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The Roles of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Health and Disease

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A Special Issue of International Journal of Molecular Sciences (ISSN 1422-0067) belonging to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: 25 December 2026 | Viewed by 7292

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Dr. Katarzyna Kaczyńska

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Department of Respiration Physiology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawińskiego 5, 02-106 Warsaw, Poland
Interests: obesity- related asthma - mechanisms and contributing factors; GLP-1 in asthma; respiratory disorders in neurodegenerative diseases; neuropeptides and opioids in regulation of breathing; reversal of post-opioid respiratory depression
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Dear Colleagues,

GLP-1 is a key endocrine hormone that plays an integral role in regulating blood glucose levels, lipid metabolism, and improving metabolic syndrome. In recent years, GLP-1 therapeutics have attracted the attention of the medical community for their innovative mechanisms of action, remarkable therapeutic efficacy, and great potential for development. I am pleased to invite you to participate in the Special Issue, “The Roles of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Health and Disease”. This Special Issue is devoted to the application of GLP-1 receptor agonists (GLP-1RAs) in various physiological and pathophysiological conditions and their effects on multiple body systems, such as the nervous, cardiovascular, musculoskeletal, endocrine, and digestive systems, among others. The role of the GLP-1 receptor in alleviating inflammation, diabetes, and obesity, in neuroprotection and enhancing cardiovascular function, as well as other areas, is welcomed. This Special Issue will collect full articles, communication articles, and review articles covering various aspects of the GLP-1 molecule, such as pathogenesis, molecular pathways, and the beneficial effects of therapy using GLP-1 agonists.

I look forward to receiving your contributions.

Dr. Katarzyna Kaczyńska
Guest Editor

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Keywords

GLP-1
GLP-1 receptor
GLP-1 signaling pathway
mechanism of action
GLP-1 agonists
human diseases
adverse effects

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Published Papers (5 papers)

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Research

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20 pages, 2321 KB

Open AccessArticle

Combination GLP-1RA and Low-Dose IL-2 Modulates Peripheral Immune Activation and Attenuates CNS Inflammatory Transcript Signatures In Vivo

by Aaron D. Thome, Jinghong Wang, Alireza Faridar, Weihua Zhao, Valerie Saetzler, David R. Beers and Stanley H. Appel

Int. J. Mol. Sci. 2026, 27(17), 7855; https://doi.org/10.3390/ijms27177855 - 2 Sep 2026

Viewed by 445

Abstract

Immune dysregulation characterized by persistent myeloid activation and associated impairment of regulatory T cell (Treg) function contributes to inflammatory signaling across peripheral and central compartments in neurodegenerative diseases. We evaluated whether combining a glucagon-like peptide-1 receptor agonist (GLP-1RA; semaglutide) with low-dose interleukin-2 (LD-IL2) could modulate myeloid-associated transcript expression and enhance Treg-associated regulatory transcripts in a subacute lipopolysaccharide (LPS)-induced model of systemic and CNS inflammation. Mice received LPS once daily for 5 days, while GLP-1RA, LD-IL2, or combination treatment was initiated 24 h after LPS onset and continued daily. Splenic immune populations were quantified, and transcript expressions were assessed in magnetically enriched CD11b⁺ myeloid cells and CD4⁺CD25⁺ Tregs, as well as in cortex and hippocampus. As monotherapies, GLP-1RA reduced myeloid expansion with modest modulation of pro-inflammatory and anti-inflammatory myeloid transcripts, whereas LD-IL2 selectively enhanced Treg numbers and increased transcripts associated with Treg stability and suppressive regulation, including Il2ra (CD25), Foxp3, Ctla4, Ikzf2 (HELIOS), Entpd1 (CD39), and Nt5e (CD73). Combination treatment significantly reduced LPS-induced myeloid Il6, Il1b, and Tnf expression and increased Arg1 expression. Combination treatment further enhanced Treg-associated Il2ra (CD25), Tgfb1, and Ctla4 expression relative to monotherapies. In cortical and hippocampal tissues, combination treatment produced more robust modulation of inflammatory transcripts compared with effects observed with monotherapies, including reductions in Il6 and Il1b and increases in Cd163 and Mrc1 (CD206) expression. Together, these findings demonstrate coordinated and complementary changes in peripheral immune-cell populations and myeloid inflammatory and Treg-associated regulatory transcripts and warrant further evaluation of this combination in inflammation-driven neurodegenerative disease. Full article

(This article belongs to the Special Issue The Roles of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Health and Disease)

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19 pages, 18390 KB

Open AccessReview

GLP-1 Receptor Agonists as Molecular Relievers of Lipotoxic Stress: From Pancreatic Beta-Cell Cholesterol Efflux to Systemic and Tissue-Specific Metabolic Protection

by Wenyi Jiang, Kensaku Fukunaga, Toshihiro Kobayashi, Takanobu Saheki, Takafumi Yoshimura, Haotian Zhang, Rathana Ly, Hitomi Imachi and Koji Murao

Int. J. Mol. Sci. 2026, 27(18), 8378; https://doi.org/10.3390/ijms27188378 (registering DOI) - 20 Sep 2026

Abstract

GLP-1RAs improve glycemia and body weight, but their effects extend beyond insulin secretion and appetite suppression. Experimental evidence indicates that GLP-1 receptor signaling can relieve lipotoxic stress by reducing lipid influx, restoring lipid trafficking, promoting cholesterol efflux, improving mitochondrial and endoplasmic reticulum homeostasis, and suppressing inflammatory and apoptotic signaling. In pancreatic beta cells, saturated fatty acids, oxidized low-density lipoprotein and excess free cholesterol disrupt membrane microdomains, insulin-granule trafficking, calcium signaling, autophagic flux and beta-cell identity. Preclinical studies with individual GLP-1RAs, principally exendin-4 and liraglutide, implicate cAMP/PKA, PI3K/Akt, ERK1/2, AMPK, Nrf2 and autophagy-related pathways in these protective responses. A relevant mechanism is induction of ATP-binding cassette transporter A1 (ABCA1): exendin-4 stimulates ABCA1 transcription through the CaMKK/CaMKIV/PREB axis, linking incretin signaling to cholesterol export and preservation of glucose-stimulated insulin secretion. Recent work indicates spatially organized GLP-1R signaling at endoplasmic reticulum–mitochondria contact sites. Preclinical genetic evidence in mouse metabolic dysfunction-associated steatohepatitis (MASH) models indicates that pericentral liver sinusoidal endothelial GLP-1 receptors contribute to weight-loss-independent semaglutide-mediated improvements in steatosis, fibrosis and immune remodeling; whether an analogous causal mechanism operates in human MASH remains unknown. This review integrates systemic nutrient unloading, beta-cell cholesterol homeostasis and intrahepatic endothelial signaling as complementary mechanisms of metabolic protection. Full article

(This article belongs to the Special Issue The Roles of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Health and Disease)

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24 pages, 5295 KB

Open AccessReview

GLP-1 and Dual GIP/GLP-1 Receptor Agonists in Pediatric Obesity: From Neuroendocrine Mechanisms to Clinical Application

by Dominika Myśliwczyk, Małgorzata Myśliwiec, Alina Minarowska and Eliza Wasilewska

Int. J. Mol. Sci. 2026, 27(18), 8191; https://doi.org/10.3390/ijms27188191 - 15 Sep 2026

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Abstract

Pediatric obesity is a chronic, multifactorial neuroendocrine disease in which disrupted gut–brain signaling, hypothalamic appetite regulation, adipose tissue dysfunction, and altered inter-organ communication sustain positive energy balance. Incretin-based therapies translate this biology into mechanism-based treatment, yet their developmental implications remain incompletely defined. This narrative review integrates evidence on GLP-1 and GIP receptor signaling with pediatric trial data and clinical implementation, with particular attention to developmental modifiers of gut–brain signaling and treatment during growth and puberty. We describe how GLP-1 receptor agonists act across central and peripheral tissues to reduce appetite, delay gastric emptying, and enhance glucose-dependent insulin secretion and examine the rationale for dual GIP/GLP-1 receptor agonism. Randomized pediatric trials demonstrate clinically meaningful BMI reduction with liraglutide and semaglutide, with the largest mean effect reported for semaglutide in adolescents; however, long-term effects on growth, puberty, bone health, body composition, and weight maintenance remain uncertain. Tirzepatide has shown greater weight-loss efficacy than selective GLP-1 receptor agonism in adults, but no randomized trial has evaluated it in pediatric obesity without diabetes. Incretin-based therapies should be integrated with nutritional, behavioral, psychological, and family-based care. Their future value will depend on durable efficacy, developmental safety, equitable access, and identification of patients most likely to benefit. Full article

(This article belongs to the Special Issue The Roles of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Health and Disease)

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22 pages, 1453 KB

Open AccessReview

Therapeutic Potential of Glucagon-like Peptide-1 Receptor Agonists in Respiratory Disorders

by Ewelina Russjan, Dominika Zając and Katarzyna Kaczyńska

Int. J. Mol. Sci. 2026, 27(13), 5803; https://doi.org/10.3390/ijms27135803 - 26 Jun 2026

Viewed by 682

Abstract

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted in response to food intake that acts biologically by binding to GLP-1 receptors. The primary function of GLP-1 is to stimulate insulin secretion and inhibit glucagon secretion, which helps limit after-meal spikes in blood glucose. GLP-1 reduces intestinal contractility, slows down gastrointestinal motility and emptying, and also acts directly on the hypothalamus, thereby regulating appetite and food intake. Due to its metabolic effects, GLP-1 forms the basis of medications currently used to treat type 2 diabetes (T2DM) and obesity. However, it has also been observed that the use of GLP-1 agonists in the treatment of obesity or diabetes has a beneficial effect on comorbid respiratory conditions. This narrative review analyzes the scientific literature and describes the most recent information on the impact of GLP-1 receptor agonist (GLP-1 RA) therapies on the most common respiratory disorders—both the beneficial and undesirable effects. We discuss evidence that acute lung injury, COVID-19, pulmonary fibrosis, asthma, chronic obstructive pulmonary disease (COPD), and obstructive sleep apnea can benefit from therapies with various GLP-1 RAs. They can complement existing lung-targeted treatments, but as research progresses, they are likely to play an ever more important role in the treatment of respiratory diseases. Full article

(This article belongs to the Special Issue The Roles of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Health and Disease)

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21 pages, 1369 KB

Open AccessReview

GLP-1 Receptor Agonists at the Crossroads of Circadian Biology, Sleep, and Metabolic Disease

by Ayush Gandhi, Ei Moe Phyu, Kwame Koom-Dadzie, Kodwo Bosomefi Dickson and Josiah Halm

Int. J. Mol. Sci. 2026, 27(6), 2853; https://doi.org/10.3390/ijms27062853 - 21 Mar 2026

Cited by 2 | Viewed by 5274

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have transformed the management of type 2 diabetes and obesity, yet their actions extend beyond glycemic control and weight loss. This narrative review synthesizes current preclinical and clinical evidence examining the bidirectional relationship between glucagon-like peptide-1 (GLP-1) receptor agonists and circadian biology. A structured literature search was conducted in PubMed using combinations of the terms ‘GLP-1,’ ‘circadian,’ ‘chronobiology,’ ‘sleep,’ ‘obesity,’ and ‘type 2 diabetes’ through January 2026. Accumulating evidence indicates that GLP-1 physiology is closely coupled to circadian timing systems and sleep–wake regulation. In this narrative review, we synthesize emerging data that reframe GLP-1RAs as chronometabolic modulators, acting at the intersection of metabolism, circadian biology, and sleep. We review circadian control of GLP-1 secretion by intestinal L-cells, emphasizing the role of core clock genes and the vulnerability of incretin rhythms to circadian misalignment from shift work, nocturnal light exposure, and sleep loss. We then examine GLP-1 receptor signaling within central and peripheral clock networks, including feedback effects on hypothalamic and hepatic circadian regulation. Emerging data suggest that GLP-1 signaling is under circadian regulation and may, in turn, influence central and peripheral clock systems. Comparative discussion of semaglutide, liraglutide, and tirzepatide highlights agent-specific pharmacokinetics and emerging clinical data linking GLP-1RA therapy to sleep outcomes, particularly obstructive sleep apnea. Finally, we outline translational opportunities for chronotherapy and precision medicine, positioning GLP-1RAs as integrative tools for metabolic and sleep-related disease rather than purely weight-centric therapies. We propose that GLP-1 receptor agonists may function as chronometabolic modulators, with potential implications for personalized chronopharmacological strategies in metabolic disease. Full article

(This article belongs to the Special Issue The Roles of Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists in Health and Disease)

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