Donath M Y, Gross D J, Cerasi E, Kaiser N
Department of Endocrinology and Metabolism, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
Diabetes. 1999 Apr;48(4):738-44. doi: 10.2337/diabetes.48.4.738.
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.
沙鼠欧黄鼠会患上与中度肥胖相关的营养依赖性糖尿病。该疾病的特征是最初出现高胰岛素血症，随后发展为与胰腺胰岛素储备耗竭相关的低胰岛素血症。在向显性糖尿病转变的过程中，研究了体内β细胞更新变化对胰岛素缺乏的影响。给予高热量饮食的血糖正常的糖尿病易患欧黄鼠在4天内出现高血糖，发现这与胰腺胰岛素含量的逐渐下降有关。这伴随着β细胞增殖活性的短暂增加以及β细胞死亡率的长期增加，最终导致胰岛结构破坏。在原代胰岛培养物中对“糖毒性”导致这些体内变化的假说进行了体外研究。将糖尿病易患欧黄鼠的胰岛暴露于高葡萄糖水平会导致β细胞DNA片段化呈剂量依赖性增加。相比之下，高葡萄糖水平不会诱导大鼠胰岛的DNA片段化，而来自抗糖尿病欧黄鼠品系的胰岛则表现出反应减弱和延迟。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不起主要作用。升高的葡萄糖浓度刺激大鼠和欧黄鼠胰岛中的β细胞增殖。然而，与大鼠胰岛中明显的长期作用不同，在欧黄鼠胰岛中仅观察到短暂且减弱的增殖反应；此外，长时间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细胞死亡以及增殖能力降低可能导致欧黄鼠的胰岛素缺乏和葡萄糖稳态恶化。高血糖的类似不利影响可能在遗传易感个体的2型糖尿病发展中起作用。
