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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 the efficacy and mechanism of candesartan in the treatment of progressive failure of pancreatic islet function and persistent hyperglycemia in diabetic condition. Methods 8-week-old db / db mice were randomly divided into 2 groups. The mice were treated with candesartan cilexetil (6 mg / kg body weight) for 6 weeks or placebo. The db / m mice were also given placebo as non-diabetic controls. Six weeks after the administration, the pancreas was obtained from the intraperitoneal glucose tolerance test and insulin, CD31, 4-hydroxynonenal (4-HNE), NADPH oxidase Immunohistochemical detection of oxidative stress markers and ultrastructural disorders of islet β cells were observed by electron microscopy. Results Candesartan improved glucose tolerance at 6 weeks and decreased pancreatic β-cell loss. Candesartan treatment significantly reduced the expression of oxidative stress products such as 8- (OH) dG, 4-HNE, p22 ~ (phox), gp91 ~ (phox) in the islets and reduced the Azan blue staining in and around the islets Extent, increase the intensity of CD31 staining of islet endothelial cells. Electron microscopy showed that candesartan significantly increased the formation of intracellular β-cell insulin particles and significantly inhibited the over-proliferation of endoplasmic reticulum and Golgi bodies and the mitochondrial swelling of β-cells in db / db diabetic mice. Conclusions Candesartan does not reverse diabetes mellitus after onset of diabetes, but effectively improves glucose tolerance. It improves oxidative stress injury, islet fibrosis, ultrastructural dysfunction of pancreatic β cells, and improves islet blood supply by reducing oxidative stress Protection of pancreatic β-cell function, delay β-cell failure.