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首页> 外文学位 >GLP-1 Receptor Agonist Exendin-4 Improves Glycemic Control Through Beta Cell and Non-beta Cell Mechanism.
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GLP-1 Receptor Agonist Exendin-4 Improves Glycemic Control Through Beta Cell and Non-beta Cell Mechanism.

机译：GLP-1受体激动剂Exendin-4通过β细胞和非β细胞机制改善了血糖控制。

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摘要

Type 2 diabates is characterized by insulin resistance and progressive beta cell loss. Glucagon like peptide-1 (GLP-1) based therapy has been applied for clinical use for the treatment of type 2 diabetes. Both GLP-1 analogues and DPPIV inhibitors normalized blood glucose control both in rodent models and human beings. However, the detailed underlying mechanism for the beneficial effects is still unclear and under hot discussion. In this dissertation, we used both in vitro INS-1E cell line and human Islet Amyloid Polypeptide (hIAPP) transgenic or normal non-diabetic rodents to evaluate the intra- and extra- pancreas effects of GLP-1 analogue exendin-4. We explored its anti-apoptotic effects in hIAPP treated INS-1E cells and found that co-incubation with exendin-4 significantly abrogated hIAPP induced INS-1E cell apoptosis. AKT was inhibited by hIAPP treatment in the INS-IE cells but re-activation by transient over-expressing constitutively activated AKT1 significantly attenuated hIAPP induced INS-1E cell apoptosis, suggesting that inhibited AKT was at least involved in the apoptotic effects of hIAPP in the in vitro system. Treatment of exendin-4 re-activated hIAPP inhibited AKT phosphorylation in the INS-1E cells and promoted cytosolic translocation of forkhead box protein O1 (FOXO1) and the nucleus translocation of Pancreatic and Duodenal Homeobox-1 (Pdx-1). Interestingly, we also observed inhibited mitochondrial biogenesis after hIAPP treatment which could be partially restored by exendin-4 treatment. Based on these in vitro data, we concluded that exendin-4 protected hIAPP induced INS-IE cell death and potentially protected the beta cells from amyloid toxicity in vivo. Indeed, we found that daily injection with 24nM/kg exendin-4 for 4 weeks significantly lowered random blood glucose in hIAPP homozygous transgenic mice due to improvement in both beta cell morphology and insulin secretion, we will confirm these preliminary data in the following experiment. We also proved that hIAPP induced ER stress in vitro, but inhibition of endoplasmic reticulum (ER) stress did not significantly inhibited hIAPP evoked INS-1E cell death. The reactive oxygen species (ROS) level and JNK phosphorylation, which was potentially correlated with hIAPP induced INS-1E cell apoptosis was not affected by neither chemical chaperone treatment nor molecular chaperone over-expression. In consistence, exendin-4 did not alter ER stress level in the hIAPP treated cells in the in vitro system, suggesting that ER stress inhibition might not be an appropriate target for antagonizing beta cell amyloid toxicity.;We further used normal non-diabetic mice to evaluate the role of aging on the therapeutic effects of exendin-4. We optimized the dosage and treating period of exendin-4 and used a relatively lower dose and shorter treatment time. We observed that IOnM/kg treatment of exendin-4 did not significantly change beta cell proliferation or insulin secretion in both young and aging mice, however, we observed a significantly improved glucose response in the oral glucose tolerance test (OGTT) in both groups of mice after exendin-4 treatment. We further tested the insulin sensitivity and found that exendin-4 improved insulin sensitivity in aging mice but not in young mice. On the contrary, it was intriguing to see that the gluco-neogenesis correlated gene expression was significantly inhibited by exendin-4 treatment in young but not in aging mice. These data suggested that the extra-pancreas effects of exendin-4 was not attenuated by aging and that the glucose lowering effects of exendin-4 in young and aging mice might be slightly different.;The above data was first proposed by our group and was important for the clinical application of GLP-1 based therapy.
机译：2型糖尿病的特征是胰岛素抵抗和逐渐的β细胞丢失。基于胰高血糖素样肽-1（GLP-1）的疗法已应用于临床，用于治疗2型糖尿病。在啮齿动物模型和人类中，GLP-1类似物和DPPIV抑制剂均使血糖控制正常化。然而，产生有益效果的详细潜在机制仍不清楚，目前仍在热议中。在本文中，我们使用了体外INS-1E细胞系和人胰岛淀粉样多肽（hIAPP）转基因或正常非糖尿病啮齿类动物来评估GLP-1类似物exendin-4的胰腺内和胰腺外作用。我们探索了其在hIAPP处理的INS-1E细胞中的抗凋亡作用，并发现与exendin-4共同孵育可显着消除hIAPP诱导的INS-1E细胞凋亡。 AKT在INS-IE细胞中受到hIAPP处理的抑制，但是瞬时过表达的组成性激活的AKT1的重新激活显着减弱了hIAPP诱导的INS-1E细胞凋亡，这表明抑制的AKT至少参与了hIAPP在细胞中的凋亡作用。体外系统。 exendin-4重新活化的hIAPP的治疗抑制了INS-1E细胞中AKT磷酸化，并促进了叉头盒蛋白O1（FOXO1）的胞质易位以及胰腺和十二指肠Homeobox-1（Pdx-1）的核易位。有趣的是，我们还观察到hIAPP处理后线粒体的生物发生受到抑制，而exendin-4处理可以部分恢复这种抑制。基于这些体外数据，我们得出结论，exendin-4保护hIAPP诱导INS-IE细胞死亡，并可能保护β细胞免受体内淀粉样蛋白毒性的影响。实际上，我们发现，由于β细胞形态和胰岛素分泌的改善，每天注射24nM / kg exendin-4 4周可显着降低hIAPP纯合转基因小鼠的随机血糖，我们将在以下实验中证实这些初步数据。我们还证明了hIAPP可以在体外诱导内质网应激，但抑制内质网（ER）应激并不能显着抑制hIAPP引起的INS-1E细胞死亡。可能与hIAPP诱导的INS-1E细胞凋亡相关的活性氧（ROS）水平和JNK磷酸化不受化学伴侣蛋白处理和分子伴侣蛋白过表达的影响。一致地，exendin-4在体外系统中未改变hIAPP处理的细胞中的ER应激水平，表明ER应激抑制可能不是拮抗β细胞淀粉样蛋白毒性的合适靶标。我们进一步使用了正常的非糖尿病小鼠评估衰老对exendin-4的治疗作用。我们优化了exendin-4的剂量和治疗时间，并使用了相对较低的剂量和较短的治疗时间。我们观察到Exendin-4的IOnM / kg治疗在年轻和衰老小鼠中均未显着改变β细胞增殖或胰岛素分泌，但是，我们在两组口服葡萄糖耐量试验（OGTT）中观察到了显着改善的葡萄糖反应。 exendin-4处理后的小鼠。我们进一步测试了胰岛素敏感性，发现exendin-4可改善衰老小鼠的胰岛素敏感性，但不能改善年轻小鼠的胰岛素敏感性。相反，令人惊奇的是，exendin-4处理在年轻小鼠中显着抑制了与糖异生相关的基因表达，但在衰老小鼠中却没有。这些数据表明，exendin-4的胰腺外作用并不会随着衰老而减弱，并且exendin-4在年轻和衰老小鼠中的降糖作用可能会有所不同。对于基于GLP-1的疗法的临床应用非常重要。

著录项

  • 作者

    Fan, Rongrong.;

  • 作者单位

    The Chinese University of Hong Kong (Hong Kong).;

  • 授予单位 The Chinese University of Hong Kong (Hong Kong).;
  • 学科 Biology Molecular.;Biogeochemistry.;Health Sciences Aging.;Health Sciences Pharmacology.
  • 学位 Ph.D.
  • 年度 2011
  • 页码 151 p.
  • 总页数 151
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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