Occurrence of Spontaneous Pancreatic Lesions in Normal and Diabetic Rats: A Potential Confounding Factor in the Nonclinical Assessment of GLP-1–Based Therapies

• DOI: 10.2337/db13-1268
• Publication Date: 2013-11-13T04:19:10Z
• Authors: Kristina D. Chadwick; Anthony M. Fletcher; M. Cecilia Parrula; Susan Bonner-Weir; Raja S. Mangipudy; Evan Janovitz; Michael J. Graziano; Denis Roy; Timothy P. Reilly
• Keywords: Amylin; Incretin

Glucagon-like peptide 1-based therapies, collectively described as incretins, produce glycemic benefits in the treatment of type 2 diabetes. Recent publications raised concern for a potential increased risk pancreatitis and pancreatic cancer with incretins based part on findings from small number rodents. However, extensive toxicology assessments substantial animals dosed up to years at high multiples human exposure do not support these concerns. We hypothesized that lesions being attributed are commonly observed background endeavored characterize incidence spontaneous three rat strains (Sprague-Dawley [S-D] rats, Zucker diabetic fatty [ZDF] rats expressing islet amyloid polypeptide [HIP]; n = 36/group) normal or high-fat diet over 4 months. Pancreatic all groups included focal exocrine degeneration, atrophy, inflammation, ductular cell proliferation, and/or observations large ducts similar those literature, an atrophy/inflammation seen S-D (42-72%), HIP (39%), ZDF (6%) rats. These data indicate common findings, without drug independent status, suggesting need exercise caution when interpreting relevance some recent reports regarding safety.