Inhibition of 11betaHSD1 with the S-phenylethylaminothiazolone BVT116429 increases adiponectin concentrations and improves glucose homeostasis in diabetic KKAy mice.
BACKGROUND
A substantial body of evidence indicates that reduced plasma adiponectin levels may be key in the development of insulin resistance, type 2 diabetes and the metabolic syndrome. Glucocorticoids decrease the levels of adiponectin in animals and humans. Cortisone is transformed to its active form cortisol, via 11beta-hydroxysteroid dehydrogenase (HSD) type 1. This study sought to ascertain if inhibition of 11beta HSD1 with a new selective inhibitor, BVT116429, affects the concentrations of circulating adiponectin with concomitant effects on glucose homeostasis in diabetic mice.


RESULTS
KKAy mice were treated with BVT116429 (3, 10, 30 mg/kg), rosiglitazone (5 mg/kg) or vehicle once daily for ten days. Plasma adiponectin levels rose in mice treated with BVT116429 and this was found to be both the hexameric and the high molecular weight multimeric forms of adiponectin. Seven days of treatment with the 11beta HSD1-inhibitor BVT116429 decreased basal insulin levels but no changes in glucose tolerance were seen. After ten days of treatment, fasting blood glucose level was decreased by BVT116429 comparable to the effects of rosiglitazone. Another 11beta HSD1 inhibitor, BVT2733, improved HbA1c but had no effect on adiponectin.


CONCLUSIONS
Inhibition of 11beta HSD1 can be expected to be beneficial for treating the pathology of type 2 diabetes mellitus. The differences seen in adiponectin between BVT116429 and BVT2733 could be explained by different pharmacodynamics exerted by the compounds in different tissues in the body. Increases in adiponectin concentrations may be an integral component in the mechanism of action of this new11beta HSD1 inhibitor and may be a useful marker of efficacy during the clinical development of 11beta HSD1 inhibitor compounds.
Sundbom
Maj
M
Biovitrum, S-112 76 Stockholm, Sweden. maj.sundbom@biovitrum.com
Kaiser
Christina
C
Björkstrand
Eva
E
Castro
Victor M
VM
Larsson
Catarina
C
Selén
Göran
G
Nyhem
Charlotte Söderberg
CS
James
Stephen R
SR
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D052242:Adiponectin / Q000097:blood*; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood* / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D010627:Phenethylamines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
D052242:Adiponectin; C530768:BVT116429; D001786:Blood Glucose; D004791:Enzyme Inhibitors; D010627:Phenethylamines; D013844:Thiazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1