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GLP-1 receptor agonist attenuates endoplasmic reticulum stress-mediated β-cell damage in Akita mice
Shunsuke Yamane1, Yoshiyuki Hamamoto2, Shin-Ichi Harashima1
1Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University.
Unlabelled:
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.
Materials And 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).
Insights
Exendin-4 (Ex-4) treatment reduced blood glucose and protected beta cells from ER stress in Akita mice. This protection against endoplasmic reticulum stress-mediated diabetes was independent of lowered blood glucose levels.
Area of Science:
- Endocrinology
- Diabetes Research
- Cell Biology
Background:
- Endoplasmic reticulum (ER) stress contributes to type 2 diabetes development.
- Glucagon-like peptide-1 receptor (GLP-1R) signaling may offer cytoprotective effects.
- Akita mice serve as a model for ER stress-mediated diabetes.
Purpose of the Study:
- To investigate the in vivo cytoprotective effect of GLP-1R signaling.
- To examine the action of exendin-4 (Ex-4), a GLP-1R agonist, on beta-cell apoptosis.
- To assess Ex-4's impact on ER stress in Akita mice.
Main Methods:
- Akita mice were treated with Ex-4, PBS, or phlorizin.
- Evaluated blood glucose, body weight, insulin-positive area, and islet number.
- Assessed beta-cell apoptosis markers: CHOP, TUNEL, and proliferation (PCNA).
Main Results:
- Ex-4 significantly reduced blood glucose and increased insulin-positive area and islet number.
- Ex-4 decreased CHOP-positive and TUNEL-positive beta-cells, and CHOP mRNA levels.
- Phlorizin controlled glucose but did not reduce apoptosis or ER stress markers.
Conclusions:
- Ex-4 treatment attenuates ER stress-mediated beta-cell damage in Akita mice.
- The protective effect is primarily via reducing apoptotic cell death.
- This reduction in apoptosis is independent of lowered blood glucose levels.