Revisiting the Complexity of GLP-1 Action from Sites of Synthesis to Receptor Activation
Open accessAbstract
Glucagon-like peptide-1 (GLP-1) is produced in gut endocrine cells and in the brain, and acts through hormonal and neural pathways to regulate islet function, satiety, and gut motility, supporting development of GLP-1 receptor (GLP-1R) agonists for the treatment of diabetes and obesity. Classic notions of GLP-1 acting as a meal-stimulated hormone from the distal gut are challenged by data supporting production of GLP-1 in the endocrine pancreas, and by the importance of brain-derived GLP-1 in the control of neural activity. Moreover, attribution of direct vs indirect actions of GLP-1 is difficult, as many tissue and cellular targets of GLP-1 action do not exhibit robust or detectable GLP-1R expression. Furthermore, reliable detection of the GLP-1R is technically challenging, highly method dependent, and subject to misinterpretation. Here we revisit the actions of GLP-1, scrutinizing key concepts supporting gut vs extra-intestinal GLP-1 synthesis and secretion. We discuss new insights refining cellular localization of GLP-1R expression and integrate recent data to refine our understanding of how and where GLP-1 acts to control inflammation, cardiovascular function, islet hormone secretion, gastric emptying, appetite, and body weight. These findings update our knowledge of cell types and mechanisms linking endogenous vs pharmacological GLP-1 action to activation of the canonical GLP-1R, and the control of metabolic activity in multiple organs.
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GLP-1R expression in peripheral tissues is generally low and restricted to rare cell types.
“Although GLP-1R expression in peripheral tissues is generally low and restricted to rare cell types (26), antiinflammatory benefits have been observed in various preclinical models”
From Antiinflammatory actions of glucagon-like peptide-1–based therapies beyond metabolic benefits (2025) · cites this paper as [26]
The Introduction (p. 5) describes low GLP1R mRNA expression, and the gastrointestinal-tract section (p. 40) identifies particular receptor-expressing cell types while finding none in enterocytes. But the review does not establish that expression across peripheral tissues is generally restricted to rare cell types; its islet consensus (p. 15) reports abundant expression in 80–95% of β-cells. (LLM, conf=0.83)
Experimental — accuracy not yet measuredGLP-1 medicines regulate inflammation partly by directly modulating immune cells, although GLP-1R expression is typically low in lymphoid organs.
“GLP-1 medicines regulate inflammation partly by directly modulating immune cells, although GLP-1R expression is typically low in lymphoid organs (Figure 1) (26).”
From Antiinflammatory actions of glucagon-like peptide-1–based therapies beyond metabolic benefits (2025) · cites this paper as [26]
The “GLP-1 action in the immune system” section (p. 44) says GLP-1R agonists reduce systemic inflammation and reports low Glp1r transcript levels in cells isolated from the thymus, spleen, and lymph nodes. It also says the mechanisms linking GLP-1R signaling to immune-cell activity remain uncertain, so it does not establish that direct immune-cell modulation partly causes the anti-inflammatory effect. (LLM, conf=0.88)
Experimental — accuracy not yet measuredGLP-1 acts through GLP-1R, which is mainly expressed in pancreatic islets, the brain, and the GI tract, and less prominently in the kidney and eyes.
“GLP-1 acts through a class 2 member of the G-coupled protein C receptor family seven-transmembrane receptor (GLP-1R) (8), which is mainly expressed in pancreatic islets, the brain, and the gastrointestinal (GI) tract (9–12), and less prominently in the kidney and eyes (11–13).”
From The science of safety: adverse effects of GLP-1 receptor agonists as glucose-lowering and obesity medications (2026) · cites this paper as [12]
GLP-1-based drugs reduce weight primarily by reducing energy intake, via activation of the GLP-1 receptor mainly on sites of action in the central nervous system.
“Notably, this drug class reduces weight primarily by reducing energy intake, via activation of the cognate GLP-1 receptor (GLP-1R), mainly on sites of action in the central nervous system (CNS) (15, 16).”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [15]
An extensive body of evidence from pharmacological studies using direct CNS injections of GLP-1R ligands supports roles for central GLP-1 signaling in eating behaviors and energy balance.
“An extensive body of evidence from pharmacological studies using direct CNS injections of GLP-1R ligands supports roles for central GLP-1 signaling in eating behaviors and energy balance (reviewed in detail in (15, 16)).”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [15]
Local injection of GLP-1 and/or GLP-1R agonists elicits anorectic effects in virtually all GLP-1R-expressing CNS regions investigated.
“Local injection of GLP-1 and/or GLP-1R agonists (GLP-1RAs) elicits anorectic effects in virtually all GLP-1R-expressing CNS regions investigated (reviewed in (15, 16)).”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [15]
A subset of GLP-1R neuron populations behind the blood-brain barrier likely represents common targets, which are both accessible to peripherally administered GLP-1RAs (probably only upon chronic dosing) and to endogenous GLP-1 released from PPGs via synapses and/or cerebrospinal fluid-mediated volume transmission.
“Finally, a subset of GLP-1R neuron populations behind the blood-brain barrier likely represents common targets, which are both accessible to peripherally administered GLP-1RAs (probably only upon chronic dosing) and to endogenous GLP-1 released from PPGs via synapses and/or cerebrospinal fluid–mediated volume transmission (15, 16, 69).”
From GLP-1 and the Neurobiology of Eating Control: Recent Advances (2025) · cites this paper as [15]
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References 229 · Cited by 289
- Authors
- McLean, B. A., Wong, C. K., Campbell, J. E., Hodson, D. J., Trapp, S., & Drucker, D. J.
- Affiliations
- Mount Sinai Hospital (CA)
- Duke University (US)
- University of Birmingham (GB)
- University College London (GB)
- Corresponding author
- Drucker, Daniel J
- Venue
- Endocrine Reviews
- Publisher
- The Endocrine Society
- Published
- 2020-12-15
- Volume
- 42
- Issue
- 2
- Pages
- 101-132
- ISSN
- 0163-769X (ISSN-L)
- 1945-7189
- PMC
- PMC7958144
- OpenAlex
- W3110662830
- Cited by
- 289
- References
- 229
- Citations by year
- 2026: 51 · 2025: 64 · 2024: 63 · 2023: 48 · 2022: 38 · 2021: 24 · 2020: 1
- FWCI
- 4.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model (vor)
- Locations
- Endocrine Reviews (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, other-oa)
- Funders
- Canadian Institutes of Health Research (154321)
- Novo Nordisk Foundation
- Medical Research Council (MR/N00275X/1, MR/S025618/1)
- European Research Council
- American Diabetes Association (1-18-JDF-017)
- National Institutes of Health (DK123075, DK125353, R01 DK095757)
- British Heart Foundation (FS/14/43/30960)
- 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 › Surgery › Pancreatic function and diabetes
- Keywords
- glucagon-like peptide-1, GLP-1 receptor, GLP-1 receptor agonists, endocrine pancreas, islet hormone secretion, gastric emptying, appetite and satiety, body weight regulation, inflammation, cardiovascular function, diabetes mellitus, obesity, gut-brain signaling
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Glucagon-Like Peptide-1 Receptor Agonists, Humans, Obesity, Glucagon-Like Peptide 1
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