Characterization and validation of a streptozotocin-induced diabetes model in the vervet monkey.
Characterization and validation of a streptozotocin-induced diabetes model in the vervet monkey.
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DOI：
10.1016/j.vascn.2011.02.003
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发表时间：
2011-05
影响因子：
1.9
通讯作者：
Wagner JD
中科院分区：
文献类型：
--
作者：
Kavanagh K;Flynn DM;Nelson C;Zhang L;Wagner JD
链脲佐菌素 (STZ) 对胰腺 β 细胞具有优先毒性，通常用于模拟许多物种（包括非人灵长类动物）的 1 型糖尿病 (DM)。我们通过静脉注射 45 只（n=8，STZ-45）或 55 mg/kg STZ（n=12，STZ-55）在 20 只长尾猴（Chlorocebus aethiops）中诱导 DM；十只对照（CTL）猴子接受了盐水。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较的血糖控制，通过可比较的糖化血红蛋白水平证实。外源性胰岛素需要量连续4周迅速增加；此后 STZ-45 胰岛素剂量稳定，而 STZ-55 剂量在 16 周内持续增加。葡萄糖耐量测试和精氨酸刺激的胰岛素分泌证实两组的胰腺 β 细胞功能均下降 80-90%。所有 STZ 猴的体重均下降，仅 STZ-45 在 16 周时恢复到基线。 STZ-55 组的血尿素氮 (BUN) 和肌酐升高。 STZ-55 也使碱性磷酸酶 (ALKP) 升高（与 CTL 相比，p<0.05），而 STZ-45 ALKP 升高在研究结束时得到解决。所有 STZ 猴的红细胞参数均下降，但 STZ-55 组的红细胞参数下降更为严重。我们已经证明，用单剂量的 STZ 可以在长尾黑颚猴中诱导并维持 DM 模型。较低剂量的 STZ (45mg/kg) 显着改善了毒性特征，而没有改变诱导 DM 的功效。最后，建议诱导后有足够的时间来解决短暂的肾脏、肝脏和血液学参数。
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 4 weeks; STZ-45 insulin doses stabilized thereafter while STZ-55 doses continued to increase through 16 weeks. 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 (45mg/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.
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