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C-terminal acylation of Lys37 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(Lys37MYR), N-AcGIP(Lys37MYR) and GIP(Lys37PAL) increased plasma insulin concentrations. GIP(Lys37MYR) and N-AcGIP(Lys37MYR) elicited protracted glucose-lowering effects when administered 24 h prior to an intraperitoneal glucose load. Daily administration of GIP(Lys37MYR) and N-AcGIP(Lys37MYR) 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.