title: (D-Ser2)Oxm[mPEG-PAL]: a novel chemically modified analogue of oxyntomodulin with antihyperglycaemic, insulinotropic and anorexigenic actions.
abstract: 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, (d-Ser(2))Oxm and (d-Ser(2))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. In vivo effects of Oxm analogues on glucose homeostasis, insulin secretion, food intake and bodyweight were examined in obese diabetic (ob/ob) mice. (d-Ser(2))Oxm[mPEG-PAL] displayed enhanced DPP-IV resistance compared to (d-Ser(2))Oxm and Oxm. All peptides demonstrated similar in vitro cAMP and insulin-releasing actions, which was associated with dual action at GLP-1 and glucagon receptors. Acute administration of (d-Ser(2))Oxm[mPEG-PAL] and (d-Ser(2))Oxm reduced plasma glucose and food intake, whilst plasma insulin levels were elevated. Once-daily administration of (d-Ser(2))Oxm[mPEG-PAL] for 14 days to ob/ob mice decreased food intake, bodyweight, plasma glucose and increased plasma insulin. Furthermore, daily (d-Ser(2))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 (d-Ser(2))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.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom.
authors.forename: Barry D
authors.initials: BD
authors.lastname: Kerr
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001067:Appetite Depressants / Q000737:chemistry / Q000494:pharmacology*; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D004435:Eating / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008820:Mice, Obese; D008969:Molecular Sequence Data; D053772:Oxyntomodulin / Q000737:chemistry* / Q000235:genetics / Q000494:pharmacology*
chemical_list: C553249:(D-Ser2)Oxm(mPEG-PAL); D001067:Appetite Depressants; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D053772:Oxyntomodulin