title: An assessment of the in vivo efficacy of the glycogen phosphorylase inhibitor GPi688 in rat models of hyperglycaemia.
abstract: OBJECTIVE
  Studies in cultured hepatocytes demonstrate glycogen synthase (GS) activation with glycogen phosphorylase (GP) inhibitors. The current study investigated whether these phenomena occurred in vivo using a novel GP inhibitor.
  
  
  METHODS
  An allosteric GP inhibitor, GPi688, was evaluated against both glucagon-mediated hyperglycaemia and oral glucose challenge-mediated hyperglycaemia to determine the relative effects against GP and GS in vivo.
  
  
  RESULTS
  In rat primary hepatocytes, GPi688 inhibited glucagons-mediated glucose output in a concentration dependent manner. Additionally GP activity was reduced and GS activity increased seven-fold. GPi688 inhibited glucagon-mediated hyperglycaemia in both Wistar (65%) & obese Zucker (100%) rats and demonstrated a long duration of action in the Zucker rat. The in vivo efficacy in the glucagon challenge model could be predicted by the equation; % glucagon inhibition=56.9+34.3[log ([free plasma]/rat IC50)], r=0.921). GPi688 also reduced the blood glucose of obese Zucker rats after a 7 h fast by 23%. In an oral glucose tolerance test in Zucker rats, however, GPi688 was less efficacious (7% reduction) than a glycogen synthase kinase-3 (GSK-3) inhibitor (22% reduction), despite also observing activation (by 45%) of GS in vivo.
  
  
  CONCLUSIONS
  Although GP inhibition can inhibit hyperglycaemia mediated by increased glucose production, the degree of GS activation induced by allosteric GP inhibitors in vivo, although discernible, is insufficient to increase glucose disposal. The data suggests that GP inhibitors might be more effective clinically against fasting rather than prandial hyperglycaemic control.
authors.affiliation: Cardiovascular & Gastrointestinal Discovery Department, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, UK. simon.poucher@astrazeneca.com
authors.forename: S M
authors.initials: SM
authors.lastname: Poucher
authors.forename: S
authors.initials: S
authors.lastname: Freeman
authors.forename: S J G
authors.initials: SJ
authors.lastname: Loxham
authors.forename: G
authors.initials: G
authors.lastname: Convey
authors.forename: J B
authors.initials: JB
authors.lastname: Bartlett
authors.forename: J
authors.initials: J
authors.lastname: De Schoolmeester
authors.forename: J
authors.initials: J
authors.lastname: Teague
authors.forename: M
authors.initials: M
authors.lastname: Walker
authors.forename: A V
authors.initials: AV
authors.lastname: Turnbull
authors.forename: A D
authors.initials: AD
authors.lastname: Charles
authors.forename: F
authors.initials: F
authors.lastname: Carey
authors.forename: S
authors.initials: S
authors.lastname: Berg
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005934:Glucagon / Q000187:drug effects / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D006006:Glycogen Synthase / Q000187:drug effects* / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006943:Hyperglycemia / Q000188:drug therapy*; D020128:Inhibitory Concentration 50; D008297:Male; D009765:Obesity / Q000378:metabolism; D015363:Quinolones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D013876:Thiophenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: C526538:2-chloro-N-(1-(2,3-dihydroxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)-6H-thieno(2,3-b)pyrrole-5-carboxamide; D001786:Blood Glucose; D015363:Quinolones; D013876:Thiophenes; D005934:Glucagon; D024981:Glycogen Phosphorylase; D006006:Glycogen Synthase; D005947:Glucose