Hyperglycemia-induced β-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes
Hyperglycemia-induced β-cell apoptosis in pancreatic islets of Psammomys obesus during development of diabetes
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DOI：
10.2337/diabetes.48.4.738
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发表时间：
1999-04-01
期刊：
影响因子：
7.7
通讯作者：
Kaiser, N
中科院分区：
文献类型：
--
作者：
Donath, MY;Gross, DJ;Kaiser, N
沙鼠Psammomys obesus发展为与中度肥胖相关的营养依赖性糖尿病。该疾病的特征在于初始高胰岛素血症，进展为与耗尽的胰腺胰岛素储备相关的低胰岛素血症。在向显性糖尿病转变的过程中，在体内研究了β细胞更新对胰岛素缺乏的贡献。正常血糖糖尿病倾向的肥胖P. obesus动物在给予高热量饮食的4天内发展为高血糖症，这被发现与胰腺胰岛素含量的进行性下降有关。这伴随着β细胞增殖活性的短暂增加和β细胞死亡率的长期增加，最终导致胰岛结构的破坏。在体外原代胰岛培养物中研究了“葡萄糖毒性”导致这些体内变化的假设。将易患糖尿病的肥胖毕赤酵母的胰岛暴露于高葡萄糖水平导致β细胞DNA片段化的剂量依赖性增加。相比之下，高葡萄糖水平不会诱导大鼠胰岛中的DNA片段化，而来自糖尿病抗性肥胖毕赤酵母系的胰岛表现出降低和延迟的反应。氨基胍在体外不能阻止葡萄糖诱导的β细胞DNA片段化，这表明一氧化氮和/或晚期糖基化终产物的形成没有发挥重要作用。升高的葡萄糖浓度刺激大鼠和肥胖胰腺胰岛中的β细胞增殖。然而，与大鼠胰岛中的显著持久作用不同，在肥胖猪胰岛中仅观察到短暂和降低的增殖反应;此外，在长期暴露于升高的葡萄糖水平后，β细胞增殖受到抑制。这些结果表明，高血糖诱导的β-细胞死亡加上增殖能力降低可能有助于胰岛素缺乏和葡萄糖稳态的恶化，在肥胖疟原虫。高血糖症的类似副作用可能在遗传易感个体的2型糖尿病演变中发挥作用。
The gerbil Psammomys obesus develops nutrition-dependent diabetes associated with moderate obesity. The disease is characterized by initial hyperinsulinemia, progressing to hypoinsulinemia associated with depleted pancreatic insulin stores. The contribution of changes in beta-cell turnover to insulin deficiency was investigated in vivo during transition to overt diabetes. Normo glycemic diabetes-prone P. obesus animals who were given a high-calorie diet developed hyperglycemia within 4 days, which was found to be associated with a progressive decline in pancreatic insulin content. This was accompanied by a transient increase in beta-cell proliferative activity and by a prolonged increase in the rate of beta-cell death, culminating in disruption of islet architecture. The hypothesis that "glucotoxicity" was responsible for these in vivo changes was investigated in vitro in primary islet cultures. Exposure of islets from diabetes-prone P. obesus to high glucose levels resulted in a dose-dependent increase in beta-cell DNA fragmentation. In contrast, high glucose levels did not induce DNA fragmentation in rat islets, whereas islets from a diabetes-resistant P. obesus line exhibited a reduced and delayed response. Aminoguanidine did not prevent glucose-induced beta-cell DNA fragmentation in vitro, suggesting that formation of nitric oxide and/or advanced glycation end products plays no major role. Elevated glucose concentrations stimulated beta-cell proliferation in both rat and P. obesus islets. However, unlike the marked long-lasting effect in rat islets, only a transient and reduced proliferative response was observed in P. obesus islets; furthermore, beta-cell proliferation was inhibited after prolonged exposure to elevated glucose levels. These results suggest that hyperglycemia-induced beta-cell death coupled with reduced proliferative capacity may contribute to the insulin deficiency and deterioration of glucose homeostasis in P. obesus. Similar adverse effects of hyperglycemia could play a role in the evolution of type 2 diabetes in genetically susceptible individuals.