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)

A rapid screening assay for chemicals inhibiting 11beta-hydroxysteroid dehydrogenase (11beta-HSD) type 1 or type 2 using lysates from stably transfected cells was developed. Here, we tested a series of environmental chemicals for anti-11beta-HSD activities. Inhibition of 11beta-HSD2, which may cause cortisol-dependent activation of the mineralocorticoid receptor with sodium retention and hypertension, was observed for several compounds, with diethylcarbamate being the most potent inhibitor (IC50 6.3 microM). Abietic acid inhibited both 11beta-HSD1 (IC50 27 microM for reduction and 2.8 microM for oxidation) and 11beta-HSD2 (IC50 12 microM). Our results demonstrate for the first time that flavanone selectively inhibits 11beta-HSD1 reductase activity: this enzyme being considered as essential for the local activation of glucocorticoids and representing a potential target for the therapeutic treatment of diabetes type 2. Flavanone and 2'-hydroxyflavanone efficiently inhibited reductive (IC50 18 and 10 microM) but not oxidative activity. We observed a reduced inhibitory effect of hydroxylated flavanone derivatives and of flavones containing a double-bond between atom C2 and C3. Flavanone was specific for 11beta-HSD1 and did not inhibit 11beta-HSD2. Our results reveal that a variety of environmental compounds exert distinct inhibitory effects on 11beta-HSD1 and 11beta-HSD2, opening the possibility for selectively modulating local cortisone/cortisol availability in vivo.
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PMID:A rapid screening assay for inhibitors of 11beta-hydroxysteroid dehydrogenases (11beta-HSD): flavanone selectively inhibits 11beta-HSD1 reductase activity. 1465 49

Glucocorticoids are potent regulators of protein, fat, and carbohydrate metabolism. To determine if cortisol production occurs within the splanchnic bed in humans, 11 nondiabetic subjects were studied using the hepatic/leg catheterization method along with an infusion of [9,11,12,12-2H4] cortisol (D4-cortisol) as proposed by Andrews et al. In the fasting state, there was net release (P < 0.05) of cortisol from the splanchnic bed (6.1 +/- 2.6 microg/min) and net uptake (P < 0.05) by the leg (1.7 +/- 0.7 microg/min). This, along with cortisol production by other tissues (e.g., the adrenals), resulted in a total-body cortisol appearance rate of 18.1 +/- 1.9 microg/min. Fractional splanchnic D4-cortisol extraction averaged 12.9 +/- 1.3% (P < 0.001), splanchnic cortisol uptake 14.8 +/- 2.0 microg/min (P < 0.001), and splanchnic cortisol production 22.2 +/- 3.3 microg/min (P < 0.001). On the other hand, fractional leg D4-cortisol extraction averaged 5.6 +/- 1.8% (P < 0.02), leg cortisol uptake 2.3 +/- 0.7 microg/min (P < 0.01), and leg cortisol production 0.4 +/- 0.4 microg/min, which did not differ from zero. Because D4-cortisol loses a deuterium during conversion to [9,12,12-2H3] cortisone (D3-cortisone), which in turn generates [9,12,12(2)H3] cortisol (D3-cortisol) via 11-beta hydroxysteroid dehydrogenase (11beta-HSD) type 1, D3-cortisol production can be used as an index of 11beta-HSD type 1 activity. Net splanchnic D3-cortisol release (3.9 +/- 0.4 microg/min) and splanchnic D3-cortisol production (7.1 +/- 0.7 microg/min) occurred (P < 0.01) in all subjects. In contrast, there was minimal leg D3-cortisol production (0.04 +/- 0.01 microg/min), resulting in a strong correlation between splanchnic D3-cortisol production and total-body 3D-cortisol production in both the fasting state (r = 0.84; P < 0.02) and during an infusion of insulin (r = 0.97; P < 0.01). Thus, splanchnic production of cortisol occurs in nondiabetic humans at rates approximating that which occurs in the remainder of the body. These data support the possibility that alterations in splanchnic cortisol production contribute to visceral fat accumulation and the hepatic insulin resistance of obesity or type 2 diabetes.
Diabetes 2004 Aug
PMID:Splanchnic cortisol production occurs in humans: evidence for conversion of cortisone to cortisol via the 11-beta hydroxysteroid dehydrogenase (11beta-hsd) type 1 pathway. 1527 85

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

It has been hypothesised that glucose intolerance or diabetes can be induced in rodents by a hypercaloric-fat diet or a hypercaloric-sucrose diet. This study was designed to examine the effects of a high-fat diet (HFD: carbohydrates 35-40% kcal, fat 50-55% kcal, protein 10-15% kcal) and a high-sucrose diet (HSD: carbohydrates 65-70% kcal, fat 25-30% kcal, protein 10-15% kcal) compared to a normal or standard diet (ND: carbohydrates 50-55% kcal, fat 15-20% kcal, protein 25-30% kcal) on fasting plasma glucose, glucose tolerance test, plasma triglycerides, plasma cholesterol, body weight, food and water consumption in male Wistar rats. After 4 months, weight gain, plasma triglycerides level, fasting plasma glucose and water intake were significantly elevated (p<0.05) in all test groups when compared to the control group. Total HDL and LDL cholesterol levels were significantly elevated (p<0.05) in the HFD group, whereas the HDL level was significantly lower in the HSD group associated with an atherogenic index significantly elevated (p<0.05) when compared to the control group. After 16 weeks of dietary treatment, an oral glucose tolerance test (OGTT) showed a significant increase in plasma glucose levels after 2-4 h of glucose challenge in all test groups. During the experiment, it was noticed that important weight gain observed in all dietary test groups was associated with a significant low (p<0.05) food consumption. The above results suggest that dietary nutrients contained in these hypercaloric diets might have an effect on insulin action and therefore, might contribute to the development of glucose intolerance and type 2 diabetes. These results also suggest that, in addition to their diabetogenic effect, these hypercaloric diets might probably have an atherogenic effect and could be use in a long-term study to induce type 2 (non-insulino-dependant) diabetes mellitus.
Diabetes Res Clin Pract 2005 Sep
PMID:Cameroon local diet-induced glucose intolerance and dyslipidemia in adult Wistar rat. 1609 18

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

Patients with diabetes mellitus are known to develop osteopenia and osteoporosis, apparently as a reduction in the process of bone formation. In order to evaluate whether bone-modulating hormones--estradiol, testosterone, and 1,25(OH)(2)D(3)--have different effects on osteoblasts derived from diabetic and from normal non-diabetic rats, we studied the specific effects of these hormones on the differentiation and function of cultured osteoblasts derived from 1-year-old Cohen diabetic rats. (The Cohen diabetic model consists of a diabetic-sensitive strain [CDs; diabetic] and a diabetic-resistant strain [CDr; normal]). The CDs and CDr male and female rats were fed on a regular diet (RD) or a high-sucrose low-copper diet (HSD; diabetogenic). On the HSD diet, only CD rats develop type 2 diabetes, while CDr do not. Bones were removed for primary osteoblast cultures, and osteoblastic responses to the bone-modulation hormones--estradiol, testosterone, and 1,25(OH)(2)D(3)--were studied. In male rats fed RD, primary cultures of osteoblasts without hormone addition to the culture medium showed that alkaline phosphatase (ALP) activity was similar in the Cohen diabetic rats (both CDr and CDs) to that of the original Sabra strain. However, collagen synthesis was reduced in the CDr and CDs compared to the Sabra strain. The addition of the hormones to the culture medium did not change ALP activity or collagen synthesis in the male-derived osteoblasts, but increased mineralization in all strains. In female rats (studied only in CDs and CDr animals) there were no differences between animals fed the RD. HSD increased the basal activity of ALP in the CDr but not in the CDs rats, and decreased the rate of collagen synthesis in both CDr and CDs (diabetic) animals. The addition of the bone-modulation hormones to the culture medium further increased ALP activity in the osteoblasts derived from the CDr animals, while decreasing ALP activity in the CDs. These hormones also decreased collagen synthesis in both strains and increased mineralization in all osteoblasts. In conclusion, the metabolic status (HSD and diabetes) in rats prior to culture affected the phenotype of cultured osteoblasts, decreasing their response to bone-modulation hormones. This decreased response, especially to estradiol, may be a major cause of the osteopenia observed in diabetes.
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PMID:Decreased response of osteoblasts obtained from aged Cohen diabetic sensitive rats to sex steroid hormones and 1,25OH2D3 in culture. 1699 16

Similarities between the metabolic syndrome and Cushing's syndrome, and reversibility of the features of Cushing's syndrome, suggest that cortisol may contribute to the pathophysiology of both conditions and that reducing cortisol action may provide a novel therapeutic approach in the metabolic syndrome. There is substantial evidence that circulating cortisol concentrations are higher in people with hypertension and glucose intolerance. The basis for this activation of the hypothalamic-pituitary-adrenal axis remains uncertain, but it may be attributable to 'programming' effects of events in early life, since it is associated with low birth weight. In obese people, intracellular cortisol levels within adipose tissue are further amplified by increased local regeneration of cortisol by the enzyme 11beta-HSD type 1. In mice, transgenic manipulations of 11beta-HSD1 have potent effects on obesity and associated features of the metabolic syndrome. Promising preclinical data suggest that novel 11beta-HSD1 inhibitors will have a role in lowering intracellular cortisol levels as a treatment for the metabolic syndrome. In addition to their metabolic effects, glucocorticoids act in the blood vessel wall. Pharmacoepidemiological studies suggest that glucocorticoid excess is an independent risk factor for cardiovascular disease. Recent data suggest that 11beta-HSD1 within the blood vessel wall influences vascular remodelling and angiogenesis, for example in the myocardium following coronary artery occlusion. Thus, glucocorticoid signalling provides a potentially tractable system to influence both risk factors for, and the outcome of, Type 2 diabetes and cardiovascular disease.
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PMID:Cortisol--cause and cure for metabolic syndrome? 1711 76

Syndrome X, the Metabolic Syndrome, and type II diabetes are closely related diseases that share risk factors and symptoms, notably insulin resistance. Several factors have been proposed either to mediate the disease(s) or to be their causes, and most converge on the endocrine/paracrine functions of the adipocyte. A common feature of such systems is their relative autonomy from systemic negative feedback regulation, for example by the HPA axis. We draw particular attention to two such mechanisms, both of which are associated with, and can cause, insulin resistance: the extra-adrenal production of corticosteroids, and the tissue renin angiotensin system of the adipocyte. These show another feature: the inter-regulation of glucocorticoid action and the RAS by positive feedback. Cortisol enhances the expression of 11 beta-HSD 1, and also of angiotensinogen and angiotensin type 1 receptors. In turn, angiotensin can stimulate further corticosteroid production, from the adrenal and perhaps from extra-adrenal sources. The instability inherent in such positive loops could account for the progressive nature of the disease(s), suggesting ways to break the circle.
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PMID:Angiotensin II, corticosteroids, type II diabetes and the metabolic syndrome. 1713 48

Adverse influences during fetal life alter the structure and function of distinct cells, organ systems or homoeostatic pathways, thereby 'programming' the individual for an increased risk of developing cardiovascular disease and diabetes in adult life. Fetal programming can be caused by a number of different perturbations in the maternal compartment, such as altered maternal nutrition and reduced utero-placental blood flow; however, the underlying mechanisms remain to be fully established. Perturbations in the maternal environment must be transmitted across the placenta in order to affect the fetus. Here, we review recent insights into how the placenta responds to changes in the maternal environment and discuss possible mechanisms by which the placenta mediates fetal programming. In IUGR (intrauterine growth restriction) pregnancies, the increased placental vascular resistance subjects the fetal heart to increased work load, representing a possible direct link between altered placental structure and fetal programming of cardiovascular disease. A decreased activity of placental 11beta-HSD-2 (type 2 isoform of 11beta-hydroxysteroid dehydrogenase) activity can increase fetal exposure to maternal cortisol, which programmes the fetus for later hypertension and metabolic disease. The placenta appears to function as a nutrient sensor regulating nutrient transport according to the ability of the maternal supply line to deliver nutrients. By directly regulating fetal nutrient supply and fetal growth, the placenta plays a central role in fetal programming. Furthermore, perturbations in the maternal compartment may affect the methylation status of placental genes and increase placental oxidative/nitrative stress, resulting in changes in placental function. Intervention strategies targeting the placenta in order to prevent or alleviate altered fetal growth and/or fetal programming include altering placental growth and nutrient transport by maternally administered IGFs (insulin-like growth factors) and altering maternal levels of methyl donors.
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PMID:Role of the placenta in fetal programming: underlying mechanisms and potential interventional approaches. 1753 98


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