title: High fat diet and GLP-1 drugs induce pancreatic injury in mice.
abstract: Glucagon Like Peptide-1 (GLP-1) drugs are currently used to treat type-2 diabetes. Safety concerns for increased risk of pancreatitis and pancreatic ductal metaplasia have accompanied these drugs. High fat diet (HFD) is a type-2 diabetes risk factor that may affect the response to GLP-1 drug treatment. The objective of the present study was to investigate the effects of diet and GLP-1 based drugs on the exocrine pancreas in mice. Experiments were designed in a mouse model of insulin resistance created by feeding a HFD or standard diet (STD) for 6weeks. The GLP-1 drugs, sitagliptin (SIT) and exenatide (EXE) were administered once daily for additional 6weeks in both mice fed HFD or STD. The results showed that body weight, blood glucose levels, and serum levels of pro-inflammatory cytokines (TNFα, IL-1β, and KC) were significantly greater in HFD mice than in STD mice regardless of GLP-1 drug treatment. The semi-quantitative grading showed that pancreatic changes were significantly greater in EXE and SIT-treated mice compared to control and that HFD exacerbated spontaneous exocrine pancreatic changes seen in saline-treated mice on a standard diet. Exocrine pancreatic changes identified in this study included acinar cell injury (hypertrophy, autophagy, apoptosis, necrosis, and atrophy), vascular injury, interstitial edema and inflammation, fat necrosis, and duct changes. These findings support HFD as a risk factor to increased susceptibility/severity for acute pancreatitis and indicate that GLP-1 drugs cause pancreatic injury that can be exacerbated in a HFD environment.
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA. Electronic address: rodney.rouse@fda.hhs.gov.
authors.forename: Rodney
authors.initials: R
authors.lastname: Rouse
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Xu
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Sharron
authors.initials: S
authors.lastname: Stewart
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001284:Atrophy; D059305:Diet, High-Fat / Q000009:adverse effects*; D000077270:Exenatide; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis; D010179:Pancreas / Q000187:drug effects* / Q000473:pathology; D010195:Pancreatitis / Q000209:etiology; D010455:Peptides / Q000633:toxicity*; D011719:Pyrazines / Q000633:toxicity*; D018027:Receptors, Glucagon / Q000819:agonists*; D000068900:Sitagliptin Phosphate; D014230:Triazoles / Q000633:toxicity*; D014688:Venoms / Q000633:toxicity*
chemical_list: C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D010455:Peptides; D011719:Pyrazines; D018027:Receptors, Glucagon; D014230:Triazoles; D014688:Venoms; D000077270:Exenatide; D000068900:Sitagliptin Phosphate
keywords: Acinar cell death; Drug-induced pancreatitis; High fat diet; Macrophage activation; Pancreatic vasculitis; Pro-inflammatory cytokines