Del Guerra Silvia, Lupi Roberto, Marselli Lorella, Masini Matilde, Bugliani Marco, Sbrana Simone, Torri Scilla, Pollera Maria, Boggi Ugo, Mosca Franco, Del Prato Stefano, Marchetti Piero
Department of Endocrinology and Metabolism, Metabolic Unit, Ospedale Cisanello, Via Paradisa 2, 56124 Pisa, Italy.
Diabetes. 2005 Mar;54(3):727-35. doi: 10.2337/diabetes.54.3.727.
To shed further light on the primary alterations of insulin secretion in type 2 diabetes and the possible mechanisms involved, we studied several functional and molecular properties of islets isolated from the pancreata of 13 type 2 diabetic and 13 matched nondiabetic cadaveric organ donors. Glucose-stimulated insulin secretion from type 2 diabetic islets was significantly lower than from control islets, whereas arginine- and glibenclamide-stimulated insulin release was less markedly affected. The defects were accompanied by reduced mRNA expression of GLUT1 and -2 and glucokinase and by diminished glucose oxidation. In addition, AMP-activated protein kinase activation was reduced. Furthermore, the expression of insulin was decreased, and that of pancreatic duodenal homeobox-1 (PDX-1) and forkhead box O1 (Foxo-1) was increased. Nitrotyrosine and 8-hydroxy-2'-deoxyguanosine concentrations, markers of oxidative stress, were significantly higher in type 2 diabetic than control islets, and they were correlated with the degree of glucose-stimulated insulin release impairment. Accordingly, 24-h exposure to glutathione significantly improved glucose-stimulated insulin release and decreased nitrotyrosine concentration, with partial recovery of insulin mRNA expression. These results provide direct evidence that the defects of insulin secretion in type 2 diabetic islets are associated with multiple islet cell alterations. Most importantly, the current study shows that the functional impairment of type 2 diabetic islets can be, at least in part, reversible. In this regard, it is suggested that reducing islet cell oxidative stress is a potential target of human type 2 diabetes therapy.
为了进一步阐明2型糖尿病胰岛素分泌的原发性改变及其可能的机制，我们研究了从13例2型糖尿病患者和13例匹配的非糖尿病尸体器官供体的胰腺中分离出的胰岛的几种功能和分子特性。2型糖尿病胰岛的葡萄糖刺激胰岛素分泌明显低于对照胰岛，而精氨酸和格列本脲刺激的胰岛素释放受影响较小。这些缺陷伴随着葡萄糖转运蛋白1和2以及葡萄糖激酶的mRNA表达降低以及葡萄糖氧化减少。此外，AMP激活的蛋白激酶激活减少。此外，胰岛素的表达降低，而胰腺十二指肠同源盒-1（PDX-1）和叉头盒O1（Foxo-1）的表达增加。氧化应激标志物硝基酪氨酸和8-羟基-2'-脱氧鸟苷的浓度在2型糖尿病胰岛中明显高于对照胰岛，并且它们与葡萄糖刺激的胰岛素释放受损程度相关。因此，24小时暴露于谷胱甘肽可显著改善葡萄糖刺激的胰岛素释放并降低硝基酪氨酸浓度，胰岛素mRNA表达部分恢复。这些结果提供了直接证据，表明2型糖尿病胰岛中胰岛素分泌的缺陷与多种胰岛细胞改变有关。最重要的是，目前的研究表明，2型糖尿病胰岛的功能损害至少部分是可逆的。在这方面，有人提出降低胰岛细胞氧化应激是人类2型糖尿病治疗的潜在靶点。
