Inhibition of 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) as a means of reducing tissue corticosteroids is showing marked potential as a treatment for type 2 diabetes. However, reduction in tissue corticosteroids may lead to upregulation of the HPA axis. Therefore this study investigates the effect of 11β-HSD1 inhibition on HPA axis biomarkers and examines whether time of dosing impacts on the biomarkers.
C57Bl6/Jax mice were fed 60% kcal fat diet for 16 weeks. Mice were given an 11β-HSD1 inhibitor (or vehicle or neither) at the previously determined corticosterone peak or nadir or both). Samples were taken at peak or nadir after 8 days.
Pro-opiomelanocortin (POMC) peptide levels were measured as a biomarker of chronic effects but not acute stressors. No changes were seen at peak or nadir after any treatment. There was a trend towards increased adrenocorticotrophic hormone (ACTH) concentrations. The corticosterone diurnal rhythm was maintained in naïve but not vehicle treated mice. When the inhibitor was administered at nadir and samples taken 2 h later corticosterone was elevated.
|Biomarker nadir values||Vehicle||Dosed at peak||Dosed at nadir||Dosed BID||N|
|POMC (pmol/l)||205±27||161±27||150±25||221±20||68, P=NS|
|ACTH (ng/l)||272±12||357±29||314±29||358±26||68, P=NS|
|Corticosterone (ng/ml)||210±27||342±36||363±57*||348±44||68 *P<0.05 vs V|
Adrenal gland weight showed no consistent changes although transient variations were observed depending when adrenals were taken. We also examined glucocorticoid receptor (GR) mRNA in liver and no change was observed after 11β-HSD1 inhibition.
Biomarkers of the HPA axis including POMC, ACTH, and adrenal weight are not altered by repeat dosing of 11β-HSD1 at peak or nadir, although plasma corticosterone is increased at the nadir. Measurement of these parameters at different phases of the circadian rhythm is important to exclude shifts in the biomarker patterns, which can occur with obesity or stress.