SUN-472 Role Of Extra-adrenal Cortisol Production In Abnormal Dexamethasone Suppression Tests In Metabolic Syndrome: Modeling And Numerical Analysis Of In Vivo 11-beta-hydroxysteroid Dehydrogenase Activities

Abstract Disclosure: R.I. Dorin: None. C.R. Qualls: None. Introduction: A high prevalence of abnormal overnight 1 mg dexamethasone (DEX) suppression test (DST) has been observed in patients with difficult to control type 2 diabetes mellitus (DM2). Stable isotope labeled cortisol (continuous infusion) studies in humans confirm a significant role of free cortisol (F) and cortisone (E) interconversions mediated by 11b-hydroxysteroid dehydrogenase (11b-HSD) enzymes in vivo. We hypothesized that higher-than-normal rates of extra-adrenal cortisol production (EACP) contribute to the frequency of abnormal DST (and robust glycemic response to glucocorticoid receptor antagonist [GRA] therapy) in this clinical setting. We further hypothesized that increased rates of EACP in metabolic syndrome could be due to increased activities of either 11b-HSD1 (E->F) and/or 11b-HSD2 (F->E). Methods: Adaptation of validated, minimal 4-compartment diffusion model(Dorin et al., J Endocr Soc 2022 Nov 14;7(2):bvac173) using conservation of mass principles to model enzyme activities (11b-HSD-mediated E-F interconversions), where EACP is defined as the sum of in vivo 11b-HSD1-mediated F appearance (nmol/min). Results: We developed a novel, physiology-based flow model in E and F for 7principal compartments (14 simultaneous differential equations). These include (i) F->E conversion in kidney, gut, and adrenal (11b-HSD2), (ii) E->F conversion in liver and fat (11b-HSD1), and (iii) vascular (central compartment) and extravascular (interstitial + intracellular) volumes without11b-HSD activities. Numerical integration (forward solution) of the model replicated experimentally observed F and E (and 11-dehydro-DEX and DEX)time series reported in the iv bolus experiment. In simulation, increased activities of either 11b-HSD1 or 11b-HSD2 resulted in higher steady state concentrations of F.CONCLUSIONS: Although the DST was originally developed to probe adrenal sources of cortisol excess, i.e. Cushing’s syndrome (CS), it may also be abnormal in a setting of increased EACP. Numerical modeling analysis supports feasibility of our hypothesis that increased EACP plays a role in the high prevalence of abnormal DST and clinical response to GRA in patients with difficult to control DM2. In test bed analysis, increased rates of EACP could be due to augmented activities of either 11b-HSD1 and/or 11b-HSD2. Conditions associated with increased EACP should be included in the differential diagnosis of patients with abnormal DST without overt features of CS. Numerical methods may provide a more clinically accessible approach (compared to 2H-labeled cortisol infusion) to distinguishing adrenal vs. extra-adrenal cortisol appearance rates in vivo. Presentation: Sunday, July 13, 2025