Marchetti Piero, Del Guerra Silvia, Marselli Lorella, Lupi Roberto, Masini Matilde, Pollera Maria, Bugliani Marco, Boggi Ugo, Vistoli Fabio, Mosca Franco, Del Prato Stefano
Department of Endocrinology and Metabolism and Diabetes, Transplant Unit, University of Pisa, Italy.
J Clin Endocrinol Metab. 2004 Nov;89(11):5535-41. doi: 10.1210/jc.2004-0150.
Several properties of pancreatic beta-cells in type 2 diabetes (T2D) were studied by using islets isolated from T2D subjects. Moreover, because metformin has protective effects on nondiabetic beta-cells exposed to high glucose or free fatty acid levels, we investigated its direct action on T2D islet cells. Diabetic islets were characterized by reduced insulin content, decreased amount of mature insulin granules, impaired glucose-induced insulin secretion, reduced insulin mRNA expression, and increased apoptosis with enhanced caspase-3 and -8 activity. These alterations were associated with increased oxidative stress, as shown by higher nitrotyrosine concentrations, increased expression of protein kinase C-beta2 and nicotinamide adenine dinucleotide phosphate reduced-oxidase, and changes in mRNA expression of manganese- superoxide dismutase, Cu/Zn-superoxide dismutase, catalase, and glutathione peroxidase. Twenty-four-hour incubation of T2D islets with metformin was associated with increased insulin content, increased number and density of mature insulin granules, improved glucose-induced insulin release, and increased insulin mRNA expression. Moreover, apoptosis was reduced, with concomitant decrease of caspase-3 and -8 activity. These changes were accompanied by reduction or normalization of several markers of oxidative stress. Thus, T2D islets have several functional and survival defects, which can be ameliorated by metformin; the beneficial effects of the drug are mediated, at least in part, by a reduction of oxidative stress.
利用从2型糖尿病（T2D）患者分离的胰岛，研究了T2D患者胰腺β细胞的几种特性。此外，由于二甲双胍对暴露于高葡萄糖或游离脂肪酸水平的非糖尿病β细胞具有保护作用，我们研究了其对T2D胰岛细胞的直接作用。糖尿病胰岛的特征是胰岛素含量降低、成熟胰岛素颗粒数量减少、葡萄糖诱导的胰岛素分泌受损、胰岛素mRNA表达降低以及细胞凋亡增加，同时半胱天冬酶-3和-8活性增强。这些改变与氧化应激增加有关，表现为硝基酪氨酸浓度升高、蛋白激酶C-β2和烟酰胺腺嘌呤二核苷酸磷酸还原氧化酶表达增加，以及锰超氧化物歧化酶、铜/锌超氧化物歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶的mRNA表达变化。将T2D胰岛与二甲双胍孵育24小时后，胰岛素含量增加、成熟胰岛素颗粒数量和密度增加、葡萄糖诱导的胰岛素释放改善以及胰岛素mRNA表达增加。此外，细胞凋亡减少，同时半胱天冬酶-3和-8活性降低。这些变化伴随着氧化应激的几种标志物的减少或恢复正常。因此，T2D胰岛存在多种功能和存活缺陷，二甲双胍可以改善这些缺陷；该药物的有益作用至少部分是通过降低氧化应激介导的。
