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HSD Activity (hsd + activity)
Selected AbstractsIn vivo activity of 11,-hydroxysteroid dehydrogenase type 1 and free fatty acid-induced insulin resistanceCLINICAL ENDOCRINOLOGY, Issue 4 2005K. Mai Summary Introduction, Free fatty acids (FFAs) induce hepatic insulin resistance and enhance hepatic gluconeogenesis. Glucocorticoids (GCs) also stimulate hepatic gluconeogenesis. The aim of this study was to investigate whether the FFA-induced hepatic insulin resistance is mediated by increased activity of hepatic 11,-hydroxysteroid dehydrogenase type 1 (11,-HSD1), accompanied by elevated hepatic cortisol levels. Methods, Following a 10-h overnight fast, six healthy male volunteers were investigated. A euglycaemic hyperinsulinaemic clamp was performed during lipid or saline infusion. To assess hepatic 11,-HSD1 activity, plasma cortisol levels were measured after oral administration of cortisone acetate during lipid or saline infusion. In addition, 11,-HSD activities were determined in vivo by calculating the urinary ratios of GC metabolites. Results, Lipid infusion increased FFAs (5·41 ± 1·00 vs. 0·48 ± 0·20 mmol/l; P < 0·005) and significantly increased insulin resistance [glucose infusion rate (GIR) 6·02 ± 2·60 vs. 4·08 ± 2·15 mg/kg/min; P < 0·005]. After lipid and saline infusions no changes in 11,-HSD1 activity were found, neither by changes in cortisone acetate to cortisol conversion nor by differences in urinary free cortisol (UFF) or cortisone (UFE), 5,-tetrahydrocortisol (THF), 5,-THF, cortisone (THE), UFF/UFE and (5,-THF + THF)/THE ratios. Conclusions, We found no change in hepatic and whole-body 11,-HSD1 activity during acute FFA-induced insulin resistance. Further studies are necessary to clarify whether 11,-HSD1 in muscle and adipose tissue is influenced by FFAs and whether 11,-HSD1 is involved in other conditions of insulin resistance. [source] Decreased cortisol production in male type 1 diabetic patientsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 7 2003M. N. Kerstens Abstract Background It is unclear whether cortisol production and the 11,HSD-mediated cortisol to cortisone interconversion are different between type 1 diabetic patients and healthy subjects. Materials and methods Fourteen male, nonobese, normotensive type 1 diabetic patients without severe complications (HbA1c < 8·5%) were studied twice during a daily sodium intake of 50 and 200 mmol, and were then compared with 14 individually matched healthy subjects. Cortisol production was assessed by the sum of urinary cortisol metabolite excretion. Urinary ratios of (tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydro-cortisone [(THF + allo-THF)/THE] and of free cortisol/free cortisone [UFF/UFE] were determined as parameters of 11,HSD activity. Results Sum of urinary cortisol metabolite excretion during low- and high-salt diet was 7·4 ± 2·5 vs. 7·7 ± 2·3 nmol min,1 m,2 (NS) in diabetic patients and 9·7 ± 2·1 vs. 11·2 ± 4·1 nmol min,1 m,2 (NS) in healthy subjects, respectively (P < 0·05 vs. healthy subjects at both diets). The allo-THF excretion and allo-THF/THF ratios were lower in the diabetic than in the healthy males during both diets (P < 0·05). Urinary (THF + alloTHF)/THE and UFF/UFE were similar in both groups and remained unchanged after salt loading. Conclusions The sum of urinary cortisol metabolite excretion as a measure of cortisol production is lower in nonobese, normotensive type 1 diabetic males with adequate glycaemic control and without severe complications, irrespective of sodium intake. We suggest that this is at least in part as result of diminished 5, reductase activity, resulting in a decreased cortisol metabolic clearance. In type 1 diabetic and in healthy males, the 11,HSD setpoint is not affected by physiological variations in sodium intake. [source] Short-term cortisol infusion in the brachial artery, with and without inhibiting 11,-hydroxysteroid dehydrogenase, does not alter forearm vascular resistance in normotensive and hypertensive subjectsEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 12 2002S. H. M. Van Uum Abstract Background Vascular tone is increased in primary hypertension, and glucocorticoids affect vascular tone. Local cortisol availability is modulated by activity of 11,-hydroxysteroid dehydrogenase (11,-HSD). As this activity may be decreased in patients with primary hypertension, vascular sensitivity to cortisol may be increased in these patients. We studied the acute effect of cortisol on forearm vascular resistance (FVR) by infusing cortisol directly into the brachial artery, both with and without inhibition of 11,-HSD, in normotensive and hypertensive subjects. Design Twenty normotensive volunteers and 20 patients with primary hypertension participated in the study. After a 10-min infusion of vehicle (glucose 5%), cortisol was infused into the brachial artery in three stepwise increasing doses (3·5, 10·5 and 35 µg per 100 mL of forearm volume), each for 10 min. Next, the participants received placebo or 500 mg glycyrrhetinic acid (GA) orally, and 150 min later the same infusion schedule was repeated. Forearm vascular resistance was measured during the last 5 min of the infused vehicle and of each dose. Arterial and forearm venous plasma samples for measurement of cortisol and cortisone were taken at the end of the infusions of glucose 5% and the highest cortisol dose. Results In both normotensive and hypertensive subjects, neither the infusion of cortisol nor the administration of GA changed FVR. Also 2 h after the cortisol infusion there remained no change in FVR in both the normotensive and hypertensive groups who received placebo. Following the infusion of the highest cortisol dose, total plasma cortisone levels in the venous plasma were decreased compared with levels in the arterial plasma (36 ± 3 and 49 ± 4 nmol L,1, respectively, P < 0·05). The protein-bound venous cortisone was 37·1 ± 4·8 nmol L,1 during the vehicle compared with 23·9 ± 3·7 nmol L,1 during the cortisol infusion (P < 0·01), whereas the free cortisone level was not altered by the cortisol infusion. Conclusions In both normotensive and hypertensive subjects, high-dose cortisol infusion both with and without 11,-HSD inhibition did not change FVR either immediately or after 2 h. We could not demonstrate in vivo 11,-HSD activity in the forearm vascular tissues. When binding of cortisone to CBG is changed, e.g. during cortisol infusion, arterio-venous changes in cortisone cannot reliably be used to assess (alterations in) local 11,-HSD activity. [source] 11b-hydroxysteroid dehydrogenase activity in proteinuric patients and the effect of angiotensin-II receptor blockadeEUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Issue 7 2002M. N. Kerstens Abstract Background It has been suggested that an altered setpoint of the 11,HSD-mediated cortisol to cortisone interconversion towards cortisol contributes to sodium retention in nephrotic syndrome patients. We studied the parameters of 11,HSD activity in proteinuric patients, in particular its activity at the kidney level. We also studied the effect of angiotensin-II receptor blockade on the parameters of 11,HSD activity. Materials and methods Serum cortisol/cortisone ratio and the urinary ratios of (tetrahydrocortisol + allo-tetrahydrocortisol)/tetrahydrocortisone [(THF + allo-THF)/THE] and of urinary free cortisol/free cortisone (UFF/UFE) were measured in eight proteinuric patients and compared with eight matched, healthy subjects. Patients were subsequently studied after 4 weeks' treatment with losartan 50 mg day,1 and placebo, respectively. Results No significant differences between the proteinuric patients and the healthy subjects were observed in the serum cortisol, serum cortisone, serum cortisol to cortisone ratio, or in the urinary excretions of THF, allo-THF, THE, sum of cortisol metabolites, or the (THF + allo-THF)/THE ratio. Urinary free cortisol excretion and the UFF/UFE ratio were lower in the proteinuric patients than in the healthy subjects (56 ± 21 vs. 85 ± 24 pmol min,1, P < 0·05, and 0·39 ± 0·07 vs. 0·63 ± 0·28, P < 0·05, respectively). Mean arterial pressure and proteinuria were reduced significantly during losartan treatment, but without concomitant changes in peripheral cortisol metabolism. Conclusions Increased renal inactivation of cortisol in proteinuric patients does not support the contention that altered 11,HSD activity contributes to sodium retention in patients with nephrotic syndrome. Losartan 50 mg d.d. reduces mean arterial pressure and proteinuria, but does not exert a significant effect on the cortisol to cortisone interconversion. [source] Effects of glycyrrhetinic acid derivatives on hepatic and renal 11,-hydroxysteroid dehydrogenase activities in ratsJOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 6 2003Yoshihito Shimoyama The purpose of this study was to examine the structure and activity relationships of glycyrrhetinic acid derivatives on the inhibition of hepatic and renal 11,-hydroxysteroid dehydrogenases (HSDs) in rats. Furthermore, we explored whether inflammatory effect of the derivatives is involved in the inhibition of 11,-HSD activity. 18,-Glycyrrhetinic acid (Ia) potently inhibited 11,-HSD activity of hepatic (IC50 (concentration giving 50% inhibition of cortisone production) = 0.09 ,m) and renal (IC50 = 0.36 ,m) homogenate. The inhibitory effect of 18,-glycyrrhetol (Id) modified at the 30-position of glycyrrhetinic acid was weaker than that of glycyrrhetinic acid itself. 18,-24-Hydroxyglycyrrhetinic acid (Ie), oxidized at the 24-position, remarkably reduced the inhibitory activity for both enzymes. 18,-11-Deoxoglycyrrhetinic acid (IIc) showed the same inhibitory effect as glycyrrhetinic acid on hepatic 11,-HSD activity, but less effect on renal 11,-HSD activity. Furthermore, the inhibitory activity of 18,-deoxoglycyrrhetol (IIa), modified at the 11- and 30-position, was markedly decreased. Dihemiphthalate derivatives (IIb, IIIb and IVb) of deoxoglycyrrhetol (IIa), 18,-olean-9(11), 12-diene-3,, 30-diol (IIIa) and olean-11, 13(18)-diene-3,, 30-diol (IVa), which are anti-inflammatory agents, also showed weak inhibition against both hepatic and renal 11,-HSDs. While glycyrrhetinic acid (200 mg kg,1, p.o.) significantly inhibited 11,-HSD activity in rat liver and kidney at 3 h after administration, compound IVb (100 mg kg,1, p.o.) had no effect on either enzyme activity. In addition, the circulating corticosterone level was slightly increased by glycyrrhetinic acid but not by compound IVb. These results suggest that the anti-inflammatory effects of compound IVb, derived from glycyrrhetinic acid, are not due to accumulation of steroids induced by the inhibition of 11,-HSD activity. Our data also showed that the 11-, 24- and 30-positions of glycyrrhetinic acid may play important roles in the differential inhibitory effects on 11,-HSD isozyme activity. [source] | ||||||||||