title: Comparison of the independent and combined metabolic effects of subchronic modulation of CCK and GIP receptor action in obesity-related diabetes.
abstract: OBJECTIVE
  Compromise of gastric inhibitory polypeptide (GIP) receptor action and activation of cholecystokinin (CCK) receptors represent mechanistically different approaches to the possible treatment of obesity-related diabetes. In the present study, we have compared the individual and combined effects of (Pro(3))GIP[mPEG] and (pGlu-Gln)-CCK-8 as an enzymatically stable GIP receptor antagonist and CCK receptor agonist molecule, respectively.
  
  
  RESULTS
  Twice-daily injections of (pGlu-Gln)-CCK-8 alone and in combination with (Pro(3))GIP[mPEG] in high-fat-fed mice for 34 days significantly decreased the energy intake throughout the entire study (P<0.05 to P<0.01). Body weights were significantly depressed (P<0.05 to P<0.01) in all treatment groups from day 18 onwards. Administration of (pGlu-Gln)-CCK-8, (Pro(3))GIP[mPEG] or a combination of both peptides significantly (P<0.01 to P<0.001) decreased the overall glycaemic excursion in response to both oral and intraperitoneal glucose challenge when compared with the controls. Furthermore, oral glucose tolerance returned to lean control levels in all treatment groups. The beneficial effects on glucose homeostasis were not associated with altered insulin levels in any of the treatment groups. In keeping with this, the estimated insulin sensitivity was restored to control levels by twice-daily treatment with (pGlu-Gln)-CCK-8, (Pro(3))GIP[mPEG] or a combination of both peptides. The blood lipid profile on day 34 was not significantly different between the high-fat controls and all treated mice.
  
  
  CONCLUSIONS
  These studies highlight the potential of (pGlu-Gln)-CCK-8 and (Pro(3))GIP[mPEG] in the treatment of obesity-related diabetes, but there was no evidence of a synergistic effect of the combined treatment.
authors.affiliation: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK. n.irwin@ulster.ac.uk
authors.forename: N
authors.initials: N
authors.lastname: Irwin
authors.forename: I A
authors.initials: IA
authors.lastname: Montgomery
authors.forename: F P M
authors.initials: FP
authors.lastname: O'Harte
authors.forename: P
authors.initials: P
authors.lastname: Frizelle
authors.forename: P R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000008:administration & dosage*; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism*; D059305:Diet, High-Fat; D004359:Drug Therapy, Combination; D002149:Energy Intake / Q000187:drug effects; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism*; D011949:Receptors, Cholecystokinin / Q000819:agonists*; D011964:Receptors, Gastrointestinal Hormone / Q000819:agonists*; D012844:Sincalide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D013997:Time Factors
chemical_list: C578541:(pGlu-Gln)-CCK-8; D019440:Anti-Obesity Agents; D001786:Blood Glucose; D011949:Receptors, Cholecystokinin; D011964:Receptors, Gastrointestinal Hormone; C041086:gastric inhibitory polypeptide receptor; D012844:Sincalide