AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats
AICAR administration causes an apparent enhancement of muscle and liver insulin action in insulin-resistant high-fat-fed rats
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DOI：
10.2337/diabetes.51.10.2886
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发表时间：
2002-10-01
期刊：
影响因子：
7.7
通讯作者：
Kraegen, EW
中科院分区：
文献类型：
--
作者：
Iglesias, MA;Ye, JM;Kraegen, EW
运动可以提高胰岛素敏感性。由于AMIP活化蛋白激酶（AMPK）在运动时肌肉代谢中起重要作用，我们研究了AMPK激活剂5-氨基咪唑-4-甲酰胺-1-β-呋喃核糖苷（AICAR）对胰岛素抵抗高脂喂养（HF）大鼠胰岛素作用的影响。大鼠接受皮下注射250 mg/kg AICAR（HF-AIC）或盐水（HF-Con）。第二天，进行正常血糖-高胰岛素钳夹研究。与HF-Con大鼠相比，HF-AIC中钳夹期间的葡萄糖输注速率增强（50%）。胰岛素刺激的葡萄糖摄取在白色股四头肌中得到改善，但在红色股四头肌中没有改善，而糖原合成在HF-AIC大鼠的红色和白色股四头肌中都得到改善。HF-AIC大鼠还表现出增加的胰岛素抑制肝葡萄糖输出（HGO）。AICAR诱导的肝脏和肌肉反应伴随着丙二酰辅酶A含量的降低。钳夹HGO与肝脏甘油三酯含量密切相关（r = 0.67，P < 0.01）。因此，单剂量AICAR导致HF大鼠全身、肌肉和肝脏胰岛素作用的明显增强，其延长超过AMFK活化的预期时间。组织脂质代谢的改变是否介导AICAR对胰岛素作用的影响仍有待确定。后续研究表明，至少有一些AICAR后胰岛素增强效应也发生在正常大鼠中。与此无关，结果表明AMFK的药理学激活可能具有治疗胰岛素抵抗状态和2型糖尿病的潜力。
Exercise improves insulin sensitivity. As AMIP-activated protein kinase (AMPK) plays an important role in muscle metabolism during exercise, we investigated the effects of the AMPK activator 5-aminoimidazole-4-carboxamide-1-beta-ribofuranoside (AICAR) on insulin action in insulin-resistant high-fat-fed (HF) rats. Rats received a subcutaneous injection of 250 mg/kg AICAR (HF-AIC) or saline (HF-Con). The next day, euglycemic-hyperinsulinemic clamp studies were performed. Glucose infusion rate during the clamp was enhanced (50%) in HF-AIC compared with HF-Con rats. Insulin-stimulated glucose uptake was improved in white but not in red quadriceps, whereas glycogen synthesis was improved in both red and white quadriceps of HF-AIC rats. HF-AIC rats also showed increased insulin suppressibility of hepatic glucose output (HGO). AICAR-induced responses in both liver and muscle were accompanied by reduced malonyl-CoA content. Clamp HGO correlated closely with hepatic triglyceride content (r = 0.67, P < 0.01). Thus, a single dose of AICAR leads to an apparent enhancement in whole-body, muscle, and liver insulin action in HF rats that extends beyond the expected time of AMFK activation. Whether altered tissue lipid metabolism mediates AICAR effects on insulin action remains to be determined. Follow-up studies suggest that at least some of the post-AICAR insulin-enhancing effects also occur in normal rats. Independent of this, the results suggest that pharmacological activation of AMFK may have potential in treating insulin-resistant states and type 2 diabetes.