坎地沙坦对db/db糖尿病小鼠胰岛功能和结构的保护  

Protection of candesartan onβ-cell function and morphology in db/db mice

作　　者：邵加庆[1] 岩下乃夕 杜宏[1] 王燕燕[1] 赵明[1] 绵田裕孝 河盛隆造 王坚[1] 

机构地区：[1]南京军区南京总医院内分泌科,210002 [2]日本东京顺天堂大学内分泌科

出　　处：《中华内分泌代谢杂志》2007年第2期110-116,共7页Chinese Journal of Endocrinology and Metabolism

基　　金：日中笹川医学奖学金资助

摘　　要：目的探讨坎地沙坦治疗延缓糖尿病状态下胰岛功能的进行性衰竭和血糖持续升高的有效性和机制。方法将8周龄的db/db小鼠随机分为2组,分别给予6周坎地沙坦酯(1 mg/kg体重)或安慰剂灌胃治疗,同窝出生的8周龄的db/m小鼠作为非糖尿病对照亦给予安慰剂治疗。投药6周后行腹腔葡萄糖耐量试验后取胰腺,进行胰岛素、CD31、8-羟-2′-脱氧鸟苷[8-(OH)dG]、4-羟壬烯醛(4-HNE)、NADPH氧化酶等氧化应激标志的免疫组化检测以及电镜观察胰岛β细胞的超微结构紊乱情况。结果坎地沙坦治疗6周改善糖耐量,减少了胰岛β细胞丢失。坎地沙坦治疗显著减少氧化应激产物如8-(OH)dG、4-HNE、p22^(phox)、gp91^(phox)在胰岛的表达,同时减轻胰岛周围及内部的Azan蓝染的程度,增加胰岛内部内皮细胞标志CD31染色的强度。电镜观察发现坎地沙坦治疗显著增加β细胞内胰岛素颗粒的形成,明显减轻db/db糖尿病小鼠β细胞内质网和高尔基体的过度增殖以及线粒体肿胀。结论在糖尿病起病后,坎地沙坦治疗并不能逆转糖尿病,但是有效地改善了糖耐量,通过减轻氧化应激损伤、胰岛纤维化、胰岛β细胞超微结构紊乱,并改善胰岛供血,从而保护胰岛β细胞功能,延缓β细胞功能衰竭。Objective To investigate whether and how candesartan treatment can attenuate the deleterious influence of hyperglycemia in diabetic（db/db） mice. Methods Eight-week-old db/db mice were randomized into candesartan cilexetil （1 mg/kg） or placebo group via garage for 6 weeks. Their age-matched nondiabetic littermates db/m mice were treated with placebo and acted as non-diabetic control group. After 6 weeks＇ treatment, intraperitoneal glucose tolerance test, immunohistochemical stainings of oxidative stress markers [ 8-（OH） dG, 4- HNE, NADPH oxidase], insulin, CD31, Azan staining and electron microscopy observation of islet β-cells were perfermed. Results As compared with placebo group, the improvement in glucose tolerance and marked saving of islet β-cell mass with candesartan for 6 weeks were noted. There were also notably decreased staining intensity in oxidative stress markers, such as 8-（OH） dG, 4-HNE, p22^phox, gp91^phox, as well as attenuated intra-islet Azan staining and enhanced endothelium marker CD31 staining in islet. Under electron microscope, candesartan-treated mice showed significantly increased granulation of insulin and ameliorated proliferations of endoplasmic reticulum and Golgi bodies. Furthermore, swelling of mitochondria was relieved to nearly normal. Conclusion After diabetic onset, candesartan treatment does not reverse the state of diabetes but may effectively improve glucose tolerance and protect β-cell function by attenuating oxidative stress, islet fibrosis, sparsity of blood supply and uhrastructure disruption, and thus delays the β-cell failure.

关 键 词：氧化应激 肾素-血管紧张素系统 血管紧张素Ⅱ 1型受体阻断剂 胰岛 糖尿病 2型 

分 类 号：R587.1[医药卫生—内分泌]