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
- 来源:
- 关键词:AgonistAlpha CellBeta CellBlack raceBlood CirculationBlood GlucoseCell LineCellsDataDiabetes MellitusDistantEventFeedbackGLP-I receptorGene TargetingGenesGenetic TranscriptionGlucagonGlucoseHalf-LifeHormonesHumanIngestionInsulinInsulin ReceptorKnock-outL Cell (Intestine)L CellsLinkLocationMeasuresMediatingModalityModelingMusNon-Insulin-Dependent Diabetes MellitusNutrientPathway interactionsPatientsPhenotypeProductionProhormone ConvertaseProprotein Convertase 1Proprotein Convertase 2Receptor SignalingRegulationReportingResolutionRodent ModelRoleSecretory CellSignal TransductionStructure of beta Cell of isletTechnologyTestingTherapeuticTissuesTranscriptTranslatingUp-Regulationblood glucose regulationdifferential expressionglucagon-like peptide 1incretin hormoneinsulin secretionisletknock-downnoveloverexpressionparacrinepreproglucagonsproglucagonresponsesingle-cell RNA sequencingtranscription factortranscriptomics
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
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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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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