Liraglutide ameliorates glycometabolism and insulin resistance through the upregulation of GLUT4 in diabetic KKAy mice
Liraglutide ameliorates glycometabolism and insulin resistance through the upregulation of GLUT4 in diabetic KKAy mice
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DOI：
10.3892/ijmm.2013.1453
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发表时间：
2013-10-01
影响因子：
5.4
通讯作者：
Wang, Bing
中科院分区：
文献类型：
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作者：
Chen, Li-Na;Lyu, Juan;Wang, Bing
利拉鲁肽是一种长效胰高血糖素样肽-1类似物，自2009年以来一直用于治疗2型糖尿病患者。在本研究中，我们使用KK/Upj-Ay/J（KKAy）小鼠在自发性糖尿病动物模型中研究了利拉鲁肽的抗糖尿病作用和作用机制。将KKAy小鼠分为2组，利拉鲁肽组（小鼠接受250 μ g/kg/天利拉鲁肽给药）和模型组（接受等量生理盐水给药）。C57 BL/6 J小鼠用作对照（用等量的生理盐水处理）。疗程6周。在该治疗期间，每周测量小鼠的空腹血糖（FBG）水平和体重。我们的研究结果显示，利拉鲁肽显著降低FBG水平、口服葡萄糖耐量试验和胰岛素耐量试验后的曲线下面积、升高血清胰岛素水平、降低胰岛素抵抗的稳态模型评估并升高胰岛素敏感性指数。此外，利拉鲁肽通过增加己糖激酶的糖酵解和丙酮酸激酶激活的糖原生成，改善了糖代谢功能障碍。胰腺的超微结构检查显示，利拉鲁肽改善了胰岛β细胞的受损状态，并增加了胰岛素分泌颗粒的数量。实时PCR结果显示，利拉鲁肽给药后葡萄糖转运蛋白4（GLUT 4）的基因表达增加。利拉鲁肽还上调肝组织和骨骼肌中GLUT 4的蛋白表达。我们的研究结果表明，利拉鲁肽通过刺激胰岛素分泌、增加糖原生成和糖酵解以及上调GLUT 4的表达来改善糖尿病KKAy小鼠的糖代谢和胰岛素抵抗。
Liraglutide, a long-lasting glucagon-like peptide-1 analogue, has been used for the treatment of patients with type 2 diabetes mellitus since 2009. In this study, we investigated the anti-diabetic effects and mechanisms of action of liraglutide in a spontaneous diabetic animal model, using KK/Upj-Ay/J (KKAy) mice. The KKAy mice were divided into 2 groups, the liraglutide group (mice were treated with 250 mu g/kg/day liraglutide) and the model group (treated with an equivalent amount of normal saline). C57BL/6J mice were used as the controls (treated with an equivalent amount of normal saline). The treatment period lasted 6 weeks. During this treatment period, fasting blood glucose (FBG) levels and the body weight of the mice were measured on a weekly basis. Our results revealed that liraglutide significantly decreased FBG levels, the area under the curve following a oral glucose tolerance test and insulin tolerance test, increased serum insulin levels, reduced homeostasis model assessment of insulin resistance and increased the insulin sensitivity index. Furthermore, liraglutide ameliorated glycometabolism dysfunction by increasing glycolysis via hexokinase and glycogenesis via pyruvate kinase activation. An ultrastructural examination of the pancreas revealed that liraglutide improved the damaged state of islet beta cells and increased the number of insulin secretory granules. The real-time PCR results revealed that the gene expression of glucose transporter 4 (GLUT4) increased following treatment with liraglutide. Liraglutide also upregulated the protein expression of GLUT4 in liver tissue and skeletal muscle. Our results suggest that liraglutide ameliorates glycometabolism and insulin resistance in diabetic KKAy mice by stimulating insulin secretion, increasing glycogenesis and glycolysis and upregulating the expression of GLUT4.