Gai W, Schott-Ohly P, Schulte im Walde S, Gleichmann H
German Diabetes Center, German Diabetes Research Institute, Heinrich-Heine University, Düsseldorf, Germany.
Exp Clin Endocrinol Diabetes. 2004 Jan;112(1):29-37. doi: 10.1055/s-2004-815724.
Streptozotocin (STZ) and alloxan (ALX) are potent diabetogens in different species of laboratory animals. Here, we describe differential in vitro effects of STZ and ALX on beta-cell molecules that are essential for glucose transport and metabolism, the glucose transporter 2 (GLUT2) and glucokinase (GK), respectively. Incubation of isolated pancreatic islets of C57 BL/6 mice with STZ or ALX for 30 min resulted in a concentration-dependent gradual loss of beta-cell function as determined by basal and D-glucose (D-G)-stimulated insulin release. ALX concentration-dependently reduced the mRNA expression of GLUT2 and GK and the effect on GLUT2 was more marked. STZ, in contrast, did not affect the mRNA expression of GLUT2 and GK, but concentration-dependently reduced the GLUT2 protein expression. Both STZ and ALX failed to affect the mRNA expression of proinsulin and of beta-actin. The deleterious effects of STZ and ALX were not due to beta-cell loss, because the total RNA yields and protein contents as well as the proinsulin mRNA expression in isolated islets of the differentially treated islets did not differ significantly from controls. Furthermore, islets that had been exposed to STZ or ALX responded to the non-glucose secretagogue arginine in a pattern comparable to that of solvent-treated cultures. When preincubating islet cultures with either D-G or its chemically closely related analogue 5-thio-D-glucose (5-T-G), different effects were obtained after treatment with either ALX or STZ. Thus, preincubation with 5-T-G protected the cultures from STZ-induced GLUT2 protein reduction, whereas D-G failed to do so. Preincubation with D-G, however, protected the cultures from ALX-induced reduction of GLUT2 and GK mRNA expression, whereas 5-T-G, at best, exerted a modest protection against ALX at a concentration of 1 mmol/l. Apparently, in vitro, GLUT2 protein is a key target molecule for STZ, while GLUT2 mRNA and GK mRNA are target molecules for ALX.
链脲佐菌素（STZ）和四氧嘧啶（ALX）在不同种类的实验动物中都是强效的致糖尿病物质。在此，我们描述了STZ和ALX分别对葡萄糖转运和代谢所必需的β细胞分子——葡萄糖转运蛋白2（GLUT2）和葡萄糖激酶（GK）——的不同体外作用。将C57 BL/6小鼠的分离胰岛与STZ或ALX孵育30分钟，导致β细胞功能呈浓度依赖性逐渐丧失，这通过基础和D -葡萄糖（D - G）刺激的胰岛素释放来确定。ALX浓度依赖性地降低了GLUT2和GK的mRNA表达，且对GLUT2的影响更为显著。相比之下，STZ不影响GLUT2和GK的mRNA表达，但浓度依赖性地降低了GLUT2蛋白表达。STZ和ALX均未影响胰岛素原和β -肌动蛋白的mRNA表达。STZ和ALX的有害作用并非由于β细胞丢失，因为差异处理胰岛的分离胰岛中的总RNA产量、蛋白质含量以及胰岛素原mRNA表达与对照相比无显著差异。此外，暴露于STZ或ALX的胰岛对非葡萄糖促分泌剂精氨酸的反应模式与溶剂处理培养物相当。当用D - G或其化学结构密切相关的类似物5 -硫代 - D -葡萄糖（5 - T - G）预孵育胰岛培养物时，用ALX或STZ处理后会得到不同的结果。因此，用5 - T - G预孵育可保护培养物免受STZ诱导的GLUT2蛋白减少，而D - G则不能。然而，用D - G预孵育可保护培养物免受ALX诱导的GLUT2和GK mRNA表达降低，而5 - T - G在1 mmol/l浓度下最多对ALX有适度的保护作用。显然，在体外，GLUT2蛋白是STZ的关键靶分子，而GLUT2 mRNA和GK mRNA是ALX的靶分子。
