Lower renal function is associated with derangement of 11-β hydroxysteroid dehydrogenase in type 2 diabetes

Abstract

Context: Derangement 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. Objectives: To compare 11β-HSD activities between patients with T2D and healthy controls, and assess whether in T2D, renal function is associated with 11β-HSD activities. Design: Cross-sectional analysis in the Diabetes and Lifestyle Cohort Twente (DIALECT-1). Setting: Referral center for T2D. Patients: Patient with T2D [n = 373, age 64 6 9 years, 58% men, 26% of patients estimated glomerular filtration rate (eGFR) < 60 mL/min·1.73m2] and healthy controls (n = 275, age 53611 years, 48% men). Mean Outcome Measure: We 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. Results: Patients 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 =20.35, P < 0.001), and a higher cortisol/cortisone ratio (β = 20.16, P = 0.001). Conclusions: In 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.