Lower Renal Function Is Associated With Derangement of 11-β Hydroxysteroid Dehydrogenase in Type 2 Diabetes

Abstract

ContextDerangement of 11-β hydroxysteroid dehydrogenase type 1 and type 2 (11β-HSD1 and 11β-HSD2), which regulate intracellular cortisol production, has been suggested in both type 2 diabetes (T2D) and chronic kidney disease (CKD). However, activity of 11β-HSD enzymes in patients with T2D and CKD has never been assessed.ObjectivesTo compare 11β-HSD activities between patients with T2D and healthy controls, and assess whether in T2D, renal function is associated with 11β-HSD activities.DesignCross-sectional analysis in the Diabetes and Lifestyle Cohort Twente (DIALECT-1).SettingReferral center for T2D.PatientsPatient with T2D [n = 373, age 64 ± 9 years, 58% men, 26% of patients estimated glomerular filtration rate (eGFR) <60 mL/min·1.73 m2] and healthy controls (n = 275, age 53 ± 11 years, 48% men).Mean Outcome MeasureWe measured cortisol, cortisone, and metabolites [tetrahydrocortisol (THF), allo-THF (aTHF), and tetrahydrocortisone (THE)] in 24-hour urine samples. Whole body 11β-HSD and 11β-HSD2 activities were calculated as the urinary (THF + aTHF)/THE and cortisol/cortisone ratios, respectively.ResultsPatients with T2D had a higher (THF + aTHF)/THE ratio [1.02 (0.84 to 1.27) vs 0.94 (0.79 to 1.0), P < 0.001] and cortisol/cortisone ratio [0.70 (0.58 to 0.83) vs 0.63 (0.54 to 0.74), P < 0.001] than healthy controls. In T2D, lower eGFR was associated with a higher (THF + aTHF)/THE ratio (β = −0.35, P < 0.001), and a higher cortisol/cortisone ratio (β = −0.16, P = 0.001).ConclusionsIn this real-life secondary care setting of patients with T2D, 11β-HSD enzymes activities were shifted to higher intracellular cortisol production in T2D, which was further aggravated in patients with CKD. Prospective analyses are warranted to investigate causality of these associations.

Effect of Vasopressin on the Hypothalamic-Pituitary-Adrenal Axis in ADPKD Patients during V2 Receptor Antagonism

“…In line with prior research in adults and children, we found that 11β-HSD type 1 activity was negatively correlated with kidney function [45,46]. Also consistent with our data is literature that indicates that the functionality of 11β-HSD type 2 declines over the course of kidney disease [47,48], although some data indicate that this phenomenon might only occur at severely impaired kidney function [49]. Since 11β-HSD type 2 is an enzyme that operates principally in the kidney, progressive decline in kidney function may indeed be expected to affect its activity.…”

“…The overall daily glucocorticoid production, as measured by the total 24 h urinary excretion of glucocorticoid compounds did not differ between the 2 groups (p = 0.32). In plasma, a significantly lower concentration of cortisone was found (41 vs. 55 [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63] nmol/L, respectively, p < 0.001), but not of cortisol (see online suppl. , p = 0.03).…”

Ipercortisolismo funzionale e sue possibili conseguenze cliniche

“…In questo caso va comunque considerata la possibilità di trovarsi di fronte a un FH, in cui l'iperattivazione dell'asse HPA secondaria agli effetti dello scarso controllo glicemico sull'ippocampo si associa all'aumentata espressione e attività della 11β-HSD1 sottocutanea e viscerale tipica degli stati di MS e, come emerge dallo studio DIALECT-1, del DM complicato da danno renale [1,19]: tale enzima potrebbe giocare un ruolo chiave nel favorire le complicanze cardiovascolari del DM (cardiopatia ischemica, aterosclerosi carotidea, nefropatia, retinopatia e neuropatia) anche in assenza di franche alterazioni nei livelli di cortisolo circolante [1].…”

Prednisolone and Prednisone Pharmacokinetics in Pediatric Renal Transplant Recipients—A Prospective Study

“…Furthermore, they found a significant correlation between high ratios and an increased risk of mortality long-term after renal transplantation. Gant et al observed that both urinary ratios of cortisol/cortisone and their corresponding metabolites in patients with type 2 diabetes were higher compared with healthy controls, and that ratios were highest in patients with concurrent lower renal function (146). A higher ratio of active vs inactive GCs in plasma or urine indicates that the peripheral GC balance as maintained by 11β-HSD enzymes has shifted toward an increase in 11β-HSD1 activity and/or a reduction in 11β-HSD2 activity.…”