Marchetti P, Bugliani M, Lupi R, Marselli L, Masini M, Boggi U, Filipponi F, Weir G C, Eizirik D L, Cnop M
Department of Endocrinology and Metabolism, Metabolic Unit, Ospedale Cisanello, University of Pisa, Via Paradisa 2, 56100, Pisa, Italy.
Diabetologia. 2007 Dec;50(12):2486-94. doi: 10.1007/s00125-007-0816-8. Epub 2007 Sep 30.
AIMS/HYPOTHESIS: Pancreatic beta cells have highly developed endoplasmic reticulum (ER) due to their role in insulin secretion. Since ER stress has been associated with beta cell dysfunction, we studied several features of beta cell ER in human type 2 diabetes.
Pancreatic samples and/or isolated islets from non-diabetic controls (ND) and type 2 diabetes patients were evaluated for insulin secretion, apoptosis (electron microscopy and ELISA), morphometric ER assessment (electron microscopy), and expression of ER stress markers in beta cell prepared by laser capture microdissection and in isolated islets.
Insulin release was lower and beta cell apoptosis higher in type 2 diabetes than ND islets. ER density volume was significantly increased in type 2 diabetes beta cells. Expression of alpha-mannosidase (also known as mannosidase, alpha, class 1A, member 1) and UDP-glucose glycoprotein glucosyl transferase like 2 (UGCGL2), assessed by microarray and/or real-time reverse transcriptase polymerase chain reaction (RT-PCR), differed between ND and type 2 diabetes beta cells. Expression of immunoglobulin heavy chain binding protein (BiP, also known as heat shock 70 kDa protein 5 [glucose-regulated protein, 78 kDa] [HSPA5]), X-box binding protein 1 (XBP-1, also known as XBP1) and C/EBP homologous protein (CHOP, also known as damage-inducible transcript 3 [DDIT3]) was not higher in type 2 diabetes beta cell or isolated islets cultured at 5.5 mmol/l glucose (microarray and real-time RT-PCR) than in ND samples. When islets were cultured for 24 h at 11.1 mmol/l glucose, there was induction of BiP and XBP-1 in type 2 diabetes islets but not in ND islets.
CONCLUSIONS/INTERPRETATION: Beta cell in type 2 diabetes showed modest signs of ER stress when studied in pancreatic samples or isolated islets maintained at physiological glucose concentration. However, exposure to increased glucose levels induced ER stress markers in type 2 diabetes islet cells, which therefore may be more susceptible to ER stress induced by metabolic perturbations.
目的/假设：胰腺β细胞因在胰岛素分泌中发挥作用而具有高度发达的内质网（ER）。由于内质网应激与β细胞功能障碍有关，我们研究了2型糖尿病患者β细胞内质网的几个特征。
对来自非糖尿病对照（ND）和2型糖尿病患者的胰腺样本和/或分离的胰岛进行胰岛素分泌、凋亡（电子显微镜和酶联免疫吸附测定）、内质网形态学评估（电子显微镜）以及通过激光捕获显微切割制备的β细胞和分离的胰岛中内质网应激标志物表达的评估。
与ND胰岛相比，2型糖尿病患者的胰岛素释放较低，β细胞凋亡较高。2型糖尿病β细胞的内质网密度体积显著增加。通过微阵列和/或实时逆转录聚合酶链反应（RT-PCR）评估的α-甘露糖苷酶（也称为甘露糖苷酶，α，1A类，成员1）和UDP-葡萄糖糖蛋白葡糖基转移酶样2（UGCGL2）的表达在ND和2型糖尿病β细胞之间存在差异。免疫球蛋白重链结合蛋白（BiP，也称为热休克70 kDa蛋白5 [葡萄糖调节蛋白，78 kDa] [HSPA5]）、X盒结合蛋白1（XBP-1，也称为XBP1）和C/EBP同源蛋白（CHOP，也称为损伤诱导转录本3 [DDIT3]）在2型糖尿病β细胞或在5.5 mmol/l葡萄糖浓度下培养的分离胰岛中的表达（微阵列和实时RT-PCR）并不高于ND样本。当胰岛在11.1 mmol/l葡萄糖浓度下培养24小时时，2型糖尿病胰岛中诱导了BiP和XBP-1，而ND胰岛中未诱导。
结论/解读：在胰腺样本或维持在生理葡萄糖浓度的分离胰岛中研究时，2型糖尿病患者β细胞显示出适度的内质网应激迹象。然而，暴露于升高的葡萄糖水平会在2型糖尿病胰岛细胞中诱导内质网应激标志物，因此2型糖尿病胰岛细胞可能更容易受到代谢紊乱诱导的内质网应激影响。
