Imeglimin Normalizes Glucose Tolerance and Insulin Sensitivity and Improves Mitochondrial Function in Liver of a High-Fat, High-Sucrose Diet Mice Model
Imeglimin Normalizes Glucose Tolerance and Insulin Sensitivity and Improves Mitochondrial Function in Liver of a High-Fat, High-Sucrose Diet Mice Model
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DOI：
10.2337/db14-1220
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发表时间：
2015-06-01
期刊：
影响因子：
7.7
通讯作者：
Rieusset, Jennifer
中科院分区：
文献类型：
--
作者：
Vial, Guillaume;Chauvin, Marie-Agnes;Rieusset, Jennifer
Imeglimin是目前处于2b阶段开发的新型口服降糖剂中的第一种。尽管伊美利明改善了人类的胰岛素敏感性，但其分子机制尚不清楚。这项研究使用了16周高脂肪高蔗糖饮食(HFHSD)小鼠的模型来表征其抗糖尿病作用。六周的伊美利明治疗显著降低了血糖，恢复了正常的糖耐量，改善了胰岛素敏感性，而不改变器官、体重和食物摄入量。这与肝脏和肌肉中胰岛素刺激的蛋白激酶B的磷酸化增加有关。在肝脏线粒体中，伊美利明使底物流向有利于复合体II的方向，如琥珀酸使呼吸增加，谷氨酸/苹果酸使呼吸恢复到对照水平。此外，伊美利明抑制复合体I和恢复复合体III的活性，提示脂肪酸氧化增加，这是由肝脏3-羟乙酰-辅酶A脱氢酶活性和乙酰肉碱水平的增加和肝脏脂肪变性的减少支持的。伊美格利明还可以减少活性氧的产生，增加线粒体！DNA最后，伊美利明对线粒体磷脂组成的影响可能参与了伊美利明对线粒体功能的影响。总之，伊美利明通过保护线粒体功能不受氧化应激的影响，并有利于HFHSD小鼠肝脏中的脂质氧化，从而使糖耐量和胰岛素敏感性正常化。
Imeglimin is the first in a new class of oral glucose-lowering agents currently in phase 2b development. Although imeglimin improves insulin sensitivity in humans, the molecular mechanisms are unknown. This study used a model of 16-week high-fat, high-sucrose diet (HFHSD) mice to characterize its antidiabetic effects. Six-week imeglimin treatment significantly decreased glycemia, restored normal glucose tolerance, and improved insulin sensitivity without modifying organs, body weights, and food intake. This was associated with an increase in insulin-stimulated protein kinase B phosphorylation in the liver and muscle. In liver mitochondria, imeglimin redirects substrate flows in favor of complex II, as illustrated by increased respiration with succinate and by the restoration of respiration with glutamate/malate back to control levels. In addition, imeglimin inhibits complex I and restores complex III activities, suggesting an increase in fatty acid oxidation, which is supported by an increase in hepatic 3-hydroxyacetyl-CoA dehydrogenase activity and acylcarnitine profile and the reduction of liver steatosis. Imeglimin also reduces reactive oxygen species production and increases mitochondria! DNA. Finally, imeglimin effects on mitochondrial phospholipid composition could participate in the benefit of imeglimin on mitochondrial function. In conclusion, imeglimin normalizes glucose tolerance and insulin sensitivity by preserving mitochondrial function from oxidative stress and favoring lipid oxidation in liver of HFHSD mice.