title: Antagonism of gastric inhibitory polypeptide (GIP) by palmitoylation of GIP analogues with N- and C-terminal modifications improves obesity and metabolic control in high fat fed mice.
abstract: Compromise of gastric inhibitory polypeptide (GIP) receptor signalling represents a possible therapeutic strategy for the treatment of obesity-related diabetes. This study has characterised and evaluated the C-terminally fatty acid derivatised GIP analogues, GIP(3-30)Cex-K(40)[Pal] and Pro(3)GIP(3-30)Cex-K(40)[Pal], as potential GIP inhibitors. Both GIP analogues lack the two N-terminal amino acids cleaved by DPP-4 and have addition of nine amino acids from the C-terminal of exendin(1-39), Cex. GIP(3-30)Cex-K(40)[Pal] and Pro(3)GIP(3-30)Cex-K(40)[Pal] effectively (p < 0.01 to p < 0.001) inhibited GIP-induced cAMP production and insulin secretion in vitro. In normal mice, GIP(3-30)Cex-K(40)[Pal] and Pro(3)GIP(3-30)Cex-K(40)[Pal] displayed a significant (p < 0.05 to p < 0.001) and prolonged inhibitory effect on GIP-induced glucose-lowering and insulin-releasing actions. When injected once daily for 21 days in obese-diabetic high fat fed mice, both GIP(3-30)Cex-K(40)[Pal] and Pro(3)GIP(3-30)Cex-K(40)[Pal] significantly reduced body weight (p < 0.01 to p < 0.001) and lowered circulating glucose (p < 0.001) and insulin (p < 0.01 to p < 0.001) concentrations. The observed beneficial changes were independent of effects on energy intake, locomotor activity or metabolic rate. Oral and intraperitoneal glucose tolerance were significantly (p < 0.05 to p < 0.001) improved in both treatment groups at the end of the study, despite reduced glucose-induced plasma insulin concentrations. This improvement of metabolic control was accompanied by enhanced (p < 0.05 to p < 0.01) insulin sensitivity compared with high fat controls. These data demonstrate the potential offered by GIP(3-30)Cex-K(40)[Pal] and Pro(3)GIP(3-30)Cex-K(40)[Pal] for the treatment of obesity-related diabetes.
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK.
authors.forename: V
authors.initials: V
authors.lastname: Pathak
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK.
authors.forename: V A
authors.initials: VA
authors.lastname: Gault
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK.
authors.forename: P R
authors.initials: PR
authors.lastname: Flatt
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, University of Ulster, Coleraine, Northern Ireland, UK. Electronic address: n.irwin@ulster.ac.uk.
authors.forename: N
authors.initials: N
authors.lastname: Irwin
mesh_terms: D000284:Administration, Oral; D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D059305:Diet, High-Fat / Q000009:adverse effects*; D004334:Drug Administration Schedule; D005749:Gastric Inhibitory Polypeptide / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005951:Glucose Tolerance Test; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000097:blood; D054878:Lipoylation; D051379:Mice; D009765:Obesity / Q000139:chemically induced / Q000188:drug therapy*
chemical_list: D019440:Anti-Obesity Agents; D001786:Blood Glucose; D007328:Insulin; D005749:Gastric Inhibitory Polypeptide
keywords: Body weight; Diabetes; GIP; Glucose homeostasis; Insulin secretion; Obesity