Improved biological activity of Gly2- and Ser2-substituted analogues of glucose-dependent insulinotrophic polypeptide
| Autor: | P Harriott, Victor A. Gault, Peter R. Flatt, Finbarr O'Harte, Mark Mooney, Clifford J. Bailey |
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| Rok vydání: | 2003 |
| Předmět: |
Blood Glucose
Spectrometry Mass Electrospray Ionization endocrine system medicine.medical_specialty Endocrinology Diabetes and Metabolism Mice Transgenic Gastric Inhibitory Polypeptide Transfection Chinese hamster Serine Mice Endocrinology In vivo Cricetinae Internal medicine Diabetes mellitus Insulin Secretion Cyclic AMP medicine Animals Humans Insulin Obesity Cells Cultured EC50 Dose-Response Relationship Drug biology Chemistry Biological activity Fibroblasts biology.organism_classification medicine.disease Glycine Mutagenesis Site-Directed hormones hormone substitutes and hormone antagonists Half-Life |
| Zdroj: | Journal of Endocrinology. 176:133-141 |
| ISSN: | 1479-6805 0022-0795 |
| Popis: | The therapeutic potential of glucagon-like peptide-1 (GLP-1) in improving glycaemic control in diabetes has been widely studied, but the potential beneficial effects of glucose-dependent insulinotropic polypeptide (GIP) have until recently been almost overlooked. One of the major problems, however, in exploiting either GIP or GLP-1 as potential therapeutic agents is their short duration of action, due to enzymatic degradation in vivo by dipeptidylpeptidase IV (DPP IV). Therefore, this study examined the plasma stability, biological activity and antidiabetic potential of two novel NH2-terminal Ala2-substituted analogues of GIP, containing glycine (Gly) or serine (Ser). Following incubation in plasma, (Ser2)GIP had a reduced hydrolysis rate compared with native GIP, while (Gly2)GIP was completely stable. In Chinese hamster lung fibroblasts stably transfected with the human GIP receptor, GIP, (Gly2)GIP and (Ser2)GIP stimulated cAMP production with EC(50) values of 18.2, 14.9 and 15.0 nM respectively. In the pancreatic BRIN-BD11 beta-cell line, (Gly2)GIP and (Ser2)GIP (10(-8) M) evoked significant increases (1.2- and 1.5-fold respectively; P |
| Databáze: | OpenAIRE |
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