Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome
Long-term AICAR administration reduces metabolic disturbances and lowers blood pressure in rats displaying features of the insulin resistance syndrome
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DOI：
10.2337/diabetes.51.7.2199
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发表时间：
2002-07-01
期刊：
影响因子：
7.7
通讯作者：
Lund, S
中科院分区：
文献类型：
--
作者：
Buhl, ES;Jessen, N;Lund, S
胰岛素抵抗综合征的特征是心血管疾病的几个危险因素。腺苷类似物5-氨基咪唑-4-甲酰胺1-β-D-呋喃核糖苷（AICAR）对AMP活化蛋白激酶的慢性化学活化已被证明可增强胰岛素作用，上调骨骼肌中的线粒体酶，并降低腹内脂肪含量。此外，已发现急性AICAR暴露减少体外孵育的大鼠肝细胞中的固醇和脂肪酸合成，以及在正葡萄糖钳夹条件下抑制大鼠中的内源性葡萄糖产生。为了研究长期施用AICAR除了对胰岛素敏感性的有益作用之外是否能够改善与胰岛素抵抗综合征相关的其它表型，将表现出胰岛素抵抗、高脂血症和高血压的肥胖Zucker（fa/fa）大鼠（n = 6）每天皮下注射AICAR（0.5mg/g体重），持续7周。肥胖对照组大鼠为配对喂养（PF）（n = 6）或随意喂养（AL）（n = 6）。瘦Zucker大鼠（fa/-）（n = 8）作为参照组。AICAR给药显著降低了血浆甘油三酯水平（AICAR与AL相比P < 0.01，AICAR与PF相比P = 0.05）和游离脂肪酸水平（AICAR与AL相比P < 0.01，AICAR与PF相比P < 0.05），并增加了HDL胆固醇水平（AICAR与AL和PF相比P < 0.01）。AICAR治疗还使收缩压降低了14.6 +/- 4.3 mmHg（P < 0.05），AICAR治疗的动物表现出腹内脂肪含量降低的趋势。此外，AICAR给药使口服葡萄糖耐量试验正常化，并使葡萄糖和胰岛素的空腹浓度降低至接近瘦动物的水平。最后，与先前的发现一致，还发现AICAR处理增强GLUT 4蛋白表达，并在主要是白色快缩肌肉中最大程度地增加胰岛素刺激的葡萄糖转运。我们的数据提供了强有力的证据表明，长期给予AICAR改善葡萄糖耐量，改善血脂谱，并降低胰岛素抵抗动物模型的收缩压。本研究进一步支持AMPK激活可能是治疗胰岛素抵抗综合征的潜在未来药理学策略的假设。
The insulin resistance syndrome is characterized by several risk factors for cardiovascular disease. Chronic chemical activation of AMP-activated protein kinase by the adenosine analog 5-aminoimidazole-4-carboxamide1-beta-D-ribofuranoside (AICAR) has been shown to augment insulin action, upregulate mitochondrial enzymes in skeletal muscles, and decrease the content of intra-abdominal fat. Furthermore, acute AICAR exposure has been found to reduce sterol and fatty acid synthesis in rat hepatocytes incubated in vitro as well as suppress endogenous glucose production in rats under euglycemic clamp conditions. To investigate whether chronic AICAR administration, in addition to the beneficial effects on insulin sensitivity, is capable of improving other phenotypes associated with the insulin resistance syndrome, obese Zucker (fa/fa) rats (n = 6) exhibiting insulin resistance, hyperlipidemia, and hypertension were subcutaneously injected with AICAR (0.5 mg/g body wt) daily for 7 weeks. Obese control rats were either pair-fed (PF) (n = 6) or ad libitum-fed (AL) (n = 6). Lean Zucker rats (fa/-) (n = 8) served as a reference group. AICAR administration significantly reduced plasma triglyceride levels (P < 0.01 for AICAR vs. AL, and P = 0.05 for AICAR vs. PF) and free fatty acids (P < 0.01 for AICAR vs. AL, and P < 0.05 for AICAR vs. PF) and increased HDL cholesterol levels (P < 0.01 for AICAR vs. AL and PF). AICAR treatment also lowered systolic blood pressure by 14.6 +/- 4.3 mmHg (P < 0.05), and AICAR-treated animals exhibited a tendency toward decreased intra-abdominal fat content. Furthermore, AICAR administration normalized the oral glucose tolerance test and decreased fasting concentrations of glucose and insulin close to the level of the lean animals. Finally, in line with previous findings, AICAR treatment was also found to enhance GLUT4 protein expression and to increase maximally insulin-stimulated glucose transport in primarily white fast-twitch muscles. Our data provide strong evidence that long-term administration of AICAR improves glucose tolerance, improves the lipid profile, and reduces systolic blood pressure in an insulin-resistant animal model. The present study gives additional support to the hypothesis that AMPK activation might be a potential future pharmacological strategy for treating the insulin resistance syndrome.