title: (pGlu-Gln)-CCK-8[mPEG]: a novel, long-acting, mini-PEGylated cholecystokinin (CCK) agonist that improves metabolic status in dietary-induced diabetes.
abstract: BACKGROUND
  Cholecystokinin (CCK) is a gastrointestinal hormone that has been proposed as a potential therapeutic option for obesity-diabetes. As such, (pGlu-Gln)-CCK-8 is an N-terminally modified CCK-8 analogue with improved biological effectiveness over the native peptide.
  
  
  METHODS
  The current study has examined the in vitro stability, biological activity and in vivo therapeutic applicability of a novel second generation mini-PEGylated form of (pGlu-Gln)-CCK-8, (pGlu-Gln)-CCK-8[mPEG].
  
  
  RESULTS
  (pGlu-Gln)-CCK-8[mPEG] was completely resistant to enzymatic degradation and in addition displayed similar insulinotropic (p<0.05 to p<0.001) and satiating effects (p<0.01 to p<0.001) as (pGlu-Gln)-CCK-8. This confirmed the capability of (pGlu-Gln)-CCK-8[mPEG] to bind to and activate the CCK receptor. Sub-chronic twice daily injection of (pGlu-Gln)-CCK-8[mPEG] in high fat fed mice for 35days significantly decreased body weight gain (p<0.05), food intake (p<0.01 to p<0.001) and triacylglycerol deposition in liver (p<0.001) and muscle (p<0.001). Furthermore, (pGlu-Gln)-CCK-8[mPEG] markedly improved intraperitoneal glucose tolerance (p<0.05) and insulin sensitivity (p<0.001). Despite this therapeutic profile, once daily injection of (pGlu-Gln)-CCK-8[mPEG] in high fat fed mice for 33days, at the same dose, was not associated with alterations in food intake and body weight. In addition, metabolic responses to exogenous glucose and insulin injection were similar to saline treated controls.
  
  
  CONCLUSIONS
  These studies emphasise the therapeutic potential of (pGlu-Gln)-CCK-8[mPEG] and similar molecules.
  
  
  CONCLUSIONS
  A more detailed analysis of the dose and administration schedule employed for (pGlu-Gln)-CCK-8[mPEG] could provide a novel and effective compound to treat obesity-diabetes.
authors.affiliation: School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK. n.irwin@ulster.ac.uk
authors.forename: Nigel
authors.initials: N
authors.lastname: Irwin
authors.forename: Pamela
authors.initials: P
authors.lastname: Frizelle
authors.forename: Finbarr P M
authors.initials: FP
authors.lastname: O'Harte
authors.forename: Peter R
authors.initials: PR
authors.lastname: Flatt
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003920:Diabetes Mellitus / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D009765:Obesity / Q000150:complications*; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D012844:Sincalide / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: C578541:(pGlu-Gln)-CCK-8; D007328:Insulin; D011092:Polyethylene Glycols; C028210:monomethoxypolyethylene glycol; D012844:Sincalide