Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

11 beta-Hydroxysteroid dehydrogenase (11 beta HSD) catalyzes the interconversion of cortisol and its inactive metabolite, cortisone, and protects the mineralocorticoid receptor from activation by cortisol. Sodium and fluid retention is a well documented phenomenon in insulin-dependent diabetes mellitus (IDDM), but it is not known whether diabetes-associated alterations in cortisol metabolism contribute to its pathogenesis. Therefore, we evaluated some aspects of cortisol metabolism by measuring urinary metabolites of cortisol and cortisone in eight microalbuminuric and eight normoalbuminuric IDDM patients and eight matched control subjects. In both IDDM groups, the overnight excretion of tetrahydrocortisol (THF), allo-tetrahydrocortisol (allo-THF), and tetrahydrocortisone (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 beta-reduction of cortisol, and the cortisol to cortisone metabolite ratio (THF+allo-THF/THE), which reflects the overall direction of the cortisol 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 hemoglobin A1c (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 leftward 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 chronic hyperglycemia-related impairment in the reduction of corticoids to tetrahydro metabolites and an imbalance in 11 beta HSD. Altered 11 beta HSD activity is unlikely to be primarily responsible for the sodium and fluid retention in IDDM. Moreover, an additional mechanism of action of angiotensin-converting enzyme inhibition might be provided by an effect on 11 beta HSD activity.
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PMID:Alterations in cortisol metabolism in insulin-dependent diabetes mellitus: relationship with metabolic control and estimated blood volume and effect of angiotensin-converting enzyme inhibition. 755 88

Recent human epidemiological studies have linked low birth weight with a substantially increased risk of non-insulin-dependent diabetes mellitus in later life. These data suggest that the intrauterine environment plays a crucial role in determining later glucose homeostasis, but the mechanism is unknown. We have proposed that exposure of the fetus to excess maternal glucocorticoids may underpin the epidemiological findings. Normally placental 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta-HSD-2) protects the fetus from the normally higher maternal levels of glucocorticoids by inactivating corticosterone and cortisol to inert 11-keto products. Here we show that administration of carbenoxolone, an inhibitor of placental 11 beta-HSD 2, to pregnant rats, leads to a significant reduction in average birth weight (20% fall). At 6 months of age, the male offspring of carbenoxolone-treated pregnancies had similar weights to controls, but showed significantly higher fasting plasma glucose (6.0 +/- 0.3 vs 4.8 +/- 0.2 mmol/l; p < 0.01) and exhibited significantly greater plasma glucose (10% higher) and insulin (38% higher) responses to an oral glucose load. These effects of carbenoxolone require intact maternal adrenal glands suggesting that inhibition of feto-placental 11 beta-HSD 2 is key. These data support the notion that deficiency of placental 11 beta-HSD, by exposing the fetus to excess maternal glucocorticoids, reduces growth and predisposes to hyperglycaemia in later life.
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PMID:Prenatal glucocorticoid exposure leads to offspring hyperglycaemia in the rat: studies with the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone. 893 95

The presence of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) activity in the kidney has been suggested to be important in the regulation of glucocorticoid-induced disorders of electrolyte balance and the control of blood pressure. To assess the possible effect of 11beta-HSD isoforms in diabetes-related hypertension, we measured the mean systolic blood pressure and the 11beta-HSD activity and mRNA levels for both 11beta-HSD1 and 11beta-HSD2 in the kidney of streptozotocin (STZ)-diabetic female rats. Three weeks after injection of STZ (65 mg/kg), the mean systolic blood pressure of diabetic rats was elevated 13.6% above that of normal rats (P<.01). The renal 11beta-HSD2 activity and level of mRNA expression were significantly decreased in diabetic rats (P<.01). However, the treatment of rats with STZ did not decrease the levels of renal 11beta-HSD1 activity and mRNA expression in diabetic rats. Insulin administered subcutaneously to diabetic rats for 2 weeks completely reversed the decrease in renal 11beta-HSD2 activity and gene expression and prevented the elevation in blood pressure in the diabetic rat. These results indicate that alteration of renal 11beta-HSD2 activity and gene expression may be primarily responsible for the changes in blood pressure of STZ-diabetic rats after early treatment with insulin.
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PMID:Gene expression of 11beta-hydroxysteroid dehydrogenase type 1 and type 2 in the kidneys of insulin-dependent diabetic rats. 949 77

The 11beta-hydroxysteroid dehydrogenase (11beta-HSD) protects the testis from the inhibitory effects of corticosterone on testosterone (T) production. The objectives of the present studies were to determine the effects of deoxycorticosterone (DOC) and its mechanism of actions on testicular 11beta-HSD activity and plasma T levels after 7 days of treatment. The results revealed that at the end of 7 days treatment, DOC significantly increased testicular 11beta-HSD activity and plasma T levels in normal rats. However, the time course showed that high plasma T levels lowered 11beta-HSD activity on day 14 and by 21 days both the levels normalized. In adrenalectomized (ADX) rats, only the enzyme activity increased significantly but not plasma T levels. Spironolactone, a competitive inhibitor of mineralocorticoid receptor (MR), did not change testicular 11beta-HSD activity in both normal and DOC treated rats suggesting that DOC did not act through MR in increasing 11beta-HSD activity. On the other hand, spironolactone significantly decreased plasma T levels in DOC treated rats. Progesterone (P), a competitive inhibitor of glucocorticoid receptors (GR) or corticosterone significantly suppressed testicular enzyme activity and plasma T levels in DOC treated normal rats. Carbenoxolone which is an inhibitor of 11beta-HSD activity significantly depressed testicular 11beta-HSD activity and plasma T levels in DOC treated normal rats. This paper suggests that DOC increased testicular 11beta-HSD activity through GR; whilst increase in plasma T levels required functioning adrenal glands. The testicular 11beta-HSD is one of the regulators of T levels and vice versa.
Exp Clin Endocrinol Diabetes 1999
PMID:Novel effects of deoxycorticosterone on testicular 11beta-hydroxysteroid dehydrogenase activity and plasma testosterone levels in normal and adrenalectomized rats. 1048 40

The effects of stress and corticosterone on testicular 11beta-hydroxysteroid dehydrogenase (11beta-HSD) oxidative activity have been controversial, whilst that of adrenocorticotrophic hormone (ACTH) have not been investigated before. Hence, the aim of the present study was to determine the in vivo effects of stress due to injection and sham operation, ACTH and corticosterone on testicular and hepatic 11beta-HSD oxidative activity and plasma testosterone levels in normal and adrenalectomized (ADX) rats and their possible mechanism of actions. Adrenalectomy reduced both testicular 11beta-HSD oxidative activity and plasma testosterone levels. The effects of injection and sham operation significantly increased plasma corticosterone levels with decreased testicular 11beta-HSD oxidative activity and plasma testosterone levels in normal but not in ADX rats. Likewise. ACTH or corticosterone treatment for 7 days decreased both testicular 11beta-HSD oxidative activity in a dose dependent manner and plasma testosterone levels in normal rats; but the values in ADX rats remained unchanged. However, none of the above values were significantly lower than that of the ADX levels. Corticosterone seems to maintain testicular 11beta-HSD oxidative activity within the range between normal and ADX rats. These changes are not attributable to diurnal rhythms, as the time of sacrifice has been fixed between 8:30 and 10:30 am. In the liver, no significant change in 11beta-HSD oxidative activity was observed with sham operation, ACTH or corticosterone treatment; but adrenalectomy significantly decreased it. In conclusion, in the intact normal rats, stress, ACTH or corticosterone modulates testicular (but not hepatic) 11beta-HSD oxidative activity indirectly through the adrenal glands and the physiological level of corticosterone is ideal for normal reproductive functions.
Exp Clin Endocrinol Diabetes 2000
PMID:In vivo effects of stress, ACTH and corticosterone on testicular 11beta-hydroxysteroid dehydrogenase oxidative activity in rats and the possible mechanism of actions. 1098 57

11beta-hydroxysteroid dehydrogenase (11beta-HSD), an enzyme regulating mineralocorticoid like action of glucocorticoid, oxidizes active cortisol to inactive cortisone. Impaired activity of this enzyme is associated with apparent mineralocorticoid excess (AME) syndrome and is characterized by hypertension and hypokalemia. Recent investigations suggest the presence of hypertensive subjects with low activity of 11beta-HSD. The blood concentration ratio of cortisone/cortisol reflects the overall conversion of cortisol to cortisone and may be an index to assess the systemic activity of 11beta-HSD. We evaluated the peripheral blood concentration ratio of cortisone/cortisol as a possible marker to identify subjects with hypertension thought to represent impaired 11beta-HSD activity. We compared this ratio in healthy subjects and patients with diabetes mellitus (DM) or chronic renal failure (CRF). Peripheral blood samples were collected from 69 healthy subjects, 44 DM, and 36 CRF patients in the morning (9:00 to 11:00 AM). Twenty-six DM patients (59%) and 32 CRF patients (89%) met the criteria for having hypertension. Serum cortisol and cortisone concentrations were determined by high performance liquid chromatography (HPLC). All values for serum cortisone and cortisol levels were within the normal range. Serum cortisone/cortisol ratio in the healthy subjects was distributed with a range of 0.113 to 0.494 (median, 0.243). Compared with healthy subjects, DM and CRF patients had significantly low (P <.01) serum cortisone/cortisol levels (median, 0.188 [range, 0.092 to 0.313] in DM and 0.088 [range, 0.031 to 0.140] in CRF). Bimodal distribution of cortisone/cortisol, found in DM patients with hypertension, represented high- and low-ratio groups around the border of the ratio 0.2. Kidney function, DM duration, and complications varied between the high- and low-ratio groups. The low ratio group (<0.2), whose 11beta-HSD activity was considered low, had an increase in blood urea nitrogen (BUN) levels and experienced nephropathy, neuropathy, retinopathy, and prolonged DM duration when compared with the group with a ratio greater than 0.2. The data suggest that the serum cortisone/cortisol ratio reflects the change in 11beta-HSD activity and is dependent kidney function. This is a possible marker to evaluate glucocorticoid excess hypertension observed in DM and CRF patients.
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PMID:Assessing systemic 11beta-hydroxysteroid dehydrogenase with serum cortisone/cortisol ratios in healthy subjects and patients with diabetes mellitus and chronic renal failure. 1143 85

The aim of this study was to investigate the effect of altered thyroid status on 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD type 1) and type 2 (11beta-HSD type 2) bioactivity in rat kidney and colon. Male Sprague-Dawley rats (250 g) were treated with either L-thyroxine (T4) or propylthiouracil (PTU) for 4 weeks. Blood were then analysed for serum thyroxine, sodium (Na+) and potassium (K+). The kidneys and colon were assayed for 11beta-HSD type 1 and 11beta-HSD type 2 bioactivity. In T4 treated rats the serum thyroxine was significantly elevated (p<0.05) whilst PTU decreased serum thyroxine significantly (p<0.001) compared to controls. Serum Na+ and K+ were within normal limits. There were no significant changes in 11beta-HSD type 1 bioactivity in both treatment groups compared to controls. However, the 11beta-HSD type 2 bioactivity in rats given thyroxine was significantly higher in the colon (p<0.003) compared to controls. We conclude that altered thyroid status had no effect on 11beta-HSD type 1 bioactivity but 11beta-HSD type 2 bioactivity was elevated in the colon of rats given supplementary thyroxine.
Exp Clin Endocrinol Diabetes 2001
PMID:11Beta-hydroxysteroid dehydrogenase bioactivity is increased in the colon but not kidneys of rats given supplementary thyroxine. 1145 35

11beta-Hydroxysteroid dehydrogenase 2 (11beta-HSD 2) converts active cortisol to inactive cortisone and thus modifies the availability of glucocorticoids for the target tissue. An additional function is the protection of the aldosterone receptor in mineralocorticoid-sensitive tissues such as the kidney and the gut. The occurrence of 11beta-HSD 2 activity was investigated in several species. Data for the pig, however, so far are missing. The activity was determined by a radio-enzyme-assay based on the conversion of tritiated cortisol to cortisone under standardized incubation conditions in supernatants of homogenates prepared from tissues of four castrates. Tissues comprised several locations along the intestinal tract and in addition kidney, lung, muscle, heart, spleen and pancreas. Highest values of the enzyme activity were found in kidney and very low activities in lung tissue but no activity in muscle, spleen, heart and pancreas. In the gut, there was a continuous increase in enzyme activity from the duodenum (0.60 pmol x min(- 1) x mg protein(- 1)) towards the colon with maximum values in the colon transversum (23.32 pmol x min(- 1) x mg protein(- 1)). In the colon the activity was 10-fold higher than in jejunum and 3-fold higher compared to ileum. The activities did not differ significantly between the colon transversum and colon descendens.
Exp Clin Endocrinol Diabetes 2001
PMID:Activities of 11beta-hydroxysteroid dehydrogenase 2 in different regions of the intestinal tract of pigs. 1157 49

There are two types of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD). 11 beta-HSD 1 is an oxoreductase interconverting biologically active cortisol and inactive cortisone. 11 beta-HSD 2 is an exclusive oxidase only converting cortisol to cortisone. It has been recognized that 11 beta-HSD 2 confers the specificity of mineralocorticoid receptor in the kidney and protects the fetus from high levels of maternal glucocorticoids in the placenta. Lack or malfunction of this enzyme could result in the development of apparent mineralocorticoid excess syndrome and intrauterine growth retardation of the fetus. 11 beta-HSD is possibly involved in a number of other physiological and pathological conditions such as stress, hypertension, diabetes mellitus and neurodegenerative disorders. The functions of 11 beta-HSD 1 are not very well understood.
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PMID:[11 beta-Hydroxysteroid dehydrogenase]. 1250 57

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD 1) catalyzes the interconversion of inactive into active glucocorticoids and has been shown to play a key role in metabolic disorders such as obesity and diabetes. 11 beta-HSD 1 belongs to the short chain dehydrogenases/reductases (SDR) and shares all common structural motifs typically for this protein superfamily. Unlike common SDRs, 11 beta-HSD 1 is N-terminally extended by a hydrophobic domain that anchors this enzyme in the endoplasmic reticulum (ER) membrane. Interestingly, the occurrence of 11 beta-HSD 1 transcripts lacking the N-terminal hydrophobic domain has repeatedly been reported in a variety of tissues, and the corresponding protein has been named 11 beta-HSD 1B. So far, no activity of 11 beta-HSD 1B has been observed, such that a physiological role could not be ascribed. In the present investigation, we showed for the first time that the truncated human 11 beta-HSD 1B form, expressed in the yeast Pichia pastoris, may indeed be active. However, this activity was prevented by the fact that 11 beta-HSD 1B is still kept attached to the ER membrane. Via computer assisted simulation and modeling, we identified a putative domain within the 11 beta-HSD 1 structure that could be responsible for this additional membrane attachment. By performing site-directed mutagenesis, heterologous expression, immunoblot analysis, and activity assays, we verified that this hydrophobic domain could indeed interact with the ER membrane and that some of the introduced mutations (V149R, V149E) led to a release of 11 beta-HSD 1B from membrane attachment without affecting its enzymatic activity. However, the activity of 11 beta-HSD 1B proved to be very unstable and was lost within hours after solubilization and release from the ER membrane. Importantly, 11 beta-HSD 1 constructs lacking the first 15 N-terminal amino acids and bearing additional amino acid substitutions (t15-V149R, t15-V149E) were then found to be soluble and to be stable in terms of enzyme activity. Combined, despite its occurrence in mammalian tissues, 11 beta-HSD 1B has obviously no physiological role since it is either inactive while being attached to the ER or it is rapidly losing activity once being released from intracellular membranes. Our findings with the t15-V149R and t15-V149E constructs are promising to further understand the complex mechanical and structural properties of 11 beta-HSD 1.
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PMID:Functional characterization of the human 11 beta-hydroxysteroid dehydrogenase 1B (11 beta-HSD 1B) variant. 1268 Jul 65


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