Time of the day for 11beta-HSD1 inhibition plays a role in improving glucose homeostasis in DIO mice.
OBJECTIVE
The physiological effects of glucocorticoids in a given tissue are driven by the local level of the active glucocorticoid, which is determined by two sources: the plasma cortisol in human (or corticosterone in rodents) and the cortisol produced locally through 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity. Because of the circadian variation of plasma glucocorticoids, the pharmacological efficacy of 11beta-HSD1 inhibition may depend on the time of the day for inhibitor administration.


METHODS
The circadian profile of corticosterone was established in lean and diet-induced obesity (DIO) C57BL/6 mice from blood collected at different time of the day. 11beta-HSD1 enzyme activity was also measured throughout the day in DIO mice. To determine the optimal timing for administration of an 11beta-HSD1 inhibitor to obtain maximum efficacy, we used a DIO mouse model and a small molecule inhibitor of 11beta-HSD1 from our thiazolinone series. Based on the circadian profile of corticosterone obtained, we administered the 11beta-HSD1 inhibitor to these animals at different times of the day and evaluated the effects on plasma glucose levels and glucose tolerance.


RESULTS
We report that corticosterone circadian rhythm was similar between lean and DIO C57BL/6 mice, and 11beta-HSD1 enzyme activity undergoes minimal variations throughout the day. Interestingly, the compound exhibited maximum efficacy if dosed in the afternoon when plasma corticosterone is high; the morning dosing when plasma corticosterone is low did not lead to efficacy.


CONCLUSIONS
These data suggest that because of the circadian rhythm of circulating glucocorticoids, the time of the day for 11beta-HSD1 inhibitor administration is important in achieving efficacy.
Véniant
M M
MM
Department of Metabolic Disorders, Amgen Inc., Thousand Oaks, CA 91320, USA. mveniant@amgen.com
Hale
C
C
Komorowski
R
R
Chen
M M
MM
St Jean
D J
DJ
Fotsch
C
C
Wang
M
M
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000273:Adipose Tissue / Q000201:enzymology*; D000818:Animals; D001786:Blood Glucose / Q000235:genetics / Q000378:metabolism*; D003345:Corticosterone / Q000008:administration & dosage / Q000097:blood*; D017931:DNA Primers; D004032:Diet; D055870:Drug Chronotherapy; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D006706:Homeostasis / Q000187:drug effects*; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology; D013997:Time Factors
C527489:2-(1-(2-fluorophenyl)ethylamino)-5-methyl-5-(trifluoromethyl)thiazol-4(5H)-one; D001786:Blood Glucose; D017931:DNA Primers; D004791:Enzyme Inhibitors; D013844:Thiazoles; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D003345:Corticosterone