11β-HSD1在糖皮质激素联合高脂喂养大鼠胰岛素抵抗中的作用

Effects of 11β-hydroxysteroid dehydrogenase type 1 on insulin resistance in rats induced by glucocorticoid and high fat diet

目的通过糖皮质激素联合高脂喂养建立胰岛素抵抗动物模型，探讨11β-羟类固醇脱氢酶1（11β-HSD1）在该模型中的表达和意义。方法32只雄性Wistar大鼠，按体重随机区组法分为对照组、地塞米松组、高脂饮食组、高脂＋地塞米松组（HFD＋DEX组），每组8只。对照组和地塞米松组喂以普通饲料，高脂饮食组和HFD＋DEX组喂以高脂饲料，8周后地塞米松组和HFD＋DEX组辅以地塞米松刺激，12周后进行胰岛素耐量试验，检测血糖、血脂、血胰岛素及皮质酮水平，计算肝指数、内脏肥胖指数及稳态模型评估一胰岛素抵抗（HOMA-IR）指数，检测11β—HSD1基因及蛋白表达情况。结果与对照组相比，其余3组均出现胰岛素抵抗，表现为：胰岛素耐量试验不敏感（注射胰岛素30min后对照组、高脂饮食组、地塞米松组和HFD＋DEX组血糖值分别下降了44．15％，28．14％，32．58％，13．53％）、高血糖、高胰岛素血症、血脂紊乱（总胆固醇、甘油三酯及游离脂肪酸升高，高密度脂蛋白．胆固醇降低）、HOMA-IR指数、肝指数及内脏肥胖指数升高，且HFD＋DEX组各项指标变化幅度最大（F=10．89～213．20，P〈0．05或P〈0．01）。另外，与对照组相比，其余3组内脏脂肪组织11β-HSD1基因及蛋白表达水平也明显升高，且HFD＋DEX组明显高于高脂饮食组及地塞米松组（F=32．64～116．00，P均〈0．01）。结论地塞米松联合高脂饮食喂养可成功建立大鼠胰岛素抵抗模型，内脏脂肪组织中11β-HSD1基因及蛋白表达升高，可能与胰岛素抵抗的发生密切相关。

Objective To set up an insulin-resistant （IR） animal model by glucocorticoid and high-fat diet, and investigate the expression of 11β-hydroxysteroid dehydrogenase type 1 （ 11β-HSD1 ） in this model and its significance. Methods Thirty-two male Wistar rats were randomly divided into four groups according to body weight randomized blocks ： control group, dexamethasone group （ DEX group）, high-fat diet group （ HFD group）, and high-fat diet plus dexamethasone group （ HFD ＋ DEX group）, with 8 rats in each group. Rats in control group and DEX group were fed with standard rat chow diet, while rats in HFD group and HFD ＋DEX group were fed with fat- and sugar-enriched diet. After 8 weeks ,dexamethasone was injected subcutaneously to DEX group and HFD ＋ DEX group. After 12 weeks, insulin tolerance test was performed, and levels of blood glucose, lipid, insulin and corticosterone were measured. Liver index, visceral obesity index and homeostasis model assessment for insulin resistance （HOMA-IR） were calculated, the expression of 11β-HSD1 gene and protein were measured. Results Compared with control group, IR was successfully induced in the other three groups, characterized by insensitivity in insulin tolerance test （ 30 minutes after insulin injection, blood glucose decreased by 44.15% ,28.14% ,32.58% or 13.53% in control group, HFD group, DEX group and HFD ＋ DEX group, respectively）, hyperglycosemia, hyperinsulinemia, dyslipidemia （elevated total cholesterol, triglyceride and free fatty acids, but reduced high density lipo- protein cholesterol）, and the increase of HOMA-IR, hepatic index and visceral obesity index, especially in HFD ＋ DEX group （F = 10.89-213.20, P 〈 0.05 or 〈 0.01 ）. In addition, compared with control group, levels of 11β-HSD1 mRNA and protein in visceral adipose tissue of the other three groups were increased sig- nificantly, especially in HFD ＋ DEX group （ F = 32.64-116.00, P 〈 0.01 ）. Conclusion The combination of dexamethasone and high-fat diet can induce IR in rat successfully, and the expression of 11β-HSD1 mRNA and protein in viseral adipose tissue are increased,which may be closely related to the occurrence of IR.