Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
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.
 ...
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

Liquorice extract has been claimed to induce inhibition of the activity of 11 beta-hydroxysteroid dehydrogenase which converts cortisol to cortisone. This enzyme is thought to protect the mineralocorticoid receptor from being occupied by endogeneous glucocorticoids in the kidney. Based on these hypotheses, we investigated the effect of low-dose glycyrrhizine on hyperkalemia due to hyporeninemic hypoaldosteronism in eight subjects with NIDDM. The mean serum potassium concentration decreased from 5.3 +/- 0.3 (SD) mEq/1 to 4.9 +/- 0.2 mEq/1 when 15 g of calcium polystyrene sulfonate, a potassium-binding resin, was given per day, and it decreased significantly to 4.4 +/- 0.4 mEq/1 with 150 mg/day of glycyrrhizine therapy. Changes in fasting plasma glucose and hemoglobin A1c were not significant. These data support the assumption that liquorice extract can be used safely in the therapy for treating hyperkalemia due to selective hypoaldosteronism in diabetes mellitus subjects.
 ...
PMID:Effect of glycyrrhizine on hyperkalemia due to hyporeninemic hypoaldosteronism in diabetes mellitus. 833 14

We present the characteristic features of mineralocorticoid receptor regulation in human mononuclear leukocytes in patients with diabetes mellitus. Eighteen diabetic patients (3M and 15F, aged from 28 to 77 years with a mean of 53 +/- 14 (mean +/- SD) years) and 7 normal subjects (6M and 1F, aged from 29 to 59 years with a mean of 41 +/- 13 years) were studied. The mean plasma aldosterone concentration in the diabetic patients was significantly lower than that in the normal subjects (137 +/- 62 vs 189 +/- 36 pmol/l, p < 0.05). Seven of the 18 diabetic patients were hypoaldosteronemic. These 7 patients, however, showed normokalemia, except one with mild hyperpotassemia. The number of binding sites of [3H]aldosterone to mineralocorticoid receptor in the diabetic patients was significantly higher than that in the normal subjects (853 +/- 281 vs 488 +/- 109 sites/cell, p < 0.05), but there was no significant difference in Kd of [3H]aldosterone binding to mineralocorticoid receptor between the diabetic patients and normal subjects (1.34 +/- 0.37 vs 0.99 +/- 0.61 nmol/l). In the diabetic patients, a significant negative correlation was observed (r = 0.70, p < 0.01) between plasma aldosterone concentration and the binding sites, but not between plasma aldosterone concentration and Kd. In the total subjects, including normal subjects and diabetic patients, a significant negative correlation was also found between plasma aldosterone concentration and binding sites (r = 0.72, p < 0.001). These results suggest that increased binding sites of mineralocorticoid receptor may help to prevent diabetic patients from being hyperkalemic.
 ...
PMID:Aldosterone binding to mineralocorticoid receptors of mononuclear leukocytes in diabetic subjects. 839 58

The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) inactivates glucocorticoids in the kidney and thus prevents glucocorticoids from occupying the non-selective mineralocorticoid receptor in epithelial tissues. Mutations in the HSD11B2 gene have been found to cause the syndrome of apparent mineralocorticoid excess, a rare autosomal recessive disease characterized by severe hypertension. Thus, this locus could also be an ideal candidate involved in the etiology of primary hypertension. We identified a polymorphism in exon 3 characterized by a GAG to GAA transition at codon 178, with the loss of an Alu I restriction site and analysed it in an association study using end-stage renal disease patients, diabetic or essential hypertensive patients and control subjects. Two-hundred and eighty nine subjects and patients were analysed; the genotype was determined by amplification of genomic DNA and subsequent digestion with Alu I restriction enzyme. The prevalence of the Alu I allele was 8.6% in healthy control subjects (n = 116). This prevalence was lower (chi 2 P = 0.035 vs. controls) than the 18.0% in a group of renal transplant patients (n = 61). The corresponding values for patients with diabetes mellitus (n = 25), hypertension (n = 41) and patients on dialysis (n = 46) were 4.0%, 4.8% and 4.3%, respectively. There was no correlation between blood pressure and the marker in non-ESRD subjects. These data indicate the presence of a polymorphic marker in exon 3 of the HSD11B2 gene; this marker is associated with end-stage renal disease but not with essential hypertension in humans.
 ...
PMID:A new polymorphic restriction site in the human 11 beta-hydroxysteroid dehydrogenase type 2 gene. 958 99

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

In vitro, cortisol and aldosterone have a similar affinity to the mineralocorticoid receptor. The 11beta-hydroxysteroid dehydrogenase catalyzes the interconversion of cortisol to its inactive 11-oxo-metabolite cortisone. This interconversion is responsible for the in vivo specificity of the mineralocorticoid receptor. A defect of this enzyme leads to a pseudohyperaldosteronism with hypertension and hypokalemia, the so-called apparent mineralocorticoid excess syndrome. Glycyrrhetinic acid, a compound of licorice, also leads to pseudohyperaldosteronism by an inhibition of the 11beta-hydroxysteroid dehydrogenase. We studied the pharmacokinetics of glycyrrhetinic acid and its effect on the 11beta-hydroxysteroid dehydrogenase. Ten healthy students, aged 24 to 38 years, were included in the study. On the first day 500 mg glycyrrhetinic acid were given orally at 08.00 h. Blood and urine samples were taken prior to and 2, 4, 7, 10 and 24 hours after ingestion of glycyrrhetinic acid. We measured the serum level of cortisol, cortisone and glycyrrhetinic acid and the urinary excretion rates of cortisol, cortisone and their 20-dihydrometabolites. For determination of glycyrrhetinic acid and steroid levels we used a fully automated liquid chromatographic analyzer which allows the highly specific and simultaneous determination of steroid profiles even in the matrix of urine. Ratios of the 11-hydroxy- and 11-oxo-metabolites were calculated and correlated to the serum level of glycyrrhetinic acid. We found a significant correlation of the steroid-ratios to the serum levels of glycyrrhetinic acid. Coefficients of correlation were 0.9873, 0.7812, 0.7396 and 0.5844 between the serum level of glycyrrhetinic acid and the cortisol/cortisone-ratio in serum (p < 0.0001), the cortisol/cortisone-ratio in urine (p = 0.0279), the 20alpha-dihydrocortisol/20alpha-dihydrocortisone-ratio in urine (p = 0.0119) and the 20beta-dihydrocortisol/20beta-dihydrocortisone-ratio in urine (p = 0.0419), respectively. We conclude that the ratios of cortisol to cortisone and of the 20-dihydrometabolites of cortisol to the 20-dihydrometabolites of cortisone provide a simple noninvasive tool for monitoring the in-vivo activity of the 11beta-hydroxysteroid dehydrogenase.
Exp Clin Endocrinol Diabetes 1999
PMID:Administration of glycyrrhetinic acid: significant correlation between serum levels and the cortisol/cortisone-ratio in serum and urine. 1054 14

Long-lasting problem on the differentiation of adenohypophyseal cell, which prepares them for their specific tasks (somatotropic, lactotropic ect.), becomes elucidated after recognition of the differentiational effect of transcription factor Pit-1. Expression of that factor in somatotrops results in STH secretion, contrary to lactotrops producing prolactin. Subclinical hypothyreosis (increased TSH with normal T3 and T4) endangers vessel not because of hypercholesterolemia, but because of changes in the dynamics of the blood flow. The idea of cardiotropic effect of thyroidal hormones is supported by the finding that administration of trijodthyronine to children after the surgical correction of heart malformations (cardiopulmonary bypass) improves myocardial function--it elevates cardiac output and decreases requirements on the intensive care. Receptors for hormones in tissues are flexible, they can be "heterooligomers" for dopamine and somatostatin. Mutations of mineralocorticoid receptor may cause hypertension in pregnancy and progesterone receptors have several isoforms. Receptors can be also activated by short exposition to a hormone. Glucocorticoids have probably also membrane receptors. Diabetes mellitus "type I" needn't to be immunogenic and DM type II not only results from down-regulation of receptors and subsequent insulin resistance, but it can be also caused by defects in insulin secretion. Insulin has receptors in the brain and participates in the appetite regulation. The attempt to use "desensibilisation" by peroraly administered insulin in patients with immunogenic DM had no effect. Stress affects memory mechanisms, heavy emotional stress during gravidity can bring congenital malformations. The decrease of mental functions in aged women depends on the level of free estradiol (the fraction, which is not bound to plasma proteins). Activation of dopaminergic neurons can be achieved by neurotropic growth factors. Nesiritide is a recombinant brain natriuretic hormone successfully tested in heart failure. The role of leptin in the appetite regulation in man is still not clear, other signalling molecules may have also an effect, e.g., ghrelin, which primarily stimulates STH secretion and brings about weight gain. Sildenafil influences nitrergic neurons elsewhere than in penis, for example it has positive effects in patients with oesophageal achalasia.
 ...
PMID:[Endocrinology 1999-2000]. 1128 21

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.
 ...
PMID:[11 beta-Hydroxysteroid dehydrogenase]. 1250 57

Patients and animals with poorly controlled or uncontrolled diabetes present with diurnal hypersecretion of glucocorticoids and altered regulation of the hypothalamo-pituitary-adrenocortical (HPA) axis. Although some of these changes are reversed with insulin replacement therapy, neuroendocrine function is not always restored to normal, even with rigorous glycemic control. In addition, stress responsiveness is also impaired in diabetes and this has important implications in the way patients with diabetes cope with many stress challenges, including the metabolic challenge of insulin-induced hypoglycemia. HPA dysregulation in diabetes appears to involve complex interactions between impaired glucocorticoid negative feedback sensitivity and factors such as hypoinsulinemia, hyperglycemia and/or hypoleptinemia, that may increase central drive of the axis. This review examines some of the evidence indicating hyperactivation of the HPA axis in patients with diabetes. Using the streptozotocin-diabetic rat as a model of type-1 diabetes, we will focus on elucidating some of the mechanisms underlying HPA dysregulation in diabetes. Hyperactivation of the HPA axis in diabetes is associated with increased expression of hypothalamic corticotrophin-releasing hormone (CRH) mRNA and hippocampal mineralocorticoid receptor (MR) mRNA. Although insulin replacement restores ACTH and corticosterone levels to normal, likely through glucocorticoid-mediated suppression of ACTH secretion, CRH and MR mRNA expression remain elevated. A better understanding of these mechanisms may be important in developing new treatment modalities for patients with diabetes mellitus.
 ...
PMID:Diabetes and the hypothalamo-pituitary-adrenal (HPA) axis. 1271 40


1 2 3 4 5 6 7 8 9 10 Next >>