Koulmanda M, Qipo A, Chebrolu S, O'Neil J, Auchincloss H, Smith R N
Islet Transplantation Laboratory, Department of Surgery, Department of Pathology, Massachusetts General Hospital, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02114, USA.
Am J Transplant. 2003 Mar;3(3):267-72. doi: 10.1034/j.1600-6143.2003.00040.x.
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 (3-6 years 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 24 h 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 0.6 ng/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 55 mg/mL successfully induces diabetes in cynomolgus monkeys with minimal liver and kidney toxicity.
链脲佐菌素（STZ）常用于诱导动物模型患糖尿病。然而，与STZ相关的发病率及其诱导糖尿病的能力在不同动物物种（包括非人灵长类动物）中因剂量不同而有所差异。为了找到能以最小毒性引发糖尿病的STZ最佳剂量，我们比较了低剂量和高剂量的STZ。给3至6岁的雄性食蟹猴分别单次注射100 mg/kg（高剂量，4只动物）或55 mg/kg（低剂量，20只动物）的STZ。定期进行血糖水平、静脉葡萄糖耐量试验（IVGTT）、胰腺活检、肝功能检查（LFTs）、肝脏活检、肾功能检查和肾脏活检。两组动物在注射STZ后24小时内均患糖尿病。两组动物的血清C肽水平从注射STZ前的2至8 ng/mL降至注射后0.01至0.6 ng/mL之间。高剂量STZ组的动物在注射后几分钟内出现短暂呕吐。在注射STZ后的第一周，高剂量组动物的肝功能检查、血尿素氮（BUN）和肌酐升高。相比之下，低剂量组动物的肝脏和肾功能检查结果正常。组织学分析表明，高剂量STZ组的动物出现明显的肝脏脂肪变性和肾脏肾小管损伤，而低剂量STZ组的动物肝脏和肾脏组织学外观正常。两组动物的胰岛通过胰岛素免疫过氧化物酶染色无法区分，且要么没有胰岛素阳性细胞，要么只有罕见的胰岛素阳性细胞。胰高血糖素染色正常。随着时间推移,低剂量糖尿病猴持续高血糖，静脉注射葡萄糖对C肽的刺激可忽略不计。我们得出结论，55 mg/mL的低剂量STZ能成功诱导食蟹猴患糖尿病，且对肝脏和肾脏的毒性最小。
