Kavanagh Kylie, Flynn David M, Nelson Chris, Zhang Li, Wagner Janice D
Department of Pathology, Section on Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
J Pharmacol Toxicol Methods. 2011 May-Jun;63(3):296-303. doi: 10.1016/j.vascn.2011.02.003. Epub 2011 Feb 26.
Streptozotocin (STZ), preferentially toxic to pancreatic beta cells, is commonly used to model Type 1 diabetes mellitus (DM) in numerous species, including nonhuman primates.
We induced DM in twenty vervet monkeys (Chlorocebus aethiops) by intravenous administration of either 45 (n=8, STZ-45) or 55 mg/kg STZ (n=12, STZ-55); ten control (CTL) monkeys received saline.
Overall there was 15% mortality, likely secondary to renal toxicity. Twice-daily insulin therapy was initiated to maintain comparable glycemic control, confirmed by comparable glycated hemoglobin levels. Exogenous insulin requirements increased rapidly for 4weeks; STZ-45 insulin doses stabilized thereafter while STZ-55 doses continued to increase through 16weeks. Glucose tolerance testing and arginine-stimulated insulin secretion confirmed 80-90% reduction in pancreatic beta cell function in both groups. Body weight was reduced in all STZ monkeys, with return to baseline only in STZ-45 at 16 wks. Elevated blood urea nitrogen (BUN) and creatinine were noted in the STZ-55 group. Alkaline phosphatase (ALKP) was also increased with STZ-55 (p < 0.05 vs. CTL) whereas STZ-45 ALKP elevation resolved by study end. Red cell parameters were reduced in all STZ monkeys, but more severely in the STZ-55 group.
We have demonstrated that a model of DM can be induced and maintained in vervets with a single dose of STZ. The lower dose of STZ (45 mg/kg) significantly improved the toxicity profile without altering efficacy in inducing DM. Finally, sufficient time following induction is recommended to allow transient renal, hepatic and hematologic parameters to resolve.
链脲佐菌素（STZ）对胰腺β细胞具有选择性毒性，常用于在包括非人灵长类动物在内的众多物种中建立1型糖尿病（DM）模型。
我们通过静脉注射45（n = 8，STZ - 45）或55 mg/kg STZ（n = 12，STZ - 55）在20只黑长尾猴（绿猴）中诱导DM；10只对照（CTL）猴接受生理盐水。
总体死亡率为15%，可能继发于肾毒性。开始每日两次胰岛素治疗以维持可比的血糖控制，糖化血红蛋白水平相当证实了这一点。外源性胰岛素需求在4周内迅速增加；此后STZ - 45胰岛素剂量稳定，而STZ - 55剂量在16周内持续增加。葡萄糖耐量试验和精氨酸刺激的胰岛素分泌证实两组胰腺β细胞功能均降低了80 - 90%。所有STZ猴体重均减轻，仅STZ - 45在16周时恢复至基线。STZ - 55组血尿素氮（BUN）和肌酐升高。STZ - 55组碱性磷酸酶（ALKP）也升高（与CTL相比，p < 0.05），而STZ - 45组ALKP升高在研究结束时消退。所有STZ猴红细胞参数均降低，但STZ - 55组更严重。
我们已经证明，单剂量STZ可在黑长尾猴中诱导并维持DM模型。较低剂量的STZ（45 mg/kg）显著改善了毒性特征，同时不改变诱导DM的疗效。最后，建议在诱导后留出足够时间，以使短暂的肾脏、肝脏和血液学参数恢复正常。
