(-Ser)Oxm[mPEG-PAL]: a novel chemically modified analogue of oxyntomodulin with antihyperglycaemic, insulinotropic and anorexigenic actions
Résumé
Oxyntomodulin (Oxm) is a hormone which has been shown to exhibit a range of potentially beneficial actions for alleviation of obesity-diabetes. However, exploitation of Oxm-based therapies has been severely restricted due to degradation by the enzyme dipeptidylpeptidase-IV (DPP-IV). Thus, the aim of this study was to assess the glucose-lowering, insulin-releasing and anorexigenic actions of chemically modified, enzyme resistant analogues of Oxm. Oxm, (-Ser)Oxm and (-Ser)Oxm[mPEG-PAL], were incubated with DPP-IV to assess enzyme stability and pancreatic beta-cells to evaluate insulin secretion. cAMP production was assessed using glucagon-like peptide-1 (GLP-1) and glucagon receptor transfected cells. effects of Oxm analogues on glucose homeostasis, insulin secretion, food intake and bodyweight were examined in obese diabetic () mice. (-Ser)Oxm[mPEG-PAL] displayed enhanced DPP-IV resistance compared to (-Ser)Oxm and Oxm. All peptides demonstrated similar cAMP and insulin-releasing actions, which was associated with dual action at GLP-1 and glucagon receptors. Acute administration of (-Ser)Oxm[mPEG-PAL] and (-Ser)Oxm reduced plasma glucose and food intake, whilst plasma insulin levels were elevated. Once-daily administration of (-Ser)Oxm[mPEG-PAL] for 14 days to mice decreased food intake, bodyweight, plasma glucose and increased plasma insulin. Furthermore, daily (-Ser)Oxm[mPEG-PAL] improved glucose tolerance, increased glucose-mediated insulin secretion, pancreatic insulin content, adiponectin and decreased both visfatin and triglyceride levels. The ability of enzyme resistant (-Ser)Oxm[mPEG-PAL] to improve glucose homeostasis, insulin secretion, satiety, bodyweight and markers of fat metabolism suggests significant promise for Oxm-based therapies for obesity-diabetes.
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