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Unlocking the multifaceted roles of GLP-1: Physiological functions and therapeutic potential
Open accessAbstract
Glucagon (GCG) like peptide 1 (GLP-1) has emerged as a powerful player in regulating metabolism and a promising therapeutic target for various chronic diseases. This review delves into the physiological roles of GLP-1, exploring its impact on glucose homeostasis, insulin secretion, and satiety. We examine the compelling evidence supporting GLP-1 receptor agonists (GLP-1RAs) in managing type 2 diabetes (T2D), obesity, and other diseases. The intricate molecular mechanisms underlying GLP-1RAs are explored, including their interactions with pathways like extracellular signal-regulated kinase 1/2 (ERK1/2), activated protein kinase (AMPK), cyclic adenine monophosphate (cAMP), mitogen-activated protein kinase (MAPK), and protein kinase C (PKC). Expanding our understanding, the review investigates the potential role of GLP-1 in cancers. Also, microribonucleic acid (RNA) (miRNAs), critical regulators of gene expression, are introduced as potential modulators of GLP-1 signaling. We delve into the link between miRNAs and T2D obesity and explore specific miRNA examples influencing GLP-1R function. Finally, the review explores the rationale for seeking alternatives to GLP-1RAs and highlights natural products with promising GLP-1 modulatory effects.
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![Fig. 1 Pleiotropic effects of GLP-1 [1]. [CNS: central nervous system; CVS: Cardiovascular system; GIT: Gastrointestinal tract; GLP-1R: Glucagon like peptide-1 receptor; VLDL: very low-density lipoprotein].](/paper-figures/6f2a32aec74643f08815438421405ffb/unlocking-the-multifaceted-roles-of-glp-1-physiological-functions-and-figure-1.jpg)
![Fig. 2 The complex interplay between GLP-1RAs and several cellular signaling pathways. [AMPK: activated protein kinase; cAMP: cyclic adenine monophosphate; ERK 1/2: extracellular signal-regulated kinase 1/2; GLP-1R: Glucagon like peptide-1 receptor; MAPK: Mitogen-activated protein kinase; PKC: protein kinase C].](/paper-figures/65b50af717f64f498dc2d3e183e32d62/unlocking-the-multifaceted-roles-of-glp-1-physiological-functions-and-figure-2.jpg)
![Fig. 3 Intracellular signaling through Gαs mediated by GLP-1R. [GLP-1R: Glucagon like peptide-1 receptor; ATP: adenosine triphosphate; cAMP: cyclic adenine monophosphate; Epac: exchange protein directly activated by cAMP; PKA: protein kinase A; ERK1/2: Extracellular signal-regulated kinase 1/2; AKT: protein kinase B; mTOR: Mammalian target of rapamycin; CREB: cAMP-response element binding protein].](/paper-figures/9657977171f74148b533a15906aa90d1/unlocking-the-multifaceted-roles-of-glp-1-physiological-functions-and-figure-3.jpg)
![Fig. 4 GLP-1R: The Key to Unlocking Weight Loss? Exploring Potential Mechanisms [2].](/paper-figures/ac3b98a069bb4ef5b524170ce758b8dc/unlocking-the-multifaceted-roles-of-glp-1-physiological-functions-and-figure-4.jpg)
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“Additionally, GLP-1 slows gastric emptying, leading to prolonged satiety and reduced food intake [24].”
From A Narrative Review on GLP-1 Receptor Agonists for Obesity in Older Women: Maximizing Weight Loss While Preserving Lean Mass (2026) · cites this paper as [24]
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“Conversely, GLP-1 suppresses glucagon secretion from pancreatic alpha cells, preventing excessive glucose production from the liver.”
From A Narrative Review on GLP-1 Receptor Agonists for Obesity in Older Women: Maximizing Weight Loss While Preserving Lean Mass (2026) · cites this paper as [24]
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Entezari, M., Hashemi, D., Taheriazam, A., Zabolian, A., Mohammadi, S., Fakhri, F., Hashemi, M., Hushmandi, K., Ashrafizadeh, M., Zarrabi, A., et al. (2021) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2021.112563 · Cited by 410
RetractedOverview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation
O'Brien, J., Hayder, H., Zayed, Y., & Peng, C. (2018) · Frontiers in Endocrinology · doi:10.3389/fendo.2018.00402 · Cited by 5,287
Once-Weekly Semaglutide in Adults with Overweight or Obesity
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AMPK: a nutrient and energy sensor that maintains energy homeostasis
Hardie, D. G., Ross, F. A., & Hawley, S. A. (2012) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3311 · Cited by 4,602
The Physiology of Glucagon-like Peptide 1
Holst, J. J. (2007) · Physiological Reviews · doi:10.1152/physrev.00034.2006 · Cited by 3,371
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A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management
Pi-Sunyer, X., Astrup, A., Fujioka, K., Greenway, F., Halpern, A., Krempf, M., Lau, D. C. W., le Roux, C. W., Violante Ortiz, R., Jensen, C. B., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1411892 · Cited by 2,724
Pathological roles of MAPK signaling pathways in human diseases
Kim, E. K., & Choi, E.-J. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.12.009 · Cited by 2,472
Lixisenatide in Patients with Type 2 Diabetes and Acute Coronary Syndrome
Pfeffer, M. A., Claggett, B., Diaz, R., Dickstein, K., Gerstein, H. C., Køber, L. V., Lawson, F. C., Ping, L., Wei, X., Lewis, E. F., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1509225 · Cited by 2,409
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Drucker, D. J. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.03.001 · Cited by 2,170
Research works printed but not linked: 3
- Wang, 2023, GLP−1 receptor agonists for the treatment of obesity: role as a promising approach, Front. Endocrinol., 14
- Rowlands, 2018, Pleiotropic Effects of GLP-1 and Analogs on Cell Signaling, Metabolism, and Function, Front. Endocrinol., 9, 10.3389/fendo.2018.00672 · DOI · Paper page
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Metadata
- Authors
- AL-Noshokaty, T. M., Abdelhamid, R., Abdelmaksoud, N. M., Khaled, A., Hossam, M., Ahmed, R., Saber, T., Khaled, S., Elshaer, S. S., & Abulsoud, A. I.
- Affiliations
- Heliopolis University (EG)
- Al-Azhar University (EG)
- Corresponding author
- Abdelhamid, Rehab
- Venue
- Toxicology Reports
- Publisher
- Elsevier BV
- Published
- 2025-06
- Volume
- 14
- Pages
- 101895
- ISSN
- 2214-7500 (ISSN-L)
- PMC
- PMC11795145
- OpenAlex
- W4406560873
- Cited by
- 30
- References
- 308
- Citations by year
- 2026: 16 · 2025: 14
- FWCI
- 4.08
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Toxicology Reports (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Keywords
- glucagon-like peptide-1, GLP-1 receptor agonists, glucose homeostasis, insulin secretion, satiety, type 2 diabetes, obesity, cancer, microRNA, ERK signaling, AMPK, cAMP signaling, MAPK signaling, protein kinase C, natural products, GLP-1 signaling
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