Antidiabetic effects of 11β-HSD1 inhibition in a mouse model of combined diabetes, dyslipidaemia and atherosclerosis
Antidiabetic effects of 11β-HSD1 inhibition in a mouse model of combined diabetes, dyslipidaemia and atherosclerosis
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DOI：
10.1111/j.1463-1326.2009.01034.x
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发表时间：
2009-07-01
影响因子：
5.8
通讯作者：
Veniant, M. M.
中科院分区：
文献类型：
--
作者：
Lloyd, D. J.;Helmering, J.;Veniant, M. M.
11 β-羟基类固醇脱氢酶1型（11 β-HSD 1）被认为是导致代谢综合征的病因，特异性抑制剂已开始作为胰岛素抵抗和该综合征其他方面（包括动脉粥样硬化）的治疗药物出现。考虑到糖皮质激素和11 β-HSD 1在抗炎反应中的作用以及炎症在动脉粥样硬化发展中的参与，11 β-HSD 1抑制可能加剧动脉粥样硬化。我们的目的是在体内研究特异性11 β-HSD 1抑制剂（2922）对动脉粥样硬化的影响，同时评估葡萄糖稳态。（三种剂量，3、10和100 mg/kg体重）（Ldlr（-/-）Apob（100/100）Lep（ob/ob））小鼠，肥胖、胰岛素抵抗、血脂异常和动脉粥样硬化的遗传模型。罗格列酮和辛伐他汀用于测试我们的模型在两种类型的治疗中的反应性。2922在降低腹股沟脂肪组织中的11 β-HSD 1活性方面是有效的（对于100 mg/kg> 90%），并且在剂量>= 10 mg/kg时在改善葡萄糖稳态方面是有效的。与对照动物相比，用2922（100 mg/kg）处理的小鼠的血浆胰岛素、血糖、葡萄糖耐量和稳态模型评估指数均得到改善。尽管这些参数有所改善，但在2922处理的小鼠中未观察到体重、脂肪或瘦组织质量的差异。有趣的是，循环脂质、促炎细胞因子和动脉粥样硬化在对2922的反应中没有改变，尽管检测到LDL胆固醇的小幅降低。重要的是，11 β-HSD 1抑制导致葡萄糖代谢改善，并且不会导致动脉粥样硬化病变面积的恶化，但在面对多种严重代谢异常时仍保留了抗糖尿病的潜力。这项研究加强了11 β-HSD 1抑制剂在代谢综合征患者中的潜在用途，而不会对动脉粥样硬化产生负面影响。
11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) is considered to contribute to the aetiology of the metabolic syndrome, and specific inhibitors have begun to emerge as treatments for insulin resistance and other facets of the syndrome, including atherosclerosis. Given the role of glucocorticoids and 11 beta-HSD1 in the anti-inflammatory response and the involvement of inflammation in the development of atherosclerosis, 11 beta-HSD1 inhibition may exacerbate atherosclerosis. Our aim was to investigate in vivo the effects of a specific 11 beta-HSD1 inhibitor (2922) on atherosclerosis while assessing glucose homeostasis.We conducted a 12-week study administering 2922 (at three doses, 3, 10 and 100 mg/kg body weight) in Ldlr 3KO (Ldlr(-/-) Apob(100/100) Lep(ob/ob)) mice, a genetic model of obesity, insulin resistance, dyslipidaemia and atherosclerosis. Rosiglitazone and simvastatin were used to test the responsiveness of our model in both types of therapy.2922 was effective in reducing 11 beta-HSD1 activity in inguinal adipose tissue (> 90% for 100 mg/kg) and was efficacious in improving glucose homeostasis at doses >= 10 mg/kg. Plasma insulin, blood glucose, glucose tolerance and homeostatic model assessment indices were all improved in mice treated with 2922 (100 mg/kg) compared with control animals. Despite an improvement in these parameters, no differences were observed in body weight, adipose or lean tissue masses in the 2922-treated mice. Interestingly, circulating lipids, proinflammatory cytokines and atherosclerosis were unaltered in response to 2922, although a small reduction in LDL cholesterol was detected.Importantly, 11 beta-HSD1 inhibition leads to improved glucose metabolism and does not result in a worsening of atherosclerotic lesion area, yet retained antidiabetic potential in the face of multiple severe metabolic aberrations. This study reinforces the potential use of 11 beta-HSD1 inhibitors in patients with the metabolic syndrome without negatively impacting atherosclerosis.