Decreased acylcarnitine content improves insulin sensitivity in experimental mice models of insulin resistance
Decreased acylcarnitine content improves insulin sensitivity in experimental mice models of insulin resistance
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DOI：
10.1016/j.phrs.2015.11.014
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发表时间：
2016-11-01
影响因子：
9.3
通讯作者：
Dambrova, Maija
中科院分区：
文献类型：
--
作者：
Liepinsh, Edgars;Makrecka-Kuka, Marina;Dambrova, Maija
胰岛素抵抗的重要病理后果是由累积的长链脂肪酸及其各自的酰基肉毒碱的有害作用引起的。本研究的目的是测试运动结合降低长链酰基肉毒碱的含量是否是改善糖尿病患者胰岛素敏感性的有效策略。（二甲基）氨基丁酸（甲基-GBB），治疗和运动以降低高脂饮食（HFD）喂养的C57 BL/6小鼠和db/db小鼠的胰岛素抵抗模型中血浆和肌肉中的酰基肉毒碱含量。甲基-GBB处理在进食和禁食状态以及当其与运动组合时诱导所有酰基肉毒碱浓度的实质性降低。在HFD喂养的小鼠中，甲基-GBB治疗改善了葡萄糖和胰岛素耐受性。甲基-GBB给药、运动和两者的组合改善了db/db小鼠的胰岛素敏感性并降低了血糖水平。MethylGBB给药以及药物与运动的组合激活了PPARce/PGCla信号通路并刺激了相应的靶基因表达。db/db小鼠的胰岛素不敏感性不是由显著增加的脂肪酸代谢引起的，而两种治疗引起的胰岛素敏感性增加与肌肉中脂肪酸代谢的降低无关，显著降低的长链酰基肉碱含量是改善胰岛素敏感性的有效策略。甲基-GBB治疗和通过每天增加一小时的体力活动改变生活方式在db/db小鼠中具有累加的胰岛素增敏作用。(C)2015爱思唯尔有限公司版权所有。
The important pathological consequences of insulin resistance arise from the detrimental effects of accumulated long-chain fatty acids and their respective acylcarnitines. The aim of this study was to test whether exercise combined with decreasing the content of long-chain acylcarnitines represents an effective strategy to improve insulin sensitivity in diabetes.We used a novel compound, 4-[ethyl(dimethyl)ammoniolbutanoate (methyl-GBB), treatment and exercise to decrease acylcarnitine contents in the plasma and muscles in the insulin resistance models of high fat diet (HFD) fed C57BL/6 mice and db/db mice.The methyl-GBB treatment induced a substantial decrease in all acylcarnitine concentrations in both fed and fasted states as well as when it was combined with exercise. In the HFD fed mice methyl-GBB treatment improved both glucose and insulin tolerance. Methyl-GBB administration, exercise and the combination of both improved insulin sensitivity and reduced blood glucose levels in db/db mice. MethylGBB administration and the combination of the drug and exercise activated the PPARce/PGCla signaling pathway and stimulated the corresponding target gene expression. Insulin insensitivity in db/db mice was not induced by significantly increased fatty acid metabolism, while increased insulin sensitivity by both treatments was not related to decreased fatty acid metabolism in muscles.The pharmacologically reduced long-chain acylcarnitine content represents an effective strategy to improve insulin sensitivity. The methyl-GBB treatment and lifestyle changes via increased physical activity for one hour a day have additive insulin sensitizing effects in db/db mice. (C) 2015 Elsevier Ltd. All rights reserved.