title: Beneficial effects of the novel cholecystokinin agonist (pGlu-Gln)-CCK-8 in mouse models of obesity/diabetes.
abstract: OBJECTIVE
  Cholecystokinin (CCK) is a rapidly degraded gastrointestinal peptide that stimulates satiety and insulin secretion. We aimed to investigate the beneficial weight-lowering and metabolic effects of the novel N-terminally modified CCK analogue, (pGlu-Gln)-CCK-8.
  
  
  METHODS
  The biological actions of (pGlu-Gln)-CCK-8 were comprehensively evaluated in pancreatic clonal BRIN BD11 cells and in vivo in high-fat-fed and ob/ob mice.
  
  
  RESULTS
  (pGlu-Gln)-CCK-8 was completely resistant to enzymatic degradation and its satiating effects were significantly (p < 0.05 to p < 0.001) more potent than CCK-8. In BRIN-BD11 cells, (pGlu-Gln)-CCK-8 exhibited enhanced (p < 0.01 to p < 0.001) insulinotropic actions compared with CCK-8. When administered acutely to high-fat-fed or ob/ob mice, (pGlu-Gln)-CCK-8 improved glucose homeostasis. Sub-chronic twice daily injections of (pGlu-Gln)-CCK-8 in high-fat-fed mice for 28 days significantly decreased body weight (p < 0.05 to p < 0.001), accumulated food intake (p < 0.05 to p < 0.001), non-fasting glucose (p < 0.05) and triacylglycerol deposition in pancreatic (p < 0.01), adipose (p < 0.05) and liver (p < 0.001) tissue, and improved oral (p < 0.05) and i.p. (p < 0.05) glucose tolerance and insulin sensitivity (p < 0.001). Similar observations were noted in ob/ob mice given twice daily injections of (pGlu-Gln)-CCK-8. In addition, these beneficial effects were not reproduced by simple dietary restriction and were not associated with changes in energy expenditure. There was no evidence for development of tolerance to (pGlu-Gln)-CCK-8, and analysis of histology or blood-borne markers for pancreatic, liver and renal function in mice treated with (pGlu-Gln)-CCK-8 suggested little abnormal pathology.
  
  
  CONCLUSIONS
  These studies emphasise the potential of (pGlu-Gln)-CCK-8 for the alleviation of obesity and insulin resistance.
authors: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK. n.irwin@ulster.ac.uk.
authors: N
authors: N
authors: Irwin
authors: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK.
authors: P
authors: P
authors: Frizelle
authors: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK.
authors: I A
authors: IA
authors: Montgomery
authors: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK.
authors: R C
authors: RC
authors: Moffett
authors: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK.
authors: F P M
authors: FPM
authors: O'Harte
authors: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, BT52 1SA, UK.
authors: P R
authors: PR
authors: Flatt
mesh_terms: D000818:Animals; D002766:Cholecystokinin / Q000819:agonists*; D015897:Comorbidity; D003920:Diabetes Mellitus / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology; D008297:Male; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D012844:Sincalide / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D002766:Cholecystokinin; D005947:Glucose; D012844:Sincalide