title: Extended exenatide administration enhances lipid metabolism and exacerbates pancreatic injury in mice on a high fat, high carbohydrate diet.
abstract: This study expanded upon a previous study in mice reporting a link between exenatide treatment and exocrine pancreatic injury by demonstrating temporal and dose responses and providing an initial mechanistic hypothesis. The design of the present study included varying lengths of exenatide exposure (3, 6 weeks to 12 weeks) at multiple concentrations (3, 10, or 30 µg/kg) with multiple endpoints (histopathology evaluations, immunoassay for cytokines, immunostaining of the pancreas, serum chemistries and measurement of trypsin, amylase, and, lipase, and gene expression profiles). Time- and dose-dependent exocrine pancreatic injury was observed in mice on a high fat diet treated with exenatide. The morphological changes identified in the pancreas involved acinar cell injury and death (autophagy, apoptosis, necrosis, and atrophy), cell adaptations (hypertrophy and hyperplasia), and cell survival (proliferation/regeneration) accompanied by varying degrees of inflammatory response leading to secondary injury in pancreatic blood vessels, ducts, and adipose tissues. Gene expression profiles indicated increased signaling for cell survival and altered lipid metabolism in exenatide treated mice. Immunohistochemistry supported gene expression findings that exenatide caused and/or exacerbated pancreatic injury in a high fat diet environment potentially by further increasing high fat diet exacerbated lipid metabolism and resulting oxidative stress. Further investigation is required to confirm these findings and determine their relevance to human disease.
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, Silver Spring, Maryland, United States of America.
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, Maryland, United States of America.
authors.forename: Leshuai
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, Silver Spring, Maryland, United States of America.
authors.forename: Katherine
authors.initials: K
authors.lastname: Shea
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, Silver Spring, Maryland, United States of America.
authors.forename: Hongfei
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, Silver Spring, Maryland, United States of America.
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, Maryland, United States of America.
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, Maryland, United States of America.
authors.forename: Barry
authors.initials: B
authors.lastname: Rosenzweig
authors.affiliation: Division of Applied Regulatory Science, Center for Drug Evaluation and Research, U. S. Food and Drug Administration, Silver Spring, Maryland, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000681:Amylases / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects*; D004040:Dietary Carbohydrates / Q000009:adverse effects*; D004334:Drug Administration Schedule; D000077270:Exenatide; D010188:Exocrine Pancreatic Insufficiency / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007004:Hypoglycemic Agents / Q000009:adverse effects*; D008049:Lipase / Q000378:metabolism; D050356:Lipid Metabolism / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019283:Pancreatitis, Acute Necrotizing / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000009:adverse effects*; D013997:Time Factors; D014357:Trypsin / Q000378:metabolism; D014688:Venoms / Q000009:adverse effects*
chemical_list: D004040:Dietary Carbohydrates; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; D000077270:Exenatide; D008049:Lipase; D000681:Amylases; D014357:Trypsin