Leptin restores the insulinotropic effect of exenatide in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and high-fat diet
Leptin restores the insulinotropic effect of exenatide in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and high-fat diet
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DOI：
10.1152/ajpendo.00272.2014
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发表时间：
2014-10-15
影响因子：
5.1
通讯作者：
Nakao, Kazuwa
中科院分区：
文献类型：
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作者：
Sakai, Takeru;Kusakabe, Toru;Nakao, Kazuwa
瘦素可减少胰腺脂质沉积，而胰腺脂质沉积随着肥胖的进展而增加，并可损害β细胞功能。胰高血糖素样肽-1 （GLP-1）和GLP-1受体激动剂的胰岛素促胰岛素作用与β细胞功能受损相关。在这项研究中，我们研究了瘦素是否可以恢复艾塞那肽（一种GLP-1受体激动剂）对肥胖增加的2型糖尿病的疗效。我们长期给药瘦素500 μ g.kg（-1）。日（-1）和/或艾塞那肽（20 μ g.kg(-1)）。在链脲佐菌素和高脂肪饮食诱导的肥胖增加的2型糖尿病小鼠模型（STZ/HFD小鼠）中持续2周。STZ/HFD小鼠表现为高血糖、超重、胰腺甘油三酯水平升高、葡萄糖刺激胰岛素分泌（GSIS）降低；此外，艾塞那肽的胰岛素调节作用减弱。然而，瘦素显著降低胰腺甘油三酯水平，并将瘦素添加到艾塞那肽（LEP/EX）中显著增强GSIS。这些结果表明，瘦素治疗恢复了艾塞那肽在小鼠体内的胰岛素促胰岛素作用。此外，LEP/EX减少了食物摄入量、体重和骨骼肌和肝脏中的甘油三酯水平，并比单药治疗更大程度地纠正了高血糖。配对饲养试验表明，LEP/EX显著降低胰腺甘油三酯水平和增强GSIS不是通过限制热量的机制实现的。这些结果表明，瘦素治疗可能恢复艾塞那肽的胰岛素促胰岛素作用，该作用与减少2型糖尿病伴肥胖增加的胰腺脂质沉积有关。瘦素和艾塞那肽联合治疗可能是2型糖尿病增肥患者的有效治疗方法。
Leptin may reduce pancreatic lipid deposition, which increases with progression of obesity and can impair beta-cell function. The insulinotropic effect of glucagon-like peptide-1 (GLP-1) and the efficacy of GLP-1 receptor agonist are reduced associated with impaired beta-cell function. In this study, we examined whether leptin could restore the efficacy of exenatide, a GLP-1 receptor agonist, in type 2 diabetes with increased adiposity. We chronically administered leptin (500 mu g.kg(-1).day(-1)) and/or exenatide (20 mu g.kg(-1).day(-1))for 2 wk in a mouse model of type 2 diabetes with increased adiposity induced by streptozotocin and high-fat diet (STZ/HFD mice). The STZ/HFD mice exhibited hyperglycemia, overweight, increased pancreatic triglyceride level, and reduced glucose-stimulated insulin secretion (GSIS); moreover, the insulinotropic effect of exenatide was reduced. However, leptin significantly reduced pancreatic triglyceride level, and adding leptin to exenatide (LEP/EX) remarkably enhanced GSIS. These results suggested that the leptin treatment restored the insulinotropic effect of exenatide in the mice. In addition, LEP/EX reduced food intake, body weight, and triglyceride levels in the skeletal muscle and liver, and corrected hyperglycemia to a greater extent than either monotherapy. The pair-feeding experiment indicated that the marked reduction of pancreatic triglyceride level and enhancement of GSIS by LEP/EX occurred via mechanisms other than calorie restriction. These results suggest that leptin treatment may restore the insulinotropic effect of exenatide associated with the reduction of pancreatic lipid deposition in type 2 diabetes with increased adiposity. Combination therapy with leptin and exenatide could be an effective treatment for patients with type 2 diabetes with increased adiposity.