探索嘌呤能受体P2RY1在2型糖尿病风险和病理生理学中的作用：来自人类功能基因组学的见解

Exploring the role of purinergic receptor P2RY1 in type 2 diabetes risk and pathophysiology: Insights from human functional genomics.

作者信息

Dance Arnaud, Fernandes Justine, Toussaint Bénédicte, Vaillant Emmanuel, Boutry Raphaël, Baron Morgane, Loiselle Hélène, Balkau Beverley, Charpentier Guillaume, Franc Sylvia, Ibberson Mark, Marre Michel, Gernay Marie, Fadeur Marjorie, Paquot Nicolas, Vaxillaire Martine, Boissel Mathilde, Amanzougarene Souhila, Derhourhi Mehdi, Khamis Amna, Froguel Philippe, Bonnefond Amélie

机构信息

Inserm UMR1283, CNRS UMR8199, European Genomic Institute for Diabetes (EGID), Institut Pasteur de Lille, Lille University Hospital, Lille, France; Université de Lille, Lille, France.

Paris-Saclay University, Paris-Sud University, UVSQ, Center for Research in Epidemiology and Population Health, Inserm U1018 Clinical Epidemiology, Villejuif, France.

出版信息

Mol Metab. 2024 Jan;79:101867. doi: 10.1016/j.molmet.2023.101867. Epub 2023 Dec 28.

DOI:10.1016/j.molmet.2023.101867

PMID:38159881

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10792753/

Abstract

OBJECTIVE

Human functional genomics has proven powerful in discovering drug targets for common metabolic disorders. Through this approach, we investigated the involvement of the purinergic receptor P2RY1 in type 2 diabetes (T2D).

METHODS

P2RY1 was sequenced in 9,266 participants including 4,177 patients with T2D. In vitro analyses were then performed to assess the functional effect of each variant. Expression quantitative trait loci (eQTL) analysis was performed in pancreatic islets from 103 pancreatectomized individuals. The effect of P2RY1 on glucose-stimulated insulin secretion was finally assessed in human pancreatic beta cells (EndoCβH5), and RNA sequencing was performed on these cells.

RESULTS

Sequencing P2YR1 in 9,266 participants revealed 22 rare variants, seven of which were loss-of-function according to our in vitro analyses. Carriers, except one, exhibited impaired glucose control. Our eQTL analysis of human islets identified P2RY1 variants, in a beta-cell enhancer, linked to increased P2RY1 expression and reduced T2D risk, contrasting with variants located in a silent region associated with decreased P2RY1 expression and increased T2D risk. Additionally, a P2RY1-specific agonist increased insulin secretion upon glucose stimulation, while the antagonist led to decreased insulin secretion. RNA-seq highlighted TXNIP as one of the main transcriptomic markers of insulin secretion triggered by P2RY1 agonist.

CONCLUSION

Our findings suggest that P2RY1 inherited or acquired dysfunction increases T2D risk and that P2RY1 activation stimulates insulin secretion. Selective P2RY1 agonists, impermeable to the blood-brain barrier, could serve as potential insulin secretagogues.

摘要

目的

人类功能基因组学已被证明在发现常见代谢紊乱的药物靶点方面具有强大作用。通过这种方法，我们研究了嘌呤能受体P2RY1在2型糖尿病（T2D）中的作用。

方法

对9266名参与者（包括4177名T2D患者）的P2RY1进行测序。然后进行体外分析以评估每个变体的功能效应。对103名接受胰腺切除术个体的胰岛进行表达定量性状位点（eQTL）分析。最后在人胰腺β细胞（EndoCβH5）中评估P2RY1对葡萄糖刺激的胰岛素分泌的影响，并对这些细胞进行RNA测序。

结果

对9266名参与者的P2YR1测序发现了22个罕见变体，根据我们的体外分析，其中7个是功能丧失变体。除一人外，携带者的血糖控制均受损。我们对人类胰岛的eQTL分析确定了位于β细胞增强子中的P2RY1变体，其与P2RY1表达增加和T2D风险降低相关，这与位于沉默区域的变体形成对比，后者与P2RY1表达降低和T2D风险增加相关。此外，一种P2RY1特异性激动剂在葡萄糖刺激时增加胰岛素分泌，而拮抗剂则导致胰岛素分泌减少。RNA测序突出显示TXNIP是由P2RY1激动剂触发的胰岛素分泌的主要转录组学标志物之一。