2-(3,4-Dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), a novel, synthetic small molecule that alleviates insulin resistance and lipid abnormalities.
2-(3,4-Dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), a novel, synthetic small molecule that alleviates insulin resistance and lipid abnormalities.
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DOI：
10.1016/j.bcp.2009.09.018
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发表时间：
2010-02-15
影响因子：
5.8
通讯作者：
Sreejayan, Nair
中科院分区：
文献类型：
--
作者：
Kandadi, Machender R.;Rajanna, Prabhakar K.;Unnikrishnan, Mazhuvancherry K.;Boddu, Sai P.;Hua, Yinan;Li, Ji;Du, Min;Ren, Jun;Sreejayan, Nair
2型糖尿病在世界范围内正以流行病的比例增长。本报告描述了一种新的合成小分子2-（3，4-二氢-2H-吡咯-1-基）-3-氧代茚满-1-酸酯（DHPO）对2型糖尿病遗传和饮食小鼠模型代谢异常的影响。DHPO（20 mg/kg/d i. p.，持续21天）在胰岛素抵抗的遗传（瘦素缺乏，ob/ob）和饮食（高脂肪喂养）小鼠模型中降低空腹血糖，改善葡萄糖处置并纠正血脂异常。此外，DHPO增强2-脱氧-D-葡萄糖（2DG）的摄取在腓肠肌的野生型小鼠和培养的肌管。2DG摄取的增加与AMPK（Thr-172）及其下游效应物乙酰辅酶A羧化酶磷酸化的增加相关，而胰岛素受体Akt磷酸化无任何变化。AMPK抑制剂化合物C减弱DHPO诱导的葡萄糖摄取，而PI 3-激酶抑制剂渥曼青霉素效果较差。此外，DHPO未能增加AMPK-α2转基因（激酶死亡）小鼠腓肠肌的葡萄糖摄取。综上所述，这些结果表明，DHPO是一种新的小分子，它能缓解与2型糖尿病相关的糖耐量受损和脂质异常。
Type-2 diabetes is growing at epidemic proportions world-wide. This report describes the effect of a novel, synthetic, small molecule 2-(3, 4-dihydro-2H-pyrrolium-1-yl)-3oxoindan-1-olate (DHPO), on metabolic abnormalities in genetic and dietary mouse models of type-2 diabetes. DHPO (20mg/kg/d i.p. for 21d) attenuated fasting blood glucose, improved glucose disposal and corrected dyslipidemia in genetic (leptin deficient, ob/ob) and dietary (high-fat-fed) mouse models of insulin resistance. In addition, DHPO augmented 2-deoxy-D-glucose (2DG) uptake in gastrocnemius muscles of wild-type mice and in cultured myotubes. The increase in 2DG-uptake was associated with an increase in the phosphorylation of AMPK (Thr-172) and its downstream effector acetyl-CoA carboxylase without any changes in the phosphorylation of Akt of insulin receptor. The AMPK inhibitor, compound C attenuated DHPO-induced glucose uptake whereas the PI3-kinase inhibitor Wortmannin was less effective. In addition, DHPO failed to augment glucose up-take in the gastrocnemius muscle from AMPK-α2-transgenic (kinase-dead) mice. Taken together, these results suggest that DHPO is a novel small molecule that alleviates impaired glucose tolerance and lipid abnormalities associated with type 2 diabetes.
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影响因子：
158.5
作者：
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通讯作者：
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