Exenatide does not evoke pancreatitis and attenuates chemically inducedpancreatitis in normal and diabetic rodents.

摘要

The risk of developing pancreatitis is elevated in type 2 diabetes and obesity.Cases of pancreatitis have been reported in type 2 diabetes patients treated withGLP-1 (GLP-1R) receptor agonists. To examine whether the GLP-1R agonist exenatidepotentially induces or modulates pancreatitis, the effect of exenatide wasevaluated in normal or diabetic rodents. Normal and diabetic rats received asingle exenatide dose (0.072, 0.24, and 0.72 nmol/kg) or vehicle. Diabetic ob/ob or HF-STZ mice were infused with exenatide (1.2 and 7.2 nmol x kg(-1) x day(-1)) orvehicle for 4 wk. Post-exenatide treatment, pancreatitis was induced withcaerulein (CRN) or sodium taurocholate (ST), and changes in plasma amylase andlipase were measured. In ob/ob mice, plasma cytokines (IL-1beta, IL-2, IL-6, MCP-1, IFNgamma, and TNFalpha) and pancreatitis-associated genes were assessed. Pancreata wereweighed and examined histologically. Exenatide treatment alone did not modifyplasma amylase or lipase in any models tested. Exenatide attenuated CRN-inducedrelease of amylase and lipase in normal rats and ob/ob mice but did not modifythe response to ST infusion. Plasma cytokines and pancreatic weight wereunaffected by exenatide. Exenatide upregulated Reg3b but not Il6, Ccl2, Nfkb1, orVamp8 expression. Histological analysis revealed that the highest doses ofexenatide decreased CRN- or ST-induced acute inflammation, vacuolation, andacinar single cell necrosis in mice and rats, respectively. Ductal cellproliferation rates were low and similar across all groups of ob/ob mice. Inconclusion, exenatide did not modify plasma amylase and lipase concentrations in rodents without pancreatitis and improved chemically induced pancreatitis innormal and diabetic rodents.