Endocrine Abstracts

Background: Despite normal aldosterone levels, diabetics often profit from the treatment with mineralocorticoid receptor (MR) antagonists (MRAs). We therefore speculated if the expression of MR and 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) were changed in cells of glomerular origin under diabetic conditions and – if not - whether the synthesis of other corticosteroid hormones, that could act on MR, was increased in diabetics.

Methods: RNA transcripts and protein expression of MR and 11β-HSD2 were assessed in human mesangial (HRMC) and glomerular endothelial cells (HRGEC) under stimulation with high glucose and/or angiotensin 2. Urinary steroid hormone metabolites of 40 type 2 diabetics (20 females, 20 males) were analysed by gas chromatography–mass spectrometry and gender matched with 300 healthy controls (170 females, 130 males) from the Swiss Kidney Project on Genes in Hypertension (SKIPOGH) cohort.

Results: Expression of MR transcripts or protein was unaltered in HRMCs and HRGECs under normal and high glucose conditions with and without stimulation with angiotensin II. Both cell lines did not express 11β-HSD2 protein or RNA. Because this would leave the MR in glomerular cells accessible to glucocorticoid hormones, we looked also for these in the urinary steroid profile of diabetics. The excretion of mineralocorticoids were significantly increased in diabetic women for 18-OH-tetrahydrocorticosterone (P<0.0001) and for tetrahydroaldosterone in diabetic men (P=0.0393). Diabetic women excreted less tetrahydrocorticosterone (P<0.0001). Only cortisol excretion was significantly reduced in diabetic men (P=0.0117). For all other assessed glucocorticoids, there was an increased synthesis either in women, men or both. Diabetic women and men excreted more 11-deoxycortisol (P=0.0013 and P=0.0081, respectively) as well as well the cortisol metabolites 5α-tetrahydrocortisol (P=0.0003, P=0.0007), 5β-tetrahydrocortisol (P<0.0001, P=0.0083) and α-cortol (P<0.0001, P=0.0079). Excretions of cortisone and β-cortol did not differ in males, but were significantly increased in diabetic women (P=0.0053 for cortisone, P<0.0001 for β-cortol).

Conclusion: MR expression does not change in cell lines of glomerular origin upon diabetic conditions. 11β-HSD2 was not found in such cells leaving them freely accessible for glucocorticoids. In steroid profiles of diabetics the synthesis of mineralocorticoids was similar to controls. Mostly, the synthesis of mineralocorticoid active glucocorticoid metabolites was found to be increased in diabetics. By blocking the receptor from these metabolites, diabetics could profit from the treatment with MRAs.