Chronic GLP-1 Receptor Activation by Exendin-4 Induces Expansion of Pancreatic Duct Glands in Rats and Accelerates Formation of Dysplastic Lesions and Chronic Pancreatitis in the KrasG12D Mouse Model
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Pancreatic duct glands (PDGs) have been hypothesized to give rise to pancreatic intraepithelial neoplasia (PanIN). Treatment with the glucagon-like peptide (GLP)-1 analog, exendin-4, for 12 weeks induced the expansion of PDGs with mucinous metaplasia and columnar cell atypia resembling low-grade PanIN in rats. In the pancreata of Pdx1-Cre; LSL-KrasG12D mice, exendin-4 led to acceleration of the disruption of exocrine architecture and chronic pancreatitis with mucinous metaplasia and increased formation of murine PanIN lesions. PDGs and PanIN lesions in rodent and human pancreata express the GLP-1 receptor. Exendin-4 induced proproliferative signaling pathways in human pancreatic duct cells, cAMP–protein kinase A and mitogen-activated protein kinase phosphorylation of cAMP-responsive element-binding protein, and increased cyclin D1 expression. These GLP-1 effects were more pronounced in the presence of an activating mutation of Kras and were inhibited by metformin. These data reveal that GLP-1 mimetic therapy may induce focal proliferation in the exocrine pancreas and, in the context of exocrine dysplasia, may accelerate formation of neoplastic PanIN lesions and exacerbate chronic pancreatitis.
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Persistent activation of GLP-1 receptors in exocrine pancreatic cells may lead to localized hyperplasia in the exocrine pancreas, consequently accelerating the formation of dysplastic lesions and pancreatitis.
“Persistent activation of GLP-1 receptors in exocrine pancreatic cells may lead to localized hyperplasia in the exocrine pancreas, consequently accelerating the formation of dysplastic lesions and pancreatitis [64].”
From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [64]
The Abstract reports focal proliferation in the exocrine pancreas after GLP-1 mimetic treatment. It also reports accelerated dysplastic lesions and chronic pancreatitis, but those outcomes were observed in a Kras-mutant mouse model predisposed to dysplasia. The claim omits that condition and presents the downstream effects more generally. (LLM, conf=0.85)
Experimental — accuracy not yet measuredA handful of preclinical studies showed that GLP-1RAs induce pancreatic inflammation, cellular proliferation and intra-epithelial neoplasia (PanIN).
“A handful of preclinical studies showed that GLP-1RAs induce pancreatic inflammation, cellular proliferation and intra-epithelial neoplasia (PanIN) (70–72).”
From Safety of Semaglutide (2021) · cites this paper as [71]
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- Authors
- Gier, B., Matveyenko, A. V., Kirakossian, D., Dawson, D., Dry, S. M., & Butler, P. C.
- Affiliations
- University of California, Los Angeles (US)
- Corresponding author
- Gier, Belinda
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2012-04-13
- Volume
- 61
- Issue
- 5
- Pages
- 1250-1262
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3331736
- OpenAlex
- W2122696108
- Cited by
- 255
- References
- 46
- Citations by year
- 2026: 12 · 2025: 21 · 2024: 19 · 2023: 5 · 2022: 6 · 2021: 9 · 2020: 8 · 2019: 11 · 2018: 12 · 2017: 16 · 2016: 19 · 2015: 26 · 2014: 33 · 2013: 48 · 2012: 10
- FWCI
- 18.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- Larry L. Hillblom Foundation
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (#DK077967, R01DK077967)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- exendin-4, GLP-1 receptor, pancreatic intraepithelial neoplasia, chronic pancreatitis, KRAS G12D, metformin, mucinous metaplasia, cAMP signaling, MAPK signaling, cyclin D1, pancreatic cancer risk
- MeSH terms
- Glucagon-Like Peptide-1 Receptor, Exenatide, Animals, Humans, Hypoglycemic Agents, Male, Metformin, Mutation, Pancreatic Ducts, Pancreatitis, Peptides, Venoms, Trans-Activators, Proto-Oncogene Proteins p21(ras), Rats, Sprague-Dawley, Receptors, Glucagon, Homeodomain Proteins, Mice, Rats
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