Glucagon challenge in the rat: a robust method for the in vivo assessment of Glycogen phosphorlyase inhibitor efficacy.
BACKGROUND
Glycogen phosphorlyase inhibitors (GPi) act on the glycogenolytic pathway decreasing hepatic glucose output, making them potential candidates for Type 2 diabetes treatment. We established a robust in vivo method to assess GPis efficacy utilising glucagon-stimulated glycogenolysis.


METHODS
Blood glucose was monitored in both male AP Wistar and AP Zucker rats using tail prick samples pre- and post intraperitoneal or subcutaneous glucagon administration. The effect of glycogen phosphorylase inhibitors GPi296 (6-60 mg kg(-1) po) and DAB (5 mg kg(-1) po) upon glucose response to subcutaneous glucagon were examined in both strains.


RESULTS
In the Wistar rat glucagon induced dose related increases in blood glucose, with the maximum increase occurring 20 min post dose (4.0+/-0.88 mmol l(-1), intraperitoneal; and 2.8+/-0.72 mmol l(-1), subcutaneous, ns). Intraperitoneal glucagon administration produced shorter duration blood glucose elevation than observed with the subcutaneous route of administration. In the Zucker rat, no differences were observed between the 10 and 13 week old rats in response to glucagon (3-200 microg kg(-1) subcutaneous). The maximum blood glucose increase was lower in the Wistar rat compared to the Zucker rats (2.9+/-0.20 vs 7.7+/-1.22 mmol l(-1), P<0.0000018). GPi296 and DAB both produced similar inhibition in each strain.


CONCLUSIONS
Subcutaneous glucagon administration induced more sustained increases in blood glucose than intraperitoneal administration. Blood glucose response to glucagon was higher in the Zucker rat compared to the Wistar rat; there was no difference in inhibition mediated by either GPi296 or DAB between the two strains. We believe that subcutaneous glucagon administration produces a robust model for the assessment of GPis in either rat strain.
Loxham
Susan J G
SJ
Cardiovascular and Gastrointestinal Discovery Department, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire, SK10 4TG, UK. susan.loxham@astrazeneca.com
Teague
Joanne
J
Poucher
Simon M
SM
De Schoolmeester
Joanne
J
Turnbull
Andrew V
AV
Carey
Frank
F
D000818:Animals; D001089:Arabinose / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000032:analysis*; D005934:Glucagon; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D050261:Glycogenolysis / Q000187:drug effects; D050113:Imino Furanoses / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008297:Male; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011924:Rats, Zucker; D013402:Sugar Alcohols / Q000494:pharmacology
D001786:Blood Glucose; D004791:Enzyme Inhibitors; D050113:Imino Furanoses; D007211:Indoles; C518797:N-(1-benzyl-3-(3,4-dihydroxypyrrolidin-1-yl)-2-hydroxy-3-oxopropyl)-5-chloro-1H-indole-2-carboxamide; D011759:Pyrrolidines; D013402:Sugar Alcohols; C058137:1,4-dideoxy-1,4-iminoarabinitol; D005934:Glucagon; D001089:Arabinose; D024981:Glycogen Phosphorylase