Del Guerra S, Grupillo M, Masini M, Lupi R, Bugliani M, Torri S, Boggi U, Del Chiaro M, Vistoli F, Mosca F, Del Prato S, Marchetti P
Department of Endocrinology and Metabolism, Metabolic Unit, University of Pisa, Pisa, Italy.
Diabetes Metab Res Rev. 2007 Mar;23(3):234-8. doi: 10.1002/dmrr.680.
Decreased beta-cell mass, mainly due to apoptosis, is crucial for the development and progression of type 2 diabetes. Chronic exposure to high glucose levels is a probable underlying mechanism, whereas the role of oral anti-diabetic agents (sulphonylureas in particular) is still unsettled.
To directly investigate more on such issues, we prepared isolated human islets, which were then cultured for 5 days in continuous normal glucose concentration (NG, 5.5 mmol/L) or normal and high (HG, 16.7 mmol/L) glucose levels (alternating every 24 h), with or without the addition of therapeutical concentration (10 micromol L) of gliclazide or glibenclamide.
Intermittent high glucose caused a significant decrease of glucose-stimulated insulin secretion, which was not further affected by either sulphonylurea. Apoptosis, as assessed by electron microscopy, was also significantly increased by alternating high glucose exposure, which was accompanied by altered mitochondria morphology and density volume, and increased concentrations of nitrotyrosine, a marker of oxidative stress. Gliclazide, but not glibenclamide, was able to significantly reduce high glucose induced apoptosis, mitochondrial alterations, and nitrotyrosine concentration increase.
Therefore, gliclazide protected human beta-cells from apoptosis induced by intermittent high glucose, and this effect was likely to be due, at least in part, to the anti-oxidant properties of the molecule.
β细胞量减少主要归因于细胞凋亡，这对2型糖尿病的发生和发展至关重要。长期暴露于高血糖水平是一种可能的潜在机制，而口服抗糖尿病药物（尤其是磺脲类药物）的作用仍未明确。
为了更直接地研究这些问题，我们制备了分离的人胰岛，然后将其在持续正常葡萄糖浓度（NG，5.5 mmol/L）或正常与高葡萄糖水平（HG，16.7 mmol/L）（每24小时交替一次）下培养5天，添加或不添加治疗浓度（10 μmol/L）的格列齐特或格列本脲。
间歇性高糖导致葡萄糖刺激的胰岛素分泌显著减少，两种磺脲类药物均未进一步影响该分泌。通过电子显微镜评估，交替暴露于高糖也显著增加了细胞凋亡，同时伴有线粒体形态和密度体积的改变，以及氧化应激标志物硝基酪氨酸浓度的增加。格列齐特而非格列本脲能够显著减少高糖诱导的细胞凋亡、线粒体改变以及硝基酪氨酸浓度增加。
因此，格列齐特可保护人β细胞免受间歇性高糖诱导的细胞凋亡，且这种作用可能至少部分归因于该分子的抗氧化特性。
