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中文摘要
翻译
本应用程序的总体目的是更好地了解内源性胰高血糖素样肽-1(GLP-1)信号传导的作用,主要是在禁食状态下,在禁食状态和随后的膳食挑战中影响α-细胞和β-细胞的功能。考虑到GLP-1主要的餐后作用,这一直是GLP-1生理学的一个被忽视的方面。然而,利用GLP-1途径的治疗药物可以降低空腹和餐后葡萄糖浓度。此外,GLP-1受体rs3765467的非同义单核苷酸多态性(non-synonymous Single Nucleotide Polymorphism, rs3765467)先前已被证明可增强对高血糖和GLP-1的反应,降低空腹血糖并预防2型糖尿病(T2DM)。GLP-1是由一种特定的激素原转化酶(PC-1/3)对胰高血糖素原进行翻译后加工产生的。有证据表明,这种酶可以在胰岛内表达,使GLP-1在当地产生。这可能以旁分泌方式增加葡萄糖刺激的胰岛素分泌和葡萄糖介导的胰高血糖素抑制。PC-1/3和GLP-1的表达在T2DM中升高,暴露于高血糖和游离脂肪酸中也升高。对这些观察结果的一种解释是,GLP-1可能至少在T2DM病程早期帮助胰岛适应代谢应激源。有趣的是,我们的初步数据显示,拮抗空腹内源性GLP-1分泌的效果在T2DM患者和非T2DM患者之间是不同的。α-细胞与β-细胞通讯的另一个方面是,胰岛内胰高血糖素浓度可以刺激胰岛素分泌,部分通过GLP-1受体发出信号。这在正常生理和T2DM中的重要性尚不清楚。本实验将阐明rs3765467如何在GLP-1受体阻断存在和不存在的情况下改变胰岛功能。此外,我们将研究内源性GLP-1分泌在T2DM中的作用,并比较对代谢应激的反应。实验条件也将使我们能够检查GLP-1信号在胰岛素分泌对胰高血糖素的反应中的作用。这些实验的成功完成将阐明内源性GLP-1在体内的作用。
英文摘要
The overall aim of this application is to better understand the role of endogenous Glucagon-Like Peptide-1(GLP-1) signaling, primarily in the fasting state, to influence α-cell and β-cell function both during the fasting state and in response to subsequent meal challenges. This has been an ignored aspect of GLP-1 physiology, given its primarily post-prandial effects. However, therapeutic agents that harness the GLP-1 pathway lower both fasting and postprandial glucose concentrations. In addition, a non-synonymous Single Nucleotide Polymorphism in the GLP-1 receptor, rs3765467, previously shown by us to enhance response to hyperglycemia and to GLP-1, lowers fasting glucose and protects from type 2 diabetes (T2DM). GLP-1 arises by post-translational processing of proglucagon by a specific prohormone convertase enzyme (PC-1/3). There is evidence that this enzyme can be expressed within the islet enabling local production of GLP-1. This may function in a paracrine fashion to augment glucose-stimulated insulin secretion and glucose mediated suppression of glucagon. Expression of PC-1/3 and GLP-1 is increased in T2DM and also by exposure to hyperglycemia and free fatty acids. An explanation of these observations is that GLP-1 may help islet adaptation to metabolic stressors at least early in the course of T2DM. Intriguingly, our preliminary data shows that the effect of antagonizing fasting endogenous GLP-1 secretion differs between people with and without T2DM. Another aspect of α-cell to β-cell communication is that intra-islet glucagon concentrations can act as stimulus to insulin secretion, signaling partially through the GLP-1 receptor. The importance of this in normal physiology and in T2DM is unknown. The proposed experiments will elucidate how rs3765467 alters islet function in the presence and absence of GLP-1 receptor blockade. In addition, we will examine the role of endogenous GLP-1 secretion in T2DM and compare responses to metabolic stress. The experimental conditions will also enable us to examine the role of GLP-1 signaling in the insulin secretory response to glucagon. Successful completion of these experiments will clarify the role of endogenous GLP-1 in vivo.
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The effect of endogenous GLP-1 secretion on islet function in vivo
  • 批准号:
    10643942
  • 项目类别:
  • 资助金额:
    $51.06万
  • 财政年份:
    2020
  • 负责人:
    Adrian Vella
  • 依托单位:
The effect of endogenous GLP-1 secretion on islet function in vivo
  • 批准号:
    10063777
  • 项目类别:
  • 资助金额:
    $52.54万
  • 财政年份:
    2020
  • 负责人:
    Adrian Vella
  • 依托单位:
The effect of endogenous GLP-1 secretion on islet function in vivo
  • 批准号:
    10197125
  • 项目类别:
  • 资助金额:
    $51.06万
  • 财政年份:
    2020
  • 负责人:
    Adrian Vella
  • 依托单位:
Glucagon secretion and action in humans
  • 批准号:
    10442194
  • 项目类别:
  • 资助金额:
    $52.05万
  • 财政年份:
    2017
  • 负责人:
    Adrian Vella
  • 依托单位:
国内基金
海外基金
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
  • 批准号:
    81973577
  • 项目类别:
    面上项目
  • 资助金额:
    55.0万元
  • 批准年份:
    2019
  • 负责人:
    辛贵忠
  • 依托单位: