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Cited by 56Diabetes Treatment and ManagementPancreatitis Pathology and TreatmentPancreatic function and diabetes

No evidence of drug‐induced pancreatitis in rats treated with exenatide for 13 weeks

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Tatarkiewicz, K., Belanger, P., Gu, G., Parkes, D., Roy, D.·2013·Diabetes, Obesity and Metabolism
DOI 10.1111/dom.12040PMC PMC3654567
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Abstract

Aims: The potential association of glucagon‐like peptide receptor agonists ( GLP‐1RAs ) with the development of pancreatitis or pancreatic malignancies in patients with diabetes has been suggested. This study evaluated the long‐term effects of the GLP‐1RA exenatide on pancreatic exocrine structure and function in the Zucker diabetic fatty ( ZDF ) rat model of type 2 diabetes. Methods: Rats received subcutaneous twice‐daily injections of 0 (control), 6, 40 and 250 µg/kg/day exenatide for 3 months. Clinical signs, body and pancreas weight, food consumption, HbA1c , fasting serum amylase, lipase, glucose and insulin concentrations were evaluated during treatment and after a 28‐day off‐drug period to assess the reversibility of any observed effects. Morphometric analysis of pancreatic ductal cell proliferation and apoptosis were performed. Results: Plasma exenatide concentrations were several‐fold higher than therapeutic levels observed in humans. No exenatide‐related effects were observed on clinical signs, lipase concentration, pancreatic weight, pancreatic histology, ductal cell proliferation or apoptosis. Exenatide improved animal survival, physical condition, glucose concentrations and HbA1c , decreased food intake, and increased serum insulin concentration. Total amylase concentrations, although within normal ranges, were slightly higher in exenatide‐treated rats; following the off‐drug period, total amylase concentrations were comparable in treated and untreated rats. Exenatide‐related minimal‐to‐moderate islet hypertrophy was observed at doses ≥6 µg/kg/day, with dose‐related increases in incidence and degree. These changes were still present after the off‐drug period. Conclusions: Chronic administration of exenatide in ZDF rats resulted in the expected metabolic benefits and improved animal survival, with no adverse effects noted on pancreatic exocrine structure and function.

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  • In two short-term mechanical studies using exenatide and liraglutide in a diabetic rat model, one rat administered exenatide died of pancreatic necrosis, while others exhibited acinar-to-ductal metaplasia and ductal hyperplasia, indicative of potential premalignant alterations.

    “two short-term mechanical studies were conducted using exenatide and liraglutide in a diabetic rat model, wherein one rat administered with exenatide died of pancreatic necrosis, while the others exhibited acinar-to-ductal metaplasia and ductal hyperplasia, indicative of potential premalignant alterations [62,63].”

    From Exploring the Side Effects of GLP-1 Receptor Agonist: To Ensure Its Optimal Positioning (2025) · cites this paper as [62]

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  • The majority of animal studies did not find any effect of GLP-1RAs on pancreatic physiology, even with doses up to 240 times the normal human dose.

    “However, the majority of animal studies did not find any effect of GLP-1RAs on pancreatic physiology, even with doses up to 240 the normal human dose (73–76).”

    From Safety of Semaglutide (2021) · cites this paper as [74]

    The Introduction summarizes several animal studies that found no pancreatitis or adverse exocrine pancreatic effects, and the Discussion reports no adverse exocrine effects in this rat study. But “no effect on pancreatic physiology” is broader than the findings: Results > Pancreatic Function and Structure reports increased amylase and islet hypertrophy. The paper describes exposure as several-fold above therapeutic human levels, not 240 times the normal human dose. Page numbers are unavailable in our copy. (LLM, conf=0.86)

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Authors
Tatarkiewicz, K., Belanger, P., Gu, G., Parkes, D., & Roy, D.
Affiliations
Amylin Pharmaceuticals, LLC San Diego CA USA
Corresponding author
Tatarkiewicz, K.
ORCID
Roy, D.
Venue
Diabetes, Obesity and Metabolism
Publisher
Wiley
Published
2012-12-07
Volume
15
Issue
5
Pages
417-426
ISSN
  • 1462-8902 (ISSN-L)
  • 1463-1326
DOI
10.1111/dom.12040
PMC
PMC3654567
OpenAlex
W2107370002
Cited by
56
References
5
Citations by year
2025: 1 · 2024: 3 · 2023: 1 · 2022: 2 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 3 · 2017: 1 · 2016: 5 · 2015: 8 · 2014: 14 · 2013: 11
FWCI
8.98
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Diabetes Obesity and Metabolism (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
European Association for the Study of Diabetes
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
  • Health Sciences › Medicine › Surgery › Pancreatitis Pathology and Treatment
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
Keywords
exenatide, GLP-1 receptor agonists, drug-induced pancreatitis, pancreatic exocrine function, apoptosis, islet hypertrophy, type 2 diabetes, Zucker diabetic fatty rats, long-term drug safety, serum amylase
MeSH terms
Glucagon-Like Peptide-1 Receptor, Exenatide, Amylases, Animals, Blood Glucose, Body Weight, Diabetes Mellitus, Experimental, Diabetes Mellitus, Type 2, Eating, Fasting, Glycated Hemoglobin, Hypoglycemic Agents, Injections, Subcutaneous, Lipase, Male, Organ Size, Pancreas, Pancreatitis, Peptides, Rats, Zucker, Venoms, Biomarkers, Apoptosis, Receptors, Glucagon, Cell Proliferation, Rats

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