Shao Jia-qing, Iwashita Noseki, Du Hong, Wang Yan-yan, Zhao Ming, Wang Jian, Watada Hirotaka, Kawamori Ryuzo
Department of Endocrinology and Metabolism, Nanjing General Hospital of Nanjing Military Command, Nanjing 210002, China.
Zhonghua Nei Ke Za Zhi. 2007 Apr;46(4):306-10.
Several epidemiological studies suggested that treatment with angiotensin II type 1 receptor blocker provided a risk reduction of developing type 2 diabetes. The aim of this study was to investigate whether and how chronic candesartan treatment can attenuate the deleterious influence of hyperactive local intra-islet renin-angiotensin system in diabetes state and relieve hyperglycemia using diabetic (db/db) mice.
8-week-old db/db mice were randomized to candesartan cilexetil 1 mg/kg, candesartan cilexetil 10 mg/kg, manidipine 10 mg/kg, or placebo via gavage for 6 weeks. Their age-matched nondiabetic littermates db/m mice were given with placebo and acted as non-diabetic controls. After 6 weeks of treatment, intraperitoneal glucose tolerance test, immunohistochemical staining of oxidative stress markers, insulin, and electron microscopy observation of the pancreatic islet cells were performed.
Chronic candesartan treatment provided a slight improvement of glucose tolerance, but greatly rescued islet beta-cell mass. Candesartan treatment also notably decreased staining intensity of oxidative stress markers, as well as candesartan-treated animals exhibited improved granulation and less remarkable endoplasmic reticulum and Golgi bodies. Furthermore, candesartan treatment greatly relieved the swelling of mitochondria to nearly normal.
After diabetes is initiated, candesartan treatment does not reverse the state of diabetes, but it slightly improves glucose tolerance, and protects beta-cell function by attenuating oxidative stress and ultrastructure disruption. These benefits are independent of blood pressure lowering. The characteristics of candesartan may make itself a novel therapeutic means for protecting from progressive beta-cell failure in diabetes.
多项流行病学研究表明，使用1型血管紧张素II受体阻滞剂进行治疗可降低患2型糖尿病的风险。本研究旨在探讨慢性坎地沙坦治疗是否以及如何减轻糖尿病状态下胰岛局部肾素 - 血管紧张素系统活性过高的有害影响，并使用糖尿病（db/db）小鼠缓解高血糖。
将8周龄的db/db小鼠随机分为坎地沙坦酯1mg/kg组、坎地沙坦酯10mg/kg组、马尼地平10mg/kg组或安慰剂组，通过灌胃给药6周。将年龄匹配的非糖尿病同窝小鼠db/m给予安慰剂作为非糖尿病对照。治疗6周后，进行腹腔葡萄糖耐量试验、氧化应激标志物的免疫组化染色、胰岛素检测以及胰岛细胞的电子显微镜观察。
慢性坎地沙坦治疗使葡萄糖耐量略有改善，但极大地挽救了胰岛β细胞量。坎地沙坦治疗还显著降低了氧化应激标志物的染色强度，并且接受坎地沙坦治疗的动物表现出更好的颗粒形成，内质网和高尔基体不那么明显。此外，坎地沙坦治疗极大地缓解了线粒体肿胀，使其接近正常状态。
糖尿病发病后，坎地沙坦治疗并不能逆转糖尿病状态，但它可轻微改善葡萄糖耐量，并通过减轻氧化应激和超微结构破坏来保护β细胞功能。这些益处与血压降低无关。坎地沙坦的特性可能使其成为预防糖尿病中β细胞进行性衰竭的一种新型治疗手段。
