title: Degradation, insulin secretion, and antihyperglycemic actions of two palmitate-derivitized N-terminal pyroglutamyl analogues of glucose-dependent insulinotropic polypeptide.
abstract: Exploitation of glucose-dependent insulinotropic polypeptide (GIP) is hindered by its short biological half-life and rapid renal clearance. To circumvent these problems, two novel acylated N-terminally modified GIP analogues, N-pGluGIP(LysPAL(16)) and N-pGluGIP(LysPAL(37)), were evaluated. In contrast to native GIP, both analogues were completely resistant to dipeptidyl peptidase IV degradation. In GIP-receptor transfected fibroblasts, N-pGluGIP(LysPAL(16)) and N-pGluGIP(LysPAL(37)) exhibited enhanced stimulation of cAMP production. Insulinotropic responses in clonal beta-cells were similar to native GIP. When administered together with glucose to ob/ob mice, the glycemic excursions were significantly less for both analogues and insulin responses were greater than native GIP. Extended insulinotropic and antihyperglycemic actions were also evident. These data indicate that palmitate-derivitized analogues of N-terminal pyroglutamyl GIP represent a novel class of stable, long-acting, and effective GIP analogues for potential type 2 diabetes therapy.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine BT52 1SA, UK.
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.forename: Brian D
authors.initials: BD
authors.lastname: Green
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gault
authors.forename: Brett
authors.initials: B
authors.lastname: Greer
authors.forename: Patrick
authors.initials: P
authors.lastname: Harriott
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Bailey
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
authors.forename: Finbarr P M
authors.initials: FP
authors.lastname: O'Harte
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D005749:Gastric Inhibitory Polypeptide / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice; D008820:Mice, Obese; D010168:Palmitates / Q000737:chemistry*; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010168:Palmitates; C498576:glucose-dependent insulinotropic polypeptide, N-pyroglutamyl-epsilon-palmitoyllysyl(16)-; C498577:glucose-dependent insulinotropic polypeptide, N-pyroglutamyl-epsilon-palmitoyllysyl(37)-; D005749:Gastric Inhibitory Polypeptide; D000242:Cyclic AMP; D018819:Dipeptidyl Peptidase 4; D011761:Pyrrolidonecarboxylic Acid