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

• Published in: PloS one 2015-06, Vol.10 (6), p.e0130757-e0130757
• Main Authors: Matsuda, Tomokazu, Takahashi, Hiroaki, Mieda, Yusuke, Shimizu, Shinobu, Kawamoto, Takeshi, Matsuura, Yuki, Takai, Tomoko, Suzuki, Emi, Kanno, Ayumi, Koyanagi-Kimura, Maki, Asahara, Shun-ichiro, Bartolome, Alberto, Yokoi, Norihide, Inoue, Hiroshi, Ogawa, Wataru, Seino, Susumu, Kido, Yoshiaki
• Format: Article
• Language: English
• Subjects: Adamantane - analogs & derivatives; Adamantane - pharmacology; Aminoimidazole Carboxamide - analogs & derivatives; Aminoimidazole Carboxamide - pharmacology; AMP; AMP-activated protein kinase; AMP-Activated Protein Kinases - genetics; AMP-Activated Protein Kinases - metabolism; Animals; Beta cells; Biophysics; CCAAT-Enhancer-Binding Protein-beta - genetics; CCAAT-Enhancer-Binding Protein-beta - metabolism; CCAAT/enhancer-binding protein; Cell Line; Diabetes; Diabetes mellitus; Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Dipeptidyl-peptidase IV; Endocrinology; Endoplasmic reticulum; Endoplasmic Reticulum Stress - physiology; Failure; Gene Expression Regulation - drug effects; Glucose; Glucose Tolerance Test; Health sciences; Homeostasis; Hypoglycemic Agents - pharmacology; Imidazole; Insulin; Insulin resistance; Insulin-Secreting Cells - cytology; Insulin-Secreting Cells - drug effects; Insulin-Secreting Cells - metabolism; Internal medicine; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Kinases; Medicine; Metabolism; Metformin; Metformin - pharmacology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Nitriles - pharmacology; Pancreas; Peptidase; Phosphorylation; Phosphorylation - drug effects; Physiology; Proteins; Pyrrolidines - pharmacology; Ribonucleotides - pharmacology; Stress; Stresses; Transgenic mice; University graduates
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0130757

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.