CAJ | 학술논문

背景:为了提高人类同种胰岛移植的临床疗效,于临床前研究设计良好大型动物模型如猪或灵长类动物是至关重要的.目的:评价不同剂量链脲酶素诱导非人类灵长类1型糖尿病模型的效能.设计、时间及地点:对比观察动物实验,于2007-10/2008-12在中南大学湘雅三医院细胞移植与基因治疗中心完成.材料:成年健康雄性恒河猴21只分为:125mg/kg链脲酶素组(n=5)、75mg/kg链脲酶素组(n=5)、50mg/kg链脲酶素组(n=11).方法:根据动物体质量,称取一定量链脲酶素,用预先配制好的缓冲液,配制为25 g,L,过滤消毒.将新鲜配置的链脲酶素按125,75,50 mg/kg剂量分别注入3组实验猴静脉内,药物注射时间为1-5 min.主要观察指标:观察用药后1-16周动物的肝、肾功能,葡萄糖代谢和组织形态学变化.结果:在125 mg/kg剂量下,由于胰腺B细胞严重受损, 2只恒河猴在给予链脲菌素后8 h因严重低血糖死亡;该组恒河猴给药1周出现肝脏转氨酶及血肌酐、尿素氮的显著升高,2-4周达峰值,1只恒河猴于链脲酶素给药后由于内源性胰岛素严重不足,外源性胰岛素不能纠正其高血糖状态,最终发生严重的糖代谢紊乱、酮症酸中毒、肝肾功能衰竭于第13天死亡,存活2只恒河猴在观察期间内肝脏转氨酶及血尿素氮、血肌酐均维持在较高水平;在75 mg/kg剂量下,恒河猴在链脲酶素给药一两周出现肝脏转氨酶及血肌酐、尿素氮的显著升高,4周后肝肾功能仍表现为不同程度的异常,其中1只恒河猴于注入链脲酶素后出现肾功能损害及机体抵抗力低下,出现眼睑肿胀、全身浮肿及臀部感染不愈,于链脲酶素给药后5周而死亡,1只动物于注入链脲酶素后出现持续高血糖状态不能纠正、食欲不振,体质量显著下降,因全身衰竭而于注药后第9周死亡:在给予50 mg/kg的剂量,肝肾功能的影响较小,表现为一过性轻度升高,4周后基本可恢复正常范围,该组仅3只动物注药后1-4周出现眼睑水肿,随后水肿消退.结论:低剂量50 mg/kg链脲酶素可能是构建多数恒河猴糖尿病模型的最佳剂量. 揹景:為瞭提高人類同種胰島移植的臨床療效,于臨床前研究設計良好大型動物模型如豬或靈長類動物是至關重要的.目的:評價不同劑量鏈脲酶素誘導非人類靈長類1型糖尿病模型的效能.設計、時間及地點:對比觀察動物實驗,于2007-10/2008-12在中南大學湘雅三醫院細胞移植與基因治療中心完成.材料:成年健康雄性恆河猴21隻分為:125mg/kg鏈脲酶素組(n=5)、75mg/kg鏈脲酶素組(n=5)、50mg/kg鏈脲酶素組(n=11).方法:根據動物體質量,稱取一定量鏈脲酶素,用預先配製好的緩遲液,配製為25 g,L,過濾消毒.將新鮮配置的鏈脲酶素按125,75,50 mg/kg劑量分彆註入3組實驗猴靜脈內,藥物註射時間為1-5 min.主要觀察指標:觀察用藥後1-16週動物的肝、腎功能,葡萄糖代謝和組織形態學變化.結果:在125 mg/kg劑量下,由于胰腺B細胞嚴重受損, 2隻恆河猴在給予鏈脲菌素後8 h因嚴重低血糖死亡;該組恆河猴給藥1週齣現肝髒轉氨酶及血肌酐、尿素氮的顯著升高,2-4週達峰值,1隻恆河猴于鏈脲酶素給藥後由于內源性胰島素嚴重不足,外源性胰島素不能糾正其高血糖狀態,最終髮生嚴重的糖代謝紊亂、酮癥痠中毒、肝腎功能衰竭于第13天死亡,存活2隻恆河猴在觀察期間內肝髒轉氨酶及血尿素氮、血肌酐均維持在較高水平;在75 mg/kg劑量下,恆河猴在鏈脲酶素給藥一兩週齣現肝髒轉氨酶及血肌酐、尿素氮的顯著升高,4週後肝腎功能仍錶現為不同程度的異常,其中1隻恆河猴于註入鏈脲酶素後齣現腎功能損害及機體牴抗力低下,齣現眼瞼腫脹、全身浮腫及臀部感染不愈,于鏈脲酶素給藥後5週而死亡,1隻動物于註入鏈脲酶素後齣現持續高血糖狀態不能糾正、食欲不振,體質量顯著下降,因全身衰竭而于註藥後第9週死亡:在給予50 mg/kg的劑量,肝腎功能的影響較小,錶現為一過性輕度升高,4週後基本可恢複正常範圍,該組僅3隻動物註藥後1-4週齣現眼瞼水腫,隨後水腫消退.結論:低劑量50 mg/kg鏈脲酶素可能是構建多數恆河猴糖尿病模型的最佳劑量.
배경:위료제고인류동충이도이식적림상료효,우림상전연구설계량호대형동물모형여저혹령장류동물시지관중요적.목적:평개불동제량련뇨매소유도비인류령장류1형당뇨병모형적효능.설계、시간급지점:대비관찰동물실험,우2007-10/2008-12재중남대학상아삼의원세포이식여기인치료중심완성.재료:성년건강웅성항하후21지분위:125mg/kg련뇨매소조(n=5)、75mg/kg련뇨매소조(n=5)、50mg/kg련뇨매소조(n=11).방법:근거동물체질량,칭취일정량련뇨매소,용예선배제호적완충액,배제위25 g,L,과려소독.장신선배치적련뇨매소안125,75,50 mg/kg제량분별주입3조실험후정맥내,약물주사시간위1-5 min.주요관찰지표:관찰용약후1-16주동물적간、신공능,포도당대사화조직형태학변화.결과:재125 mg/kg제량하,유우이선B세포엄중수손, 2지항하후재급여련뇨균소후8 h인엄중저혈당사망;해조항하후급약1주출현간장전안매급혈기항、뇨소담적현저승고,2-4주체봉치,1지항하후우련뇨매소급약후유우내원성이도소엄중불족,외원성이도소불능규정기고혈당상태,최종발생엄중적당대사문란、동증산중독、간신공능쇠갈우제13천사망,존활2지항하후재관찰기간내간장전안매급혈뇨소담、혈기항균유지재교고수평;재75 mg/kg제량하,항하후재련뇨매소급약일량주출현간장전안매급혈기항、뇨소담적현저승고,4주후간신공능잉표현위불동정도적이상,기중1지항하후우주입련뇨매소후출현신공능손해급궤체저항력저하,출현안검종창、전신부종급둔부감염불유,우련뇨매소급약후5주이사망,1지동물우주입련뇨매소후출현지속고혈당상태불능규정、식욕불진,체질량현저하강,인전신쇠갈이우주약후제9주사망:재급여50 mg/kg적제량,간신공능적영향교소,표현위일과성경도승고,4주후기본가회복정상범위,해조부3지동물주약후1-4주출현안검수종,수후수종소퇴.결론:저제량50 mg/kg련뇨매소가능시구건다수항하후당뇨병모형적최가제량.
BACKGROUND: It is of great importance in improving the clinical effect of human islet allograft to study and design models of such large animals as pigs or primates preclinically.OBJECTIVE: To evaluate the effect of different doses of streptozotocin (STZ) on inducing diabetes type Ⅰ models of nonhuman primates.DESIGN, TIME AND SETTING: A contrast observational animal experiment was performed in the Cell Transplantation and Gene Therapy Center, the Third Xiangya Hospital of Central South University from October 2007 to December 2008. MATERIALS: A total of 21 adult male rhesus monkeys were divided into a 125 mg/kg STZ group (n =5), a 75 mg/kg STZ group (n=5) and a 50 mg/kg STZ group (n=11).METHODS: STZ weighed with regard to body mass of animals was prepared into 25 g/L STZ solution with buffer that was prepared in advance. After being filtered and degermed, the new-prepared STZ of 125 mg/kg, 75 mg/kg and 50 mg/kg were administered by intravenous injection into the experimental monkeys respectively, which took 1-5 minutes.MAIN OUTCOME MEASURES: Liver and renal function, glucose metabolism and histomorphological changes of animals during 1-16 weeks following administration.RESULTS: In 125 mg/kg STZ group, two rhesus monkeys died, in 8 hours following STZ administration, of serious hypoglycemia caused by severely damaged pancreas β cells; All rhesus monkeys in this group had got significantly increased liver transaminase, serum creatinine and urea nitrogen at week 1 following STZ administration, which reached a peak during 2-4 weeks; One rhesus monkey in this group showed severe shortage of endogenous trypsin and hyperglycemia irreversible by exogenous insulin following STZ administration, and finally died at day 13 following STZ administration due to the glucose metabolic disorder, ketoacidosis, liver and renal failure; The other two survivors in this group kept high level of liver transaminase,urea nitrogen and serum creatinine throughout the observation period. In 75 mg/kg STZ group, rhesus monkeys presented significantly increased liver transaminase, serum creatinine and urea nitrogen at week 1-2 following STZ administration; After 4 weeks following administration, their liver and renal function presented with abnormality of different degrees; One rhesus monkey in this group had got injured renal function, decreased power of resistance, eyelid edema, general dropsy and irreversible infected rump after injection of STZ, and finally died at the end of week 5 following administration; Another rhesus in this group presented with irreversible continuous hyperglycemia, inappetence and significantly decreased weight, and finally died ofsystemic failure at week 9 following administration. In the 50 mg/kg STZ group, renal function of monkeys were slightly affected, with a transient mild rise which return to the normal level by the end of week 4 following administration; Only 3 animals in this group appeared eyelid edema during 1-4 weeks following administration which disappeared afterwards.CONCLUSION: STZ of 50 mg/kg is possibly the optimal dose for inducing diabetes models in most rhesus monkeys.