GLP-1 receptor agonist attenuates endoplasmic reticulum stress-mediated β-cell damage in Akita mice.
Aims/Introduction:  Endoplasmic reticulum (ER) stress is one of the contributing factors in the development of type 2 diabetes. To investigate the cytoprotective effect of glucagon-like peptide 1 receptor (GLP-1R) signaling in vivo, we examined the action of exendin-4 (Ex-4), a potent GLP-1R agonist, on β-cell apoptosis in Akita mice, an animal model of ER stress-mediated diabetes.


METHODS
Ex-4, phosphate-buffered saline (PBS) or phlorizin were injected intraperitoneally twice a day from 3 to 5 weeks-of-age. We evaluated the changes in blood glucose levels, bodyweights, and pancreatic insulin-positive area and number of islets. The effect of Ex-4 on the numbers of C/EBP-homologous protein (CHOP)-, TdT-mediated dUTP-biotin nick-end labeling (TUNEL)- or proliferating cell nuclear antigen-positive β-cells were also evaluated.


RESULTS
Ex-4 significantly reduced blood glucose levels and increased both the insulin-positive area and the number of islets compared with PBS-treated mice. In contrast, there was no significant difference in the insulin-positive area between PBS-treated mice and phlorizin-treated mice, in which blood glucose levels were controlled similarly to those in Ex-4-treated mice. Furthermore, treatment of Akita mice with Ex-4 resulted in a significant decrease in the number of CHOP-positive β-cells and TUNEL-positive β-cells, and in CHOP mRNA levels in β-cells, but there was no significant difference between the PBS-treated group and the phlorizin-treated group. Proliferating cell nuclear antigen staining showed no significant difference among the three groups in proliferation of β-cells.


CONCLUSIONS
These data suggest that Ex-4 treatment can attenuate ER stress-mediated β-cell damage, mainly through a reduction of apoptotic cell death that is independent of lowered blood glucose levels. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00075.x, 2010).
Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University.
Shunsuke
S
Yamane
Center for Diabetes and Endocrinology, Tazuke Kofukai Medical Research Institute, Kitano Hospital.
Yoshiyuki
Y
Hamamoto
Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University.
Shin-Ichi
S
Harashima
Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University.
Norio
N
Harada
Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University.
Akihiro
A
Hamasaki
Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University.
Kentaro
K
Toyoda
Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University.
Kazuyo
K
Fujita
Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University.
Erina
E
Joo
Division of Diabetes, Clinical Nutrition and Endocrinology, Department of Medicine, Kansai Electric Power Hospital, Osaka, Japan.
Yutaka
Y
Seino
Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University ; CREST of Japan Science and Technology (JST), Kyoto.
Nobuya
N
Inagaki
Apoptosis; Endoplasmic reticulum stress; Glucagon‐like peptide‐1