The effect of low versus high dose of streptozotocin in cynomolgus monkeys (Macaca fascilularis)
The effect of low versus high dose of streptozotocin in cynomolgus monkeys (Macaca fascilularis)
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DOI：
10.1034/j.1600-6143.2003.00040.x
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发表时间：
2003-03-01
影响因子：
8.8
通讯作者：
Smith, RN
中科院分区：
文献类型：
--
作者：
Koulmanda, M;Qipo, A;Smith, RN
链脲佐菌素(STZ)常用于诱发动物模型糖尿病。然而，与STZ相关的发病率及其诱发糖尿病的能力在不同动物物种中因剂量不同而不同，包括非人类灵长类动物。为了找到能以最小毒性引发糖尿病的最佳剂量，我们对低剂量和高剂量的STZ进行了比较。雄性食蟹猴(3~6岁)单次注射链脲佐菌素100 mg/kg(大剂量，4只)或55 mg/kg(小剂量，20只)。定期进行血糖水平、静脉葡萄糖耐量试验(IVGTT)、胰腺活检、肝功能检测(LFTs)、肝活检、肾功能检测和肾活检。两组动物在注射STZ后24小时内均出现糖尿病。两组患者血清C肽水平均由STZ前的2~8 ng/m L降至STZ后的0.01~0.6 ng/m L。注射高剂量STZ的动物在注射后几分钟内出现一过性呕吐。在注射STZ后的第一周，高剂量组动物出现了LFTS、BUN和肌酐的升高。相比之下，低剂量的动物肝肾功能测试正常。组织学分析显示，给予高剂量STZ的动物出现了明显的肝脏脂肪变性和肾脏小管损伤，而给予低剂量STZ的动物的肝和肾组织学看起来正常。胰岛素免疫过氧化物酶染色显示两组患者的胰岛都无法区分，要么没有胰岛素阳性细胞，要么罕见的胰岛素阳性细胞。胰高血糖素染色正常。随着时间的推移，低剂量糖尿病猴子持续保持高血糖，静脉注射葡萄糖对C肽的刺激可以忽略不计。结论：55 mg/mLSTZ可成功诱导食蟹猴糖尿病，且对肝脏和肾脏的毒性最小。
Streptozotocin (STZ) is often used to induce diabetes in animal models. However, morbidity associated with STZ and its ability to induce diabetes vary with different dosages among different animal species, including nonhuman primates. To find an optimal dose of STZ that would cause diabetes with minimal toxicity, we compared low and high doses of STZ. Male cynomolgus monkeys (3-6years old) were given a single dose of 100 mg/kg (high dose, 4 animals) or 55 mg/kg (low dose, 20 animals) of STZ. Blood glucose levels, intravenous glucose tolerance test (IVGTT), pancreatic biopsies, liver function tests (LFTs), liver biopsies, kidney function tests, and kidney biopsies were performed periodically. Animals from both groups developed diabetes within 24h after administration of STZ. Serum C-peptide levels in both groups decreased from 2 to 8 ng/mL before STZ to between 0.01 and 0.6ng/mL after STZ. Animals with the high dose of STZ developed transient vomiting within minutes after injection. During the first week after STZ injection, high-dose animals developed elevated LFTs, BUN and creatinine. In contrast, low-dose animals had normal liver and kidney function tests. Histological analysis showed that animals given the high dose of STZ developed marked steatosis of the liver and tubular injury in the kidneys, whereas animals given the low dose of STZ had normal-looking liver and kidney histology. The pancreatic islets in both groups were indistinguishable by immunoperoxidase staining for insulin, and showed either no insulin-positive cells or rare insulin-positive cells. Glucagon staining was normal. Over time, low-dose diabetic monkeys remained persistently hyperglycemic with negligible C-peptide stimulation by intravenous glucose. We conclude that low-dose STZ at 55mg/mL successfully induces diabetes in cynomolgus monkeys with minimal liver and kidney toxicity.