| (D-Ser2)Oxm[mPEG-PAL]: a novel chemically modified analogue of oxyntomodulin with antihyperglycaemic, insulinotropic and anorexigenic actions. | |
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MedLine Citation:
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PMID: 20735990 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Barry D Kerr; Peter R Flatt; Victor A Gault |
Publication Detail:
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Type: Comparative Study; Journal Article Date: 2010-08-22 |
Journal Detail:
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Title: Biochemical pharmacology Volume: 80 ISSN: 1873-2968 ISO Abbreviation: Biochem. Pharmacol. Publication Date: 2010 Dec |
Date Detail:
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Created Date: 2010-10-18 Completed Date: 2010-11-05 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0101032 Medline TA: Biochem Pharmacol Country: England |
Other Details:
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Languages: eng Pagination: 1727-35 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, United Kingdom. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Appetite Depressants / chemistry, pharmacology* Blood Glucose / drug effects, metabolism Cell Line Eating / drug effects*, physiology Humans Hypoglycemic Agents / chemistry, pharmacology* Insulin / secretion* Male Mice Mice, Obese Molecular Sequence Data Oxyntomodulin / chemistry*, genetics, pharmacology* |
| Chemical | |
Reg. No./Substance:
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0/(D-Ser2)Oxm(mPEG-PAL); 0/Appetite Depressants; 0/Blood Glucose; 0/Hypoglycemic Agents; 0/Oxyntomodulin; 11061-68-0/Insulin |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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