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.
Highlights
Pancreatic beta cell mass can be affected negatively by events that disrupt cellular homeostasis, such as oxidative stress or autophagic dysfunction
Enhanced CCAAT enhancer binding protein β (C/EBPβ) expression caused by endoplasmic reticulum (ER) stress decreases AMPK activity
We examined the possibility that C/EBPβ, the expression of which is enhanced by ER stress, affects AMPK activity
Summary
Pancreatic beta cell mass can be affected negatively by events that disrupt cellular homeostasis, such as oxidative stress or autophagic dysfunction. We have shown that the transcription factor C/EBPβ, which is expressed at low levels under normal circumstances, is highly induced by ER stress in pancreatic beta cells [5]. The accumulation of C/EBPβ weakens these cells against ER stress and reduces pancreatic beta cell mass by inhibiting induction of the molecular chaperone 78-kDa glucose-regulated protein (GRP78), which is the major ER chaperone in all eukaryotes that enables the essential process of productive folding in the ER [6,7,8,9]. It has been reported that accumulation of C/EBPβ is observed in the pancreatic beta cells of type 2 diabetes patients but is not found in patients with normal glucose tolerance [10]. Elucidation of the mechanisms that control C/EBPβ expression is important to discovering novel therapeutic targets for ameliorating pancreatic beta cell failure
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