Abstract
C-terminal acylation of Lys(37) with myristic (MYR; tetradecanoic acid), palmitic (PAL; hexadecanoic acid) and stearic (octadecanoic acid) fatty acids with or without N-terminal acetylation was employed to develop long-acting analogues of the glucoregulatory hormone, glucose-dependent insulinotropic polypeptide (GIP). All GIP analogues exhibited resistance to dipeptidylpeptidase-IV (DPP-IV) and significantly improved in vitro cAMP production and insulin secretion. Administration of GIP analogues to ob/ob mice significantly lowered plasma glucose-GIP(Lys(37)MYR), N-AcGIP(Lys(37)MYR) and GIP(Lys(37)PAL) increased plasma insulin concentrations. GIP(Lys(37)MYR) and N-AcGIP(Lys(37)MYR) elicited protracted glucose-lowering effects when administered 24h prior to an intraperitoneal glucose load. Daily administration of GIP(Lys(37)MYR) and N-AcGIP(Lys(37)MYR) to ob/ob mice for 24 days decreased glucose and significantly improved plasma insulin, glucose tolerance and beta-cell glucose responsiveness. Insulin sensitivity, pancreatic insulin content and triglyceride levels were not changed. These data demonstrate that C-terminal acylation particularly with myristic acid provides a class of stable, longer-acting forms of GIP for further evaluation in diabetes therapy.
Original language | English |
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Pages (from-to) | 1008-1016 |
Number of pages | 9 |
Journal | Biochemical Pharmacology |
Volume | 78 |
Issue number | 8 |
Early online date | 29 May 2009 |
DOIs | |
Publication status | Published - 15 Oct 2009 |
Keywords
- animals
- blood glucose
- cyclic AMP
- fatty acids
- gastric inhibitory polypeptide
- glucose tolerance test
- half-life
- homeostasis
- hypoglycemic agents
- inhibitory concentration 50
- insulin
- insulin-secreting cells
- mice
- obese mice
- time factors