Extended exenatide administration enhances lipid metabolism and exacerbates pancreatic injury in mice on a high fat, high carbohydrate diet.

Rodney Rouse,Jun Zhang,Leshuai Zhang,Katherine Shea,Lin Xu,Sharron Stewart,Hongfei Zhou,Barry Rosenzweig,Francisco X Real

doi:10.1371/journal.pone.0109477

Rodney Rouse, Jun Zhang + Show 7 more

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https://doi.org/10.1371/journal.pone.0109477

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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.

Highlights

Drugs active in the Glucagon-Like Peptide-1 (GLP-1) signaling pathway treat type-2 diabetes mellitus
In spite of null findings for pancreatic injury in initial pre-clinical studies and clinical trial submissions to the FDA, by 2008, adverse event reports indicated a possible link between GLP-1 drugs and acute pancreatitis [2]
In sections labeled with TdT-mediated dUTP-biotin nick end labeling (TUNEL), a single positive nucleus (Figure 4G) was occasionally found in acinar cell areas with normal H & E morphology while numerous positive nuclei and fragmented nuclei were located in severely injured areas (Figure 4H) in EXE treated mice

Summary

Introduction

Drugs active in the Glucagon-Like Peptide-1 (GLP-1) signaling pathway treat type-2 diabetes mellitus. Immunohistochemical staining was undertaken to quantify injury observed in 30 mg/kg EXE treated mice relative to controls after 12 weeks of treatment. Treated with saline or EXE (3, 10, 30 mg/mg, once daily by subcutaneous injection) for 3, 6, or 12 weeks and demonstrates a significant dose- and time-dependent increase in EXE-associated exocrine pancreatic injury.

Results

Conclusion