Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea; Department of Internal Medicine, Healthcare Research Institute, Seoul National University Hospital Healthcare System Gangnam Center, Seoul 06236, Republic of Korea.
Innovative Research Institute for Cell Therapy, Seoul 03080, Republic of Korea.
Metabolism. 2019 Aug;97:87-91. doi: 10.1016/j.metabol.2018.12.007. Epub 2019 Jan 4.
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.
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 (6-16 mg/kg/day) of GSK2656157 and glimepiride were administrated to the mice for 8 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.
High-glucose and palmitate treatment significantly increased PERK phosphorylation in the isolated islets. Suppression of GSIS and glucose-stimulated Ca transit was also observed. PI at 40 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 10 mg/kg/day significantly enhanced GSIS and reduced blood glucose levels compared to the vehicle. The effects were similar to those by 10 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.
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.
我们曾报道过，使用 PERK 抑制剂（PI）部分抑制 PERK 可通过诱导内质网伴侣 BIP 增强胰腺胰岛和小鼠的葡萄糖刺激胰岛素分泌（GSIS）。因此，我们研究了 PI 在糖尿病状态下是否也具有相同的作用。
在 20mM 葡萄糖和 0.5mM 棕榈酸存在的情况下，用 GSK2606414 处理小鼠胰岛以检测 GSIS。为了建立 2 型糖尿病（DM）的小鼠模型，雄性 C57BL/6J 小鼠喂食高脂肪饮食并注射链脲佐菌素。给小鼠施用几种剂量（6-16mg/kg/天）的 GSK2656157 和格列美脲 8 周，并评估代谢表型，如体重、血糖水平、胰岛素分泌和敏感性，然后测量胰腺的变化。
高葡萄糖和棕榈酸处理显著增加了分离胰岛中 PERK 的磷酸化。还观察到 GSIS 和葡萄糖刺激的钙转运的抑制。40nM 的 PI 可使 PERK 磷酸化减少 40%，显著恢复 GSIS 和细胞质钙。在诱导体重显著增加和明显高血糖的小鼠中，与载体相比，10mg/kg/天的 PI 可显著增强 GSIS 并降低血糖水平。其作用与 10mg/kg/天的格列美脲相似。PI 的给药不会引起β细胞质量或胰腺胰岛素含量的变化，但是高剂量 PI 会降低胰腺重量。
在代谢应激下，低剂量的 PI 可显著增强体外和体内的 GSIS，并改善模拟 2 型 DM 的小鼠的高血糖，提示其可能成为 2 型 DM 的一种新的治疗方法。
