title: Comparison of independent and combined metabolic effects of chronic treatment with (pGlu-Gln)-CCK-8 and long-acting GLP-1 and GIP mimetics in high fat-fed mice.
abstract: OBJECTIVE
  The incretin hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) and cholecystokinin (CCK) are gastrointestinal peptides with important physiological effects. However, rapid enzymatic degradation results in short-lived biological actions.
  
  
  METHODS
  This study has examined metabolic actions of exendin-4, GIP[mPEG] and a novel CCK-8 analogue, (pGlu-Gln)-CCK-8 as enzymatically stable forms of GLP-1, GIP and CCK, respectively.
  
  
  RESULTS
  All peptides significantly (p < 0.01-p < 0.001) stimulated insulin secretion from BRIN BD11 cells, and acute in vivo experiments confirmed prominent antihyperglycaemic and insulinotropic responses to GLP-1 or GIP receptor activation in normal mice. Twice daily injection of (pGlu-Gln)-CCK-8 alone and in combination with exendin-4 or GIP[mPEG] in high fat-fed mice significantly decreased accumulated food intake (p < 0.05-p < 0.01), body weight gain (p < 0.05-p < 0.01) and improved (p < 0.05) insulin sensitivity in high fat-fed mice. However, there was no evidence for superior effects compared to (pGlu-Gln)-CCK-8 alone. Combined treatment of (pGlu-Gln)-CCK-8 and exendin-4 resulted in significantly (p < 0.05) lowered circulating glucose levels and improved (p < 0.05) intraperitoneal glucose tolerance. These effects were superior to either treatment regime alone but not associated with altered insulin concentrations. A single injection of (pGlu-Gln)-CCK-8, or combined with exendin-4, significantly (p < 0.05) lowered blood glucose levels 24 h post injection in untreated high fat-fed mice.
  
  
  CONCLUSIONS
  This study highlights the potential of (pGlu-Gln)-CCK-8 alone and in combination with incretin hormones for the treatment of type 2 diabetes.
authors: SAAD Centre for Pharmacy and Diabetes, School of Biomedical Sciences, University of Ulster, Northern Ireland, UK. n.irwin@ulster.ac.uk
authors: N
authors: N
authors: Irwin
authors: K
authors: K
authors: Hunter
authors: I A
authors: IA
authors: Montgomery
authors: P R
authors: PR
authors: Flatt
mesh_terms: D000818:Animals; D019440:Anti-Obesity Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001069:Appetite Regulation / Q000187:drug effects; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000188:drug therapy*; D059305:Diet, High-Fat / Q000009:adverse effects; D004359:Drug Therapy, Combination; D000077270:Exenatide; D005749:Gastric Inhibitory Polypeptide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D006943:Hyperglycemia / Q000517:prevention & control; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D054795:Incretins / Q000494:pharmacology / Q000627:therapeutic use; D007328:Insulin / Q000819:agonists / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009765:Obesity / Q000150:complications / Q000188:drug therapy* / Q000209:etiology; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D012844:Sincalide / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D013997:Time Factors; D014688:Venoms / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C578541:(pGlu-Gln)-CCK-8; D019440:Anti-Obesity Agents; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D010455:Peptides; D014688:Venoms; D005749:Gastric Inhibitory Polypeptide; D000077270:Exenatide; D012844:Sincalide