Defining alpha-cell PC1/3 expression regulation for type 2 diabetes

定义 2 型糖尿病的 α 细胞 PC1/3 表达调控

基本信息

  • 批准号:
    10376866
  • 负责人:
  • 金额:
    $ 5.18万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-03-18 至 2024-03-17
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY Glucagon-like peptide-1 (GLP-1) enhances islet function by potentiating glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells; however, the mechanisms by which GLP-1 potentiates GSIS remain incompletely defined. In the classic model, GLP-1 secreted by the intestinal L cells in response to the ingestion of nutrients stimulates the β-cell GLP-1 receptor (GLP-1R) to enhance GSIS. This model is currently in question, as the short half-life of GLP-1 and its rapid degradation present limitations as to how GLP-1 can mediate effects in distant targets, such as pancreatic β-cells. In explanation of such limitations, there is an emerging hypothesis suggesting that GLP-1 locally produced by α-cells acts in a paracrine manner on neighboring β-cells to stimulate GSIS, which ultimately promotes lowering of glycemia. Proglucagon is expressed in the gut and α-cells and is cleaved to form GLP-1 or the counter-regulatory hormone, glucagon, depending on the prohormone convertase (PC) type present. It was previously thought that the tissue-specific processing of proglucagon was due to the differential expression of PC1/3 and PC2, but several studies in rodent models and humans have shown that α- cells can produce active GLP-1 and express PC1/3. However, the mechanisms by which α-cell PC1/3 expression is regulated are unknown. Identifying a mechanism to increase α-cell PC1/3 expression to increase GLP-1 production at the expense of glucagon will provide a powerful therapeutic modality for the regulation of blood glucose concentrations in patients with T2DM. We have shown that increased β-cell GLP-1R signaling increases α-cell PC1/3 and GLP-1 expression. My preliminary data suggest that insulin may serve as potential intermediate by which β-cell GLP-1R signaling alters α-cell proglucagon processing. Specifically, I hypothesize that β-cell GLP-1R signaling increases α-cell PC1/3 expression through both α-cell insulin receptor (IR) dependent and independent pathways. In Aim 1, I will assess the role of α-cell IR signaling to determine whether insulin is necessary to alter the secretory phenotype of α-cells by measuring glucose regulation, GSIS, and PC1/3 expression in α-cell-specific Irα-cell +/+ and Irα-cell -/- mice with and without stimulation by exogenous GLP-1. In Aim 2, I will determine the pathways through which β-cell GLP-1R signaling increases α-cell PC1/3 expression by single-cell RNA-sequencing of islets from inducible β-cell-specific Glp-1rβ-cell+/+ and Glp-1r-cell-/- mice, as well as human islets with β-cell-specific GLP-1R knockout. Together, these studies will define a link between the pathways regulating α-cell PC1/3 expression and GLP-1 production; thus, enabling targeting of the α-cell secretory phenotype for the treatment of T2DM.
项目总结

项目成果

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Marlena Meta Holter其他文献

Marlena Meta Holter的其他文献

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{{ truncateString('Marlena Meta Holter', 18)}}的其他基金

Defining alpha-cell PC1/3 expression regulation for type 2 diabetes
定义 2 型糖尿病的 α 细胞 PC1/3 表达调控
  • 批准号:
    10591485
  • 财政年份:
    2020
  • 资助金额:
    $ 5.18万
  • 项目类别:
Defining alpha-cell PC1/3 expression regulation for type 2 diabetes
定义 2 型糖尿病的 α 细胞 PC1/3 表达调控
  • 批准号:
    10222553
  • 财政年份:
    2020
  • 资助金额:
    $ 5.18万
  • 项目类别:

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