Specific PERK inhibitors enhanced glucose-stimulated insulin secretion in a mouse model of type 2 diabetes.
Metabolism
; 97: 87-91, 2019 08.
Article
en En
| MEDLINE
| ID: mdl-30615948
BACKGROUND: We have reported that partial PERK attenuation using PERK inhibitors (PI) enhanced glucose-stimulated insulin secretion (GSIS) from pancreatic islets and mice through induction of ER chaperone BIP. Therefore, we investigated if PI would have the same effects in a diabetic condition as well. METHODS: GSK2606414 was treated to mouse islets under 20-mM glucose and 0.5-mM palmitate to examine GSIS. To generate a mouse model of type 2 diabetes mellitus (DM), male C57BL/6J mice were fed with high-fat diet and injected with streptozotocin. Several doses (6-16â¯mg/kg/day) of GSK2656157 and glimepiride were administrated to the mice for 8â¯weeks, and metabolic phenotypes were evaluated such as body weight, blood glucose levels, insulin secretion and sensitivity, and then changes in the pancreas were measured. RESULTS: High-glucose and palmitate treatment significantly increased PERK phosphorylation in the isolated islets. Suppression of GSIS and glucose-stimulated Ca2+ transit was also observed. PI at 40â¯nM which decreased PERK phosphorylation by 40% significantly recovered the GSIS and cytosolic calcium. In the mice where significant weight gain and prominent hyperglycemia were induced, PI at 10â¯mg/kg/day significantly enhanced GSIS and reduced blood glucose levels compared to the vehicle. The effects were similar to those by 10â¯mg/kg/day of glimepiride. Administration of PI did not induce changes in beta cell mass or pancreatic insulin contents, however, high dose PI decreased pancreatic weight. CONCLUSION: PI at low dose significantly enhanced GSIS in vitro and in vivo under metabolic stress and improved hyperglycemia in the mice mimicking type 2 DM, suggesting a potential as a new therapeutic approach for type 2 DM.
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Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
EIF-2 Quinasa
/
Diabetes Mellitus Tipo 2
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Secreción de Insulina
/
Glucosa
/
Insulina
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Metabolism
Año:
2019
Tipo del documento:
Article