Mechanism of Defective Incretin Action in Beta Cells during Type 2 Diabetes Mellitus

2 型糖尿病期间 β 细胞中肠促胰岛素功能缺陷的机制

基本信息

  • 批准号:
    10427438
  • 负责人:
  • 金额:
    $ 48.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-07-01 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT The incretin-mediated potentiation of glucose-stimulated insulin secretion (GSIS) accounts for 50% of postprandial insulin secretion and is essential for physiologic glycemic regulation. Upon nutrient stimulus, the two principal incretin hormones glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1) are secreted, respectively, from intestinal endocrine K- and L-cells and reach β-cells via the circulation, where they bind their receptors, GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) to amplify GSIS. While circulating incretin hormone levels are not impacted by T2DM, incretin effects on β-cell GSIS are significantly diminished in T2DM patients. However, the precise mechanisms underlying diabetes-associated blunting of incretin signaling in β-cells remain unclear. In T2DM, pharmacologic means to increase circulating GLP-1 levels improves GSIS and glycemic control. In contrast, the GIP-mediated incretin effect is notably absent in T2DM; and pharmacologic means to increase circulating GIP concentrations is not met with any GSIS improvement. The molecular mechanisms underlying diminished response to GLP-1 and absent response to GIP in T2DM remain poorly understood. T2DM is in part linked to a chronic inflammatory state with increased levels of local and circulating inflammatory cytokines that negatively impact insulin action in peripheral tissues and negatively impact the endocrine pancreas. We have therefore examined the role of pro-inflammatory cytokines that are elevated in T2DM on incretin signaling in islet -cells. Conversely, we have also interrogated the anti-inflammatory cholinergic signaling system through nicotinic acetylcholine receptors (nAchR) in modulating incretin signaling. Based on our preliminary studies, we hypothesize that TNFα - signaling through its receptor TNFR1 on β- cells - activates the Ser/Thr G-protein receptor kinase 2 (GKR2) in a non-canonical manner to suppress Gαs- activation and cAMP synthesis by ligand activated GIPR and by GLP-1R. Thus, our findings establish a mechanistic link between inflammatory cytokines in T2DM with diminished incretin signaling in β-cells. Our preliminary studies also indicate that in a murine model of T2DM, stimulating the α7 nicotinic acetylcholine receptor (α7-nAchR) reactivates GIPR signaling in β-cells to potentiate GSIS and improve glycemia. Our mechanistic studies indicate that α7-nAchR signaling phosphorylates (TNFα-activated) GRK2 at serine 670 to counteract its inhibitory effects on GIPR and GLP-1R-mediated cAMP synthesis. We now seek to expand our novel and exciting findings specifically a) to understand the role of TNFR1- GRK2-mediated signaling on in vivo β-cell function, on GIP and GLP-1R action as well as how TNFR1 signaling modulates α-cell gene expression in the context of obesity and T2DM; b) to specifically understand the role of GRK2 in mediating resistance to β-cell incretin action in T2DM; and c) to understand the beneficial role of anti- inflammatory α7-nAchR signaling in β-cells in the context of T2DM. We will use complementary in vivo and in vitro approaches to elucidate these important signaling pathways in β-cells using newly generated unique mouse models as well as in vitro in human islets and β-cells. The outcomes of our studies will yield important insights into how inflammatory cytokines of T2DM impact incretin signaling and β-cell function. Our proposed studies will also provide new insights into the effects of nicotinic acetylcholine signaling in β-cells. Finally, our studies identify potentially new receptor targets with the potential to ameliorate β-cell dysfunction in T2DM. .
项目总结/文摘

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Mehboob A Hussain其他文献

Mehboob A Hussain的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Mehboob A Hussain', 18)}}的其他基金

Mechanism of Defective Incretin Action in Beta Cells during Type 2 Diabetes Mellitus
2 型糖尿病期间 β 细胞中肠促胰岛素功能缺陷的机制
  • 批准号:
    10313849
  • 财政年份:
    2021
  • 资助金额:
    $ 48.35万
  • 项目类别:
Mechanism of Defective Incretin Action in Beta Cells during Type 2 Diabetes Mellitus
2 型糖尿病期间 β 细胞中肠促胰岛素功能缺陷的机制
  • 批准号:
    10619654
  • 财政年份:
    2021
  • 资助金额:
    $ 48.35万
  • 项目类别:
In vivo Cell-Specific Exosome Analysis
体内细胞特异性外泌体分析
  • 批准号:
    10231459
  • 财政年份:
    2021
  • 资助金额:
    $ 48.35万
  • 项目类别:
In vivo Cell-Specific Exosome Analysis
体内细胞特异性外泌体分析
  • 批准号:
    10398194
  • 财政年份:
    2021
  • 资助金额:
    $ 48.35万
  • 项目类别:
Glucagon signaling in metabolic homeostasis
代谢稳态中的胰高血糖素信号传导
  • 批准号:
    10424554
  • 财政年份:
    2020
  • 资助金额:
    $ 48.35万
  • 项目类别:
Glucagon signaling in metabolic homeostasis
代谢稳态中的胰高血糖素信号传导
  • 批准号:
    10261596
  • 财政年份:
    2020
  • 资助金额:
    $ 48.35万
  • 项目类别:
Hepatic endocrine suppression of the pancreatic beta-cell
胰腺β细胞的肝脏内分泌抑制
  • 批准号:
    8817887
  • 财政年份:
    2014
  • 资助金额:
    $ 48.35万
  • 项目类别:
Hepatic endocrine suppression of the pancreatic beta-cell
胰腺β细胞的肝脏内分泌抑制
  • 批准号:
    9671615
  • 财政年份:
    2014
  • 资助金额:
    $ 48.35万
  • 项目类别:
Control of hepatic and b-cell function by co-activators
共激活剂对肝细胞和 B 细胞功能的控制
  • 批准号:
    8010071
  • 财政年份:
    2010
  • 资助金额:
    $ 48.35万
  • 项目类别:
High-Throughput Screen For FDA Approved Drugs That Amplify Beta-Cell Mass In Vivo
高通量筛选 FDA 批准的体内放大 β 细胞质量的药物
  • 批准号:
    8045193
  • 财政年份:
    2010
  • 资助金额:
    $ 48.35万
  • 项目类别:

相似海外基金

Spatiotemporal dynamics of acetylcholine activity in adaptive behaviors and response patterns
适应性行为和反应模式中乙酰胆碱活性的时空动态
  • 批准号:
    24K10485
  • 财政年份:
    2024
  • 资助金额:
    $ 48.35万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Structural studies into human muscle nicotinic acetylcholine receptors
人体肌肉烟碱乙酰胆碱受体的结构研究
  • 批准号:
    MR/Y012623/1
  • 财政年份:
    2024
  • 资助金额:
    $ 48.35万
  • 项目类别:
    Research Grant
CRCNS: Acetylcholine and state-dependent neural network reorganization
CRCNS:乙酰胆碱和状态依赖的神经网络重组
  • 批准号:
    10830050
  • 财政年份:
    2023
  • 资助金额:
    $ 48.35万
  • 项目类别:
Study on biological significance of acetylcholine and the content in food resources
乙酰胆碱的生物学意义及其在食物资源中的含量研究
  • 批准号:
    23K05090
  • 财政年份:
    2023
  • 资助金额:
    $ 48.35万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
alpha7 nicotinic acetylcholine receptor allosteric modulation and native structure
α7烟碱乙酰胆碱受体变构调节和天然结构
  • 批准号:
    10678472
  • 财政年份:
    2023
  • 资助金额:
    $ 48.35万
  • 项目类别:
Diurnal Variation in Acetylcholine Modulation of Dopamine Dynamics Following Chronic Cocaine Intake
慢性可卡因摄入后乙酰胆碱对多巴胺动力学调节的昼夜变化
  • 批准号:
    10679573
  • 财政年份:
    2023
  • 资助金额:
    $ 48.35万
  • 项目类别:
Differential Nicotinic Acetylcholine Receptor Modulation of Striatal Dopamine Release as a Mechanism Underlying Individual Differences in Drug Acquisition Rates
纹状体多巴胺释放的烟碱乙酰胆碱受体差异调节是药物获取率个体差异的机制
  • 批准号:
    10553611
  • 财政年份:
    2022
  • 资助金额:
    $ 48.35万
  • 项目类别:
Striatal Regulation of Cortical Acetylcholine Release
纹状体对皮质乙酰胆碱释放的调节
  • 批准号:
    10549320
  • 财政年份:
    2022
  • 资助金额:
    $ 48.35万
  • 项目类别:
Structural basis of nicotinic acetylcholine receptor gating and toxin inhibition
烟碱乙酰胆碱受体门控和毒素抑制的结构基础
  • 批准号:
    10848770
  • 财政年份:
    2022
  • 资助金额:
    $ 48.35万
  • 项目类别:
Mechanisms of nicotinic acetylcholine receptor modulation of cocaine reward
烟碱乙酰胆碱受体调节可卡因奖赏的机制
  • 批准号:
    10672207
  • 财政年份:
    2022
  • 资助金额:
    $ 48.35万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了