GLP-1R in Diabetes and Obesity: A Therapeutic Target with Promising Horizons

Glucagon-like peptide-1 receptor (GLP-1R), glucagon receptor (GCGR), and glucose-dependent insulinotropic polypeptide receptor (GIPR) play essential roles in maintaining glucose homeostasis and metabolic function, making them critical therapeutic targets for both diabetes and obesity. GLP-1R enhances insulin secretion, regulates blood glucose levels, and promotes satiety, while GIPR and GCGR contribute to energy balance and glucose metabolism. Therapeutic agents such as GLP-1R agonists (e.g., semaglutide and liraglutide), dual agonists (e.g., tirzepatide), and triple agonists (e.g., retatrutide) have shown great promise in treating these metabolic disorders[1]. On July 10, 2024, Kuei-Pin Huang et al. published a study in Nature titled “Dissociable hindbrain GLP1R circuits for satiety and aversion”, demonstrating that future anti-obesity drugs could selectively target GLP-1R neurons in the nucleus tractus solitarius (NTS) to reduce aversive responses like nausea and improve treatment adherence and efficacy[2].

1. Overview of Obesity and Current R&D Landscape

The global obesity crisis remains severe. According to a recent Lancet report, over 1 billion people worldwide were affected by obesity in 2022. Since 1990, adult obesity has more than doubled globally, while obesity in children and adolescents (ages 5–19) has tripled[3]. By 2035, it is projected that over 4 billion people will be overweight or obese, posing a significant burden on public health systems. As the obese population continues to rise and breakthroughs in GLP-1-based weight-loss medications advance, the anti-obesity drug pipeline has expanded rapidly in recent years. GLP-1R agonists remain a major research focus. Chinese pharmaceutical companies are actively innovating around GLP-1-related challenges through differentiated strategies—such as long-acting GLP-1R agonists, orally available small-molecule GLP-1 agonists, dual/triple agonists, and combination therapies that promote both weight loss and muscle gain. Today, GLP-1 has undoubtedly become one of the hottest targets in drug development. In 2023, the star product semaglutide reached a staggering $21.2 billion in global sales, earning the title of the new “King of Drugs” and setting a strong precedent for future GLP-1-based therapies. As a result, an influx of players has entered the field, making the GLP-1 track increasingly vibrant and competitive.

2. Structure of GLP-1R Target

GLP-1 receptor (GLP-1R) is a G protein–coupled receptor (GPCR) located on pancreatic cells and neurons in the brain. It is encoded by the GLP1R gene on chromosome 6, spanning approximately 40 kb and containing around 14 exons. Both human and rat GLP-1Rs consist of 463 amino acids, while mouse GLP-1R comprises 489 amino acids, showing 91% and 84% homology with the human receptor, respectively. GLP-1R belongs to the glucagon receptor family, a subgroup of class B GPCRs. Unlike most class A GPCRs, class B receptors such as GLP-1R contain not only the classical seven-transmembrane domain (TMD) but also a relatively large extracellular domain (ECD) composed of 120–160 amino acid residues. Both the ECD and TMD cooperatively participate in peptide ligand binding and receptor activation, making GLP-1R a structurally distinct and functionally important receptor in the GPCR superfamily[4].

Figure 1. Structure of GLP-1R Target.

3. Distribution and Functions of GLP-1R

In the pancreas, GLP-1 receptors (GLP-1Rs) are predominantly expressed in islet β-cells. Beyond the pancreas, GLP-1R is widely distributed in multiple tissues and organs, including the stomach, small intestine, heart, kidneys, lungs, and brain[5]. As its name suggests, the primary function of GLP-1R is to bind with glucagon-like peptide-1 (GLP-1) to regulate blood glucose levels. Once activated by GLP-1 or synthetic GLP-1R agonists, the receptor exerts a variety of physiological effects. In pancreatic islet cells, GLP-1R promotes β-cell proliferation, stimulates insulin synthesis and secretion, and inhibits both glucagon synthesis and release. In the gastrointestinal tract, GLP-1R inhibits gastric acid secretion and gastrointestinal motility, delays gastric emptying, enhances satiety, and reduces food intake. Within the nervous system, GLP-1R exhibits neuroprotective effects, helps counteract anorexia, and enhances memory. In the cardiovascular system, GLP-1R improves cardiac function and reduces inflammation[6].

Additionally, GLP-1R can promote β-cell proliferation and differentiation by activating intracellular signaling pathways such as PI3K, MAPK, and Ras/MAPK. Furthermore, GLP-1R plays a key role in suppressing apoptosis by regulating cAMP response element-binding protein (CREB) and anti-apoptotic proteins such as Bcl-2 and Bcl-XL[7].

Figure 2. The role of GLP1 or GLP1R agonists.

4. How's the GLP-1R-Related Signaling Mechanisms?

GLP-1R is a pleiotropic G protein–coupled receptor (GPCR) that is primarily activated by its endogenous ligand GLP-1 or its analogs, playing a crucial role in pancreatic signal regulation. The receptor activation follows the classical “two-domain model”, in which the C-terminal region of the ligand first binds to the extracellular domain (ECD) of the receptor, triggering conformational changes and exposing the core domain. Subsequently, the N-terminal portion of the ligand binds to the transmembrane core domain, thereby completing receptor activation[8]. Once activated, GLP-1R primarily couples with Gαs proteins, initiating the adenylate cyclase (AC)/cyclic AMP (cAMP) signaling cascade. This leads to the conversion of ATP to cAMP, elevation of intracellular cAMP levels, and subsequent activation of protein kinase A (PKA) and exchange protein directly activated by cAMP 2 (EPAC2), which together regulate insulin granule exocytosis[9].

Studies have also shown that GLP-1R can interact with Gαq and other G proteins, highlighting the receptor’s signaling diversity. Additionally, upon activation, the intracellular C-terminal tail and specific intracellular loops of GLP-1R are phosphorylated by GPCR kinases (GRKs), facilitating the recruitment of β-arrestin. β-arrestin not only mediates receptor internalization and desensitization, but also acts as a signaling scaffold to initiate G protein–independent signaling pathways, further enriching the downstream outputs of GLP-1R[10]. These multifaceted regulatory mechanisms contribute to the receptor’s critical role in maintaining glucose homeostasis and insulin secretion, making GLP-1R a key therapeutic target for type 2 diabetes[11].

GLP-1R has long been recognized as a major target in diabetes pharmacotherapy, with multiple GLP-1 analog drugs successfully developed and approved for clinical use, generating billions of dollars in annual sales. In 2017, the Stevens lab and Zhijie Liu’s group resolved the inactive-state transmembrane domain (TMD) crystal structure of GLP-1R and published their findings in Nature. Subsequently, several active-state full-length GLP-1R structures bound to agonists have also been elucidated. However, the structure of full-length GLP-1R in its unbound (ligand-free) state, particularly the conformation of the extracellular domain, remains poorly understood, which limits our mechanistic insight into ligand recognition and receptor activation.

Figure 3. Overview of glucagon-like peptide (GLP-1) receptor activation in the beta cell[12].

5. Clinical Drug Development Progress of GLP-1R

In the domestic Chinese market, GLP-1–based therapies are undergoing rapid development, as GPCRs regulate critical physiological functions via GLP-1, glucagon (GCG), and glucose-dependent insulinotropic polypeptide (GIP). Targeting these receptors, approximately 40 pharmaceutical companies have launched clinical development programs for GLP-1–related drugs in obesity indications. These programs include various targeting strategies: GLP-1R monotherapy, dual agonists targeting GLP-1R/GIPR, triple agonists targeting GLP-1R/GCGR/GIPR, and combinations involving GLP-1R/GCGR/FGF21R. Drug modalities cover a broad spectrum, including synthetic peptides, recombinant proteins, small-molecule chemical drugs, biosimilars, and fusion proteins. The development of multi-target combination therapies centered on GLP-1R aims to achieve synergistic efficacy, which has become a mainstream trend in the clinical research of anti-obesity therapeutics[13].

In the international arena, the U.S. Food and Drug Administration (FDA) has approved several drugs targeting GLP-1R, GIPR, and GCGR for the treatment of type 2 diabetes and obesity. These include GLP-1 receptor agonists such as semaglutide, liraglutide, dulaglutide, and PEG-loxenatide, as well as the dual GLP-1R/GIPR agonist tirzepatide[14]. Meanwhile, numerous clinical trials are ongoing, and a number of investigational agents are in preclinical stages.

Among domestic drug developers, Innovent Biologics' mazdutide injection has entered the New Drug Application (NDA) phase. In addition, 7 drugs are currently in Phase III clinical trials, 13 in Phase II, and 14 in Phase I. Notable examples include:

Retatrutide, a triple agonist targeting GIPR/GLP-1R/GCGR, currently in Phase III;

Survodutide, a dual GCGR/GLP-1R agonist, also in Phase III;

IONIS-GCGR Rx, a GCGR-targeting therapeutic developed using antisense technology, now in Phase II.

7. Advantages and Risks of GLP-1R as a Therapeutic Target

As a key target for the treatment of type 2 diabetes and obesity, the glucagon-like peptide-1 receptor (GLP-1R) has garnered significant attention in recent years and demonstrated notable clinical benefits[15]. However, GLP-1R also presents certain limitations and potential risks that cannot be overlooked. The most common adverse effects of GLP-1R agonists are gastrointestinal symptoms, such as nausea, vomiting, and diarrhea, which are particularly pronounced during the early stages of treatment and may affect patient adherence. In addition, therapeutic responses to GLP-1R agonists vary significantly among individuals, and the underlying mechanisms remain incompletely understood. Animal studies have suggested a possible association between GLP-1R agonists and C-cell hyperplasia of the thyroid, although definitive evidence in humans is still lacking, warranting continued safety monitoring. Furthermore, while weight loss is a desired outcome, some GLP-1R agonists may lead to a reduction in skeletal muscle mass, which is of particular concern in elderly patients or those with sarcopenia. As the popularity of GLP-1–based drugs continues to rise, the emergence of counterfeit medications in the market also poses a potential threat to patient safety[16].

GLP-1R holds great promise in the treatment of diabetes and obesity; however, its potential risks and side effects must be carefully considered, and medications should be used under proper medical supervision. To address these concerns, the development of next-generation GLP-1R agonists and multi-target therapies is actively underway, with the goal of providing safer and more effective treatment options.

Summary

The glucagon-like peptide-1 receptor (GLP-1R) has emerged as one of the most prominent therapeutic targets in the field of metabolic diseases in recent years. Its significance extends far beyond glycemic control, positioning it at the intersection of obesity, diabetes, cardiovascular conditions, and even neurodegenerative disorders. With the clinical success of GLP-1–based therapies in regulating body weight and blood glucose, the scientific and commercial interest in GLP-1R has intensified globally. Across both basic research and clinical translation, GLP-1R demonstrates remarkable potential. Drug development efforts targeting this receptor are rapidly evolving from single agonists to multi-target, long-acting, oral, and combination therapies. Fueled by robust industrial expansion, ongoing investment, and supportive policy environments, the GLP-1R field is experiencing unprecedented momentum. Looking ahead, continued advancements in technology and deeper insights into the receptor’s biology are expected to unlock further therapeutic breakthroughs. GLP-1R is poised to become a pivotal node in the precision treatment of metabolic disorders and a cornerstone of next-generation drug innovation.

References

[1] Müller, T. D., et al. (2021). The new biology and pharmacology of glucagon. Nature Reviews Drug Discovery, 20, 843–862.

[2] Huang, K.-P., et al. (2024). Dissociable hindbrain GLP1R circuits for satiety and aversion. Nature, published 10 July 2024.

[3] NCD Risk Factor Collaboration (NCD-RisC). (2024). Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3,663 population-based studies with 222 million children, adolescents, and adults. The Lancet, 403(10434), 918–933.

[4] Jazayeri, A., et al. (2017). Structural basis for GLP-1 receptor activation by peptide agonists. Nature, 546(7657), 254–258.

[5] Drucker, D. J. (2018). Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metabolism, 27(4), 740–756.

[6] Nauck, M. A., & Meier, J. J. (2019). Incretin hormones: Their role in health and disease. Diabetes, Obesity and Metabolism, 21(S1), 5–21.

[7] Kim, S. J., Nian, C., McIntosh, C. H. S. (2005). Activation of glucagon-like peptide-1 receptor modulates signaling pathways regulating pancreatic β-cell proliferation and survival. Diabetes, 54(6), 1686–1695.

[8] Song, G., Yang, D., Wang, Y., et al. (2017). Human GLP-1 receptor transmembrane domain structure in complex with a peptide agonist. Nature, 546(7657), 254–258.

[9] Holz, G. G., Kang, G., Harbeck, M., Roe, M. W., & Chepurny, O. G. (2006). Cellular mechanisms of action of GLP-1 on pancreatic β-cells: The role of cAMP signaling in insulin secretion. Diabetes, 55(Suppl 2), S10–S18.

[10] Luttrell, L. M., Maudsley, S., & Bohn, L. M. (2015). Fulfilling the promise of "biased" GPCR agonism. Molecular Pharmacology, 88(3), 579–588.

[11]Zhang, Y., Sun, B., Feng, D., et al. (2020). Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein. Nature, 546(7657), 248–253.

[12] Mayendraraj, A., Rosenkilde, M. M., & Gasbjerg, L. S. (2022). GLP-1 and GIP receptor signaling in beta cells – A review of receptor interactions and co-stimulation. Peptides, 151, 170749.

[13] Nauck, M. A., & Quast, D. R. (2021). Clinical development and approval status of GLP-1 receptor agonists, dual, and triple agonists for treating type 2 diabetes and obesity. Frontiers in Endocrinology, 12, 645020.

[14] Wharton, S., Calanna, S., & Davies, M. (2023). Tirzepatide: a dual GIP/GLP-1 receptor agonist for the treatment of type 2 diabetes and obesity. Drugs, 83(5), 483–496.

[15] Nauck, M. A., & Meier, J. J. (2019). Management of endocrine disease: Are all GLP-1 agonists equal in the treatment of type 2 diabetes and obesity? European Journal of Endocrinology, 181(6), R211–R234.

[16] Rosenstock, J., et al. (2023). Advances in incretin-based therapies: Current perspectives and emerging treatments. The Lancet Diabetes & Endocrinology, 11(1), 34–46.