ALTERATIONS IN CORTISOL METABOLISM IN INSULIN-DEPENDENT DIABETES-MELLITUS - RELATIONSHIP WITH METABOLIC CONTROL AND ESTIMATED BLOOD-VOLUME AND EFFECT OF ANGIOTENSIN-CONVERTING ENZYME-INHIBITION

11 beta-Hydrdxysteroid dehydrogenase (11 beta HSD) catalyzes the inter conversion of cortisol and its inactive metabolite, cortisone, and pro tects the mineralocorticoid receptor from activation by cortisol. Sodi um and fluid retention isa well documented phenomenon in insulin-depen dent diabetes mellitus (IDDM), but it is not known whether diabetes-as sociated alterations in cortisol metabolism contribute td its pathogen esis. Therefore, we evaluated some aspects of cortisol metabolism by m easuring urinary metabolites of cortisol and cortisone in eight microa lbuminuric and eight normoalbuminmuric IDDM patients and eight matched control subjects. In both IDDM groups, the overnight excretion of tet rahydrocortisol (THF), allo-tetrahydrocortisol (allo-THF), and tetrahy drocortisone (THE) was lower than that in the control group (P < 0.05 to P < 0.01). Both the allo-THF/THF ratio, a parameter of 5 alpha/5 be ta-reduction of cortisol, anti the cortisol to cortisone metabolite ra tio (THF+allo-THF/THE), which reflects the overall direction of the co rtisol to cortisone interconversion, were lower in the IDDM groups (P < 0.05 to P < 0.01). In the combined subjects (n = 24), allo-THF, allo -THF/THF, and THF+allo-THF/THE were inversely correlated with hemoglob in A(1c) (r = -0.69, P < 0.001; r = -0.61, P < 0.01; and r = -0.58, P < 0.01, respectively). Upper arm segmental blood volume, estimated by an electrical impedance technique, was positively correlated with the cortisol to cortisone metabolite ratio in both the control subjects (r = 0.77; P < 0.05) and the IDDM patients in whom it was measured (r = 0.56; P < 0.05; n = 13), whereas the regression line was shifted leftw ard in IDDM (i.e. a lower ratio at the same blood volume; P < 0.03, by analysis of covariance). In seven microalbuminuric IDDM patients, the angiotensin-converting enzyme inhibitor, enalapril (10 mg daily for 6 -12 weeks), resulted in a moderate further lowering of the cortisol to cortisone metabolite ratio (P < 0.05). The present data suggest a chr onic hyperglycemia-related impairment in the reduction of corticoids t o tetrahydro metabolites and an imbalance in 11 beta HSD activity ed 1 1 beta HSD activity is unlikely to be primarily responsible for the so dium and fluid retention in IDDM. Moreover, an additional mechanism of action of angioteasin-converting enzyme inhibition might be provided by an effect on 11 beta HSD activity.