AMPK activity. In an opposite manner, incubation of MIN6 cells with AICAR or metformin activated AMPK, which suppressed C/EBPβ expression. In addition, administration of the dipeptidyl peptidase-4 inhibitor vildagliptin and metformin to pancreatic beta cell-specific C/EBPβ transgenic mice decreased C/EBPβ expression levels and enhanced pancreatic beta cell mass in proportion to the recovery of AMPK activity. Enhanced C/EBPβ expression and decreased AMPK activity act synergistically to induce ER stress-associated pancreatic beta cell failure.
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Matsuda
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mieda
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kawamoto
authors.affiliation: Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Matsuura
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takai
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Suzuki
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Ayumi
authors.initials: A
authors.lastname: Kanno
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Koyanagi-Kimura
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Shun-ichiro
authors.initials: S
authors.lastname: Asahara
authors.affiliation: Naomi Berrie Diabetes Center, Department of Medicine, Columbia University, New York, United States of America.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bartolome
authors.affiliation: Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Norihide
authors.initials: N
authors.lastname: Yokoi
authors.affiliation: Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Ogawa
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Molecular and Metabolic Medicine, Department of Physiology and Cell Biology, Kobe University Graduate School of Medicine, Kobe, Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Seino
authors.affiliation: Division of Diabetes and Endocrinology, Department of Internal Medicine, Kobe University Graduate School of Medicine, Kobe, Japan; Division of Medical Chemistry, Department of Biophysics, Kobe University Graduate School of Health Sciences, Kobe, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kido
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000218:Adamantane / Q000031:analogs & derivatives / Q000494:pharmacology; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism / Q000473:pathology; D008687:Metformin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology; D012265:Ribonucleotides / Q000494:pharmacology; D000077597:Vildagliptin
chemical_list: D022782:CCAAT-Enhancer-Binding Protein-beta; D007004:Hypoglycemic Agents; D009570:Nitriles; D011759:Pyrrolidines; D012265:Ribonucleotides; D000620:Aminoimidazole Carboxamide; D008687:Metformin; D055372:AMP-Activated Protein Kinases; C031143:AICA ribonucleotide; D000077597:Vildagliptin; D000218:Adamantane