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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In humans, a hyperactivity of glucocorticoid metabolism was postulated to be involved in the intrauterine programming of the metabolic syndrome in adulthood. We studied in rats the effects of overfeeding, obtained by reducing the size of the litter in the immediate postnatal period, a time crucial for neuroendocrine maturation such as late gestation in humans. Overfeeding induced early-onset obesity and accelerated the maturation of the hypothalamo-pituitary-adrenal (HPA) axis together with an upregulation of adipose tissue glucocorticoid receptor (GR) mRNA. In adulthood, neonatally overfed rats presented with moderate increases in basal and stress-induced corticosterone secretion and striking changes in visceral adipose tissue glucocorticoid signaling, that is, enhanced GR and 11beta-hydroxysteroid dehydrogenase type 1 mRNA levels. The above-mentioned alterations in the endocrine status of overfed rats were accompanied by a moderate overweight status and significant metabolic disturbances comparable to those described in the metabolic syndrome. Our data demonstrate for the first time that postnatal overfeeding accelerates the maturation of the HPA axis and leads to permanent upregulation of the HPA axis and increased adipose tissue glucocorticoid sensitivity. Thus, the experimental paradigm of postnatal overfeeding is a powerful tool to understand the pathophysiology of glucocorticoid-induced programming of metabolic axes.
Diabetes 2005 Jan
PMID:Postnatal diet-induced obesity in rats upregulates systemic and adipose tissue glucocorticoid metabolism during development and in adulthood: its relationship with the metabolic syndrome. 1561 29

The adverse and beneficial effects of postmenopausal hormone replacement therapy include: ischemic heart disease, stroke, pulmonary embolism, breast cancer, an increased rate of onset of asthma as well as reductions in the incidence of diabetes in women with known coronary artery disease and osteoporotic fractures. These varied effects can be explained by the down regulation of 11beta-hydroxysteroid dehydrogenase by estradiol, which results in a reduction of tissue specific cortisol production. The reduction in local cortisol production which diminishes the endogenous anti-inflammatory effects, also allows for the progression of both vascular and pulmonary inflammation. The decrease in cortisol activation reduces insulin resistance and anti-proliferative effects thereby reducing the potential for diabetes but allowing for the emergence of malignancy. Furthermore, the decreased local tissue availability of cortisol reduces the tendency for the development of osteoporosis. New techniques and drugs are being developed to evaluate the modulation of 11beta-HSD1 activity. Further study should result in new ways to control both inflammation and metabolism.
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PMID:Estradiol induced inhibition of 11beta-hydroxysteroid dehydrogenase 1: an explanation for the postmenopausal hormone replacement therapy effects. 1595 Mar 94

Cortisol is regenerated from cortisone by 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1), amplifying glucocorticoid action in adipose tissue and liver. 11HSD1 inhibitors are being developed for type 2 diabetes and may be most effective in obesity, where adipose 11HSD1 is increased. However, the magnitude of regeneration of cortisol in different tissues in humans is unknown, hindering understanding of the pathophysiological and therapeutic importance of 11HSD1. In eight healthy men, we infused 9,11,12,12-(2)H4-cortisol and measured tracer enrichment in the hepatic vein as an indicator of total splanchnic cortisol generation. Oral cortisone (25 mg) was then given to measure first-pass hepatic cortisol generation. In steady state, splanchnic cortisol production was 45 +/- 11 nmol/min when arterialized plasma cortisone concentration was 92 +/- 7 nmol/l. Extrapolation from hepatic cortisol generation after oral cortisone suggested that, at steady state, the liver contributes 15.2 nmol/min and extrahepatic splanchnic tissue contributes 29.8 nmol/min to the total splanchnic cortisol production. We conclude that tissues draining into the portal vein, including visceral adipose tissue, contribute substantially to the regeneration of cortisol. Thus, in addition to free fatty acids and adipokines, the portal vein delivers cortisol to the liver, and inhibition of 11HSD1 in visceral adipose tissue may indeed be valuable in ameliorating insulin resistance in obesity.
Diabetes 2005 May
PMID:The contribution of visceral adipose tissue to splanchnic cortisol production in healthy humans. 1585 21

Glucocorticoids are involved in the regulation of spermatogenesis in the boar testis by initiating apoptosis in early stages of germ cell development. Because cortisol activity is modulated by the 11beta-hydroxysteroid dehydrogenase system (11beta-HSD), the present study determined both 11beta-activating (reductive) and inactivating (oxidative) enzyme activities in testicular tissue preparations of control boars (n = 5), GnRH-immunized boars (n = 5), and immunized, estradiol-infused boars (n = 6) by radioenzyme assay based on the conversion of tritiated cortisol to cortisone in the presence of NAD+ (inactivation) or tritiated cortisone to cortisol in the presence of NADPH (activation). The presence of both isoforms, 11beta-HSD 1 and 11beta-HSD 2, was confirmed by RTPCR in testicular tissue of control boars. Additionally, cortisol, testosterone, estradiol, and LH were determined in blood plasma sampled twice before killing. Immunization led to a drop of LH from 4.3 +/- 0.3 pmol/L to 1.0 +/- 0.3 pmol/L (testosterone: 11.63 +/- 0.83 nmol/L vs. 0.28 +/- 0.07 nmol/L; 17beta-estradiol: 512.61 +/- 47.60 pmol/L vs. 77.05 +/- 14.00 pmol/L). Low 11beta-HSD reductive activity was found in boars (1 pmol steroid x min (-1) x mg (-1)). It decreased to trace amounts in immunized boars (0.07 pmol steroid x min (-1) x mg (-1)). Oxidative activity was found in boars with 10.19 +/- 2.28 pmol steroid x min (-1) x mg (-1) protein. Immunization led to a sharp decrease (0.08 +/- 0.03 pmol x min (-1) x mg (-1)). Infusion of 17beta-estradiol significantly elevated peripheral estradiol concentrations to 752.07 +/- 24.19 pmol/L which still is a physiological concentration in this species. The infusion led to a minimal reductive activity (0.04 pmol steroid x min (-1) x mg (-1)), but led to a 6-fold rise of the 11beta-HSD oxidative activity to 0.47 +/- 0.14 pmol x min (-1) x mg (-1) compared to immunized boars. It is concluded that the 11beta-HSD system is involved in the regulation of cortisol activity in the testis and thus in the regulation of spermatogenesis.
Exp Clin Endocrinol Diabetes 2005 May
PMID:Characterization of 11beta-hydroxysteroid dehydrogenase activity in testicular tissue of control and GnRH-immunized boars as a possible regulator of spermatogenesis. 1592 11

A number of epidemiological studies worldwide have demonstrated a relationship between poor early growth and an increased susceptibility to insulin resistance, visceral obesity, type 2 diabetes and other features of the metabolic syndrome in adulthood. However, the mechanistic basis of this relationship and the relative roles of genes and the environment remain a subject of debate. The 'thrifty phenotype' hypothesis proposes that poor fetal nutrition leads to programming of metabolism and an adult phenotype that is adapted to poor but not plentiful nutrition. The maternal reduced-protein rat model has been used to examine the importance of the maternal environment in determining susceptibility to adult disease. Pregnant and lactating rat dams are fed a diet containing 80 g protein/kg as compared with 200 g protein/kg, which leads to growth restriction in utero. Offspring of low-protein dams have increased susceptibility to diabetes, insulin resistance and hypertension when fed a palatable high-fat diet that promotes obesity. Administration of leptin during pregnancy and lactation to these protein-restricted dams produces offspring that have increased metabolic rate and do not become obese or insulin resistant when fed on a high-fat diet. Increased glucocorticoid exposure, particularly during late gestation, has been linked with insulin resistance in adulthood. High levels of fetal glucocorticoids may result from a decreased activity of placental 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 2, which normally protects the fetus from high maternal glucocorticoid levels. Leptin administration to protein-restricted dams inhibits the suppression of 11beta-HSD-2 and may be one mechanism by which the metabolic syndrome is prevented.
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PMID:Fetal origins of insulin resistance and obesity. 1596 Aug 59

The identification of small molecules that fall within the biologically relevant subfraction of vast chemical space is of utmost importance to chemical biology and medicinal chemistry research. The prerequirement of biological relevance to be met by such molecules is fulfilled by natural product-derived compound collections. We report a structural classification of natural products (SCONP) as organizing principle for charting the known chemical space explored by nature. SCONP arranges the scaffolds of the natural products in a tree-like fashion and provides a viable analysis- and hypothesis-generating tool for the design of natural product-derived compound collections. The validity of the approach is demonstrated in the development of a previously undescribed class of selective and potent inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 with activity in cells guided by SCONP and protein structure similarity clustering. 11beta-hydroxysteroid dehydrogenase type 1 is a target in the development of new therapies for the treatment of diabetes, the metabolic syndrome, and obesity.
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PMID:Charting biologically relevant chemical space: a structural classification of natural products (SCONP). 1630 44

Despite major advances in understanding monogenic causes of morbid obesity, the complex genetic and environmental etiology of idiopathic metabolic syndrome remains poorly understood. One hypothesis suggests that similarities between the metabolic disease of plasma glucocorticoid excess (Cushing's syndrome) and idiopathic metabolic syndrome results from increased glucocorticoid reamplification within adipose tissue by 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD-1). Indeed, 11beta-HSD-1 is now a major therapeutic target. Because much supporting evidence for a role of adipose 11beta-HSD-1 comes from transgenic or obese rodents with single-gene mutations, we investigated whether the predicted traits of metabolic syndrome and glucocorticoid metabolism were coassociated in a unique polygenic model of obesity developed by long-term selection for divergent fat mass (Fat and Lean mice with 23 vs. 4% fat as body weight, respectively). Fat mice exhibited an insulin-resistant metabolic syndrome including fatty liver and hypertension. Unexpectedly, Fat mice had a marked intra-adipose (11beta-HSD-1) and plasma glucocorticoid deficiency but higher liver glucocorticoid action. Furthermore, metabolic disease was exacerbated only in Fat mice when challenged with exogenous glucocorticoids or a high-fat diet. Our data suggest that idiopathic metabolic syndrome might associate with such a novel pattern of glucocorticoid action and sensitivity in humans, with implications for tissue-specific therapeutic targeting of 11beta-HSD-1.
Diabetes 2005 Dec
PMID:A polygenic model of the metabolic syndrome with reduced circulating and intra-adipose glucocorticoid action. 1630 51

Selective inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) have considerable potential as treatments for metabolic diseases, such as diabetes mellitus type 2 or obesity. Here, we report the discovery and synthesis of a series of novel benzothiazole derivatives and their inhibitory activities against 11beta-HSD1 from human hepatic microsomes measured using a radioimmunoassay (RIA) method. The benzothiazole derivatives 1 and 2 showed greater than 80% inhibition for 11beta-HSD1 at 10 microM and exhibited IC50 values in the low micromolar range. The preliminary SAR study suggested the introduction of a chlorine substituent at the 4 position of the benzothiazole ring greatly enhanced the inhibitory activities. Docking studies with the benzothiazole derivative 1 into the crystal structure of human 11beta-HSD1 revealed how the molecule may interact with the enzyme and cofactor.
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PMID:Benzothiazole derivatives as novel inhibitors of human 11beta-hydroxysteroid dehydrogenase type 1. 1632 33

The splanchnic bed produces cortisol at rates approximating extraadrenal tissues by converting cortisone to cortisol via the 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 pathway. It is not known whether splanchnic cortisol production is regulated by nutrient ingestion and/or by the accompanying changes in hormone secretion. To address this question, 18 healthy humans were randomized to ingest either a mixed meal or to receive an intravenous saline infusion while total-body, splanchnic, and D3 cortisol production (an index of 11beta-HSD type 1 activity) were measured using the combined hepatic catheterization and D4 cortisol infusion methods. Fasting glucose and insulin concentrations did not differ on the meal and saline study days. Glucose and insulin concentrations increased after meal ingestion, peaking at 11.0 +/- 1.0 mmol/l and 451 +/- 64 pmol/l, respectively, at 45 min, then fell to baseline thereafter. In contrast, glucose and insulin concentrations slowly fell to 5.1 +/- 0.1 mmol/l and 27 +/- 6 pmol/l during the 6 h of observation on the saline study day. Fasting cortisol concentration did not differ on the meal and saline study days. Cortisol increased (P < 0.05) to a peak of 353 +/- 55 nmol/l after meal ingestion but did not change after saline infusion. The increase in cortisol after meal ingestion was associated with an increase in both total body cortisol (from 748 +/- 63 to 1,620 +/- 235 nmol/min; P < 0.01) and total body D3 cortisol (from 99 +/- 11 to 143 +/- 11 nmol/min; P < 0.01) production, whereas there was no change in either on the saline study day. The increase in total-body cortisol and D3 cortisol production after meal ingestion originated in extrasplanchnic tissues since splanchnic cortisol production (mean 0-360 min: 254 +/- 83 vs. 262 +/- 36 nmol/min) and splanchnic D3 cortisol production (mean 0-360 min: 72 +/- 22 vs. 77 +/- 14 nmol/min) did not differ on the meal and saline study days. We conclude that ingestion of a mixed meal does not alter either splanchnic cortisol production or the conversion of D4 cortisol to D3 cortisol or, therefore by implication, flux via the splanchnic 11beta-HSD type 1 pathway.
Diabetes 2006 Mar
PMID:Effect of nutrient ingestion on total-body and splanchnic cortisol production in humans. 1650 29

Human 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) catalyzes the interconversion of cortisone into active cortisol. 11betaHSD1 inhibition is a tempting target for the treatment of a host of human disorders that might benefit from blockade of glucocorticoid action, such as obesity, metabolic syndrome, and diabetes type 2. Here, we report an in silico screening study aimed at identifying new selective inhibitors of human 11betaHSD1 enzyme. In the first step, homology modeling was employed to build the 3D structure of 11betaHSD1. Further, molecular docking was used to validate the predicted model by showing that it was able to discriminate between known 11betaHSD1 inhibitors or substrates and non-inhibitors. The homology model was found to reproduce closely the crystal structure that became publicly available in the final stages of this work. Finally, we carried out structure-based virtual screening experiments on both the homology model and the crystallographic structure with a database of 114,000 natural molecules. Among these, 15 molecules were consistently selected as inhibitors based on both the model and crystal structures of the enzyme, implying a good quality for the homology model. Among these putative 11betaHSD1 inhibitors, two were flavonone derivatives that have already been shown to be potent inhibitors of the enzyme.
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PMID:Comparison of a homology model and the crystallographic structure of human 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) in a structure-based identification of inhibitors. 1678 99


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