GLP-1R and GIPR crosstalk modulates insulinotropic signaling pathways

IF 9 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Chemical Biology Pub Date : 2026-09-17 Epub Date: 2026-07-08 DOI:10.1016/j.chembiol.2026.06.003

Peter Lindquist, Luuk R. Hoegen Dijkhof, Anna K. Drzazga, Pierre Sabatier, Tomasz M. Stepniewski, Louise Granlund, Maico Y. Lechner, Yi Zhong, Lærke S. Gasbjerg, Bolette Hartmann, Volker M. Lauschke, Jens J. Holst, Jesper V. Olsen, Olle Korsgren, Jana Selent, Shane C. Wright, Alexander S. Hauser, Mette M. Rosenkilde

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Rosenkilde","doi":"10.1016/j.chembiol.2026.06.003","DOIUrl":null,"url":null,"abstract":"<div><ul><li><span>•</span><span><div>GLP-1 and semaglutide (but not exendin 4 or GIP) induce GLP-1R-GIPR heterodimerization</div></span></li><li><span>•</span><span><div>GLP-1R/GIPR crosstalk rewires receptor trafficking and signaling</div></span></li><li><span>•</span><span><div>GLP-1R boosts GIPR signaling β-arrestin-dependently, while GIPR dampens GLP-1R</div></span></li><li><span>•</span><span><div>GIPR expression associates with adiposity and diabetes-related human phenotypes</div></span></li></ul></div><div>Drugs targeting the GLP-1R and GIPR have transformed the treatment of type 2 diabetes and obesity, but their combined mechanisms are not fully understood. We discovered ligand-dependent heterodimerization between GLP-1R and GIPR, which alters their signaling. Structurally, the dimerization occurs between TM4 of GLP-1R and TM1 and TM2 of GIPR. We found that different GLP-1R agonists promote receptor dimerization in various ways, unlike GIPR agonists, resulting in different signaling outcomes in human pancreatic islets. Additionally, GLP-1R-GIPR heterodimers co-internalize upon GLP-1R activation, affecting GIPR’s intracellular localization. Receptor stoichiometry influences signaling modulation: Higher GLP-1R levels enhance GIPR responses β-arrestin dependently, while higher GIPR levels reduce GLP-1R activity. Notably, changes in GIPR expression are associated with adiposity and diabetic traits. These interactions influence receptor signaling, trafficking, drug responses, and metabolic phenotypes. Our research redefines incretin receptor pharmacology by highlighting heterodimerization and receptor balance as key to signaling regulation. 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引用次数: 0

Abstract

•
GLP-1 and semaglutide (but not exendin 4 or GIP) induce GLP-1R-GIPR heterodimerization
•
GLP-1R/GIPR crosstalk rewires receptor trafficking and signaling
•
GLP-1R boosts GIPR signaling β-arrestin-dependently, while GIPR dampens GLP-1R
•
GIPR expression associates with adiposity and diabetes-related human phenotypes

Drugs targeting the GLP-1R and GIPR have transformed the treatment of type 2 diabetes and obesity, but their combined mechanisms are not fully understood. We discovered ligand-dependent heterodimerization between GLP-1R and GIPR, which alters their signaling. Structurally, the dimerization occurs between TM4 of GLP-1R and TM1 and TM2 of GIPR. We found that different GLP-1R agonists promote receptor dimerization in various ways, unlike GIPR agonists, resulting in different signaling outcomes in human pancreatic islets. Additionally, GLP-1R-GIPR heterodimers co-internalize upon GLP-1R activation, affecting GIPR’s intracellular localization. Receptor stoichiometry influences signaling modulation: Higher GLP-1R levels enhance GIPR responses β-arrestin dependently, while higher GIPR levels reduce GLP-1R activity. Notably, changes in GIPR expression are associated with adiposity and diabetic traits. These interactions influence receptor signaling, trafficking, drug responses, and metabolic phenotypes. Our research redefines incretin receptor pharmacology by highlighting heterodimerization and receptor balance as key to signaling regulation. It offers a framework for designing new therapeutics that leverage receptor crosstalk and expression dynamics for better metabolic health.

Drugs targeting glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide receptors (GLP-1R and GIPR) show strong clinical effects in type 2 diabetes and obesity. Both GIPR agonism and antagonism enhance GLP-1R agonist efficacy, indicating important incretin receptor crosstalk. We show that GLP-1 and semaglutide, but not exendin-4, promote heterodimerization between GLP-1R and GIPR through interactions between TM4 of GLP-1R and TM1/2 of GIPR. Phosphoproteomics and molecular dynamics reveal that dimerizing and non-dimerizing agonists differentially influence GLP-1R, activating divergent signaling pathways in human pancreatic islets. Moreover, semaglutide and exenatide display distinct patterns in their FDA-reported safety profiles. When co-expressed, GLP-1R enhances GIPR signaling in a β-arrestin-dependent manner, while increasing GIPR levels decreases GLP-1R signaling. Additionally, we show that changes in GIPR expression are clinically associated with adiposity and diabetic phenotypes. These findings highlight heterodimerization and receptor expression as key modulators of GLP-1R/GIPR signaling, offering mechanistic insights, and guiding drug design strategies that incorporate receptor crosstalk.

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GLP-1R和GIPR串扰调节促胰岛素信号通路。

靶向胰高血糖素样肽-1和葡萄糖依赖性胰岛素多肽受体（GLP-1R和GIPR）的药物在2型糖尿病和肥胖症中具有较强的临床疗效。GIPR的激动作用和拮抗作用均增强GLP-1R激动作用，提示重要的肠促胰岛素受体串扰。我们发现GLP-1和semaglutide，而不是exendin-4，通过GLP-1R的TM4和GIPR的TM1/2之间的相互作用促进GLP-1R和GIPR之间的异源二聚化。磷酸化蛋白质组学和分子动力学表明，二聚化和非二聚化激动剂对GLP-1R的影响不同，激活了人类胰岛中不同的信号通路。此外，西马鲁肽和艾塞那肽在fda报告的安全性概况中显示出不同的模式。当共表达时，GLP-1R以β-抑制蛋白依赖的方式增强GIPR信号传导，而增加GIPR水平会降低GLP-1R信号传导。此外，我们发现GIPR表达的变化在临床上与肥胖和糖尿病表型相关。这些发现强调了异源二聚化和受体表达是GLP-1R/GIPR信号的关键调节剂，提供了机制见解，并指导了结合受体串扰的药物设计策略。

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来源期刊

Cell Chemical Biology Biochemistry, Genetics and Molecular Biology-Molecular Medicine

CiteScore

14.70

自引率

2.30%

发文量

143

期刊介绍： Cell Chemical Biology, a Cell Press journal established in 1994 as Chemistry & Biology, focuses on publishing crucial advances in chemical biology research with broad appeal to our diverse community, spanning basic scientists to clinicians. Pioneering investigations at the chemistry-biology interface, the journal fosters collaboration between these disciplines. We encourage submissions providing significant conceptual advancements of broad interest across chemical, biological, clinical, and related fields. Particularly sought are articles utilizing chemical tools to perturb, visualize, and measure biological systems, offering unique insights into molecular mechanisms, disease biology, and therapeutics.