Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoids may underlie the association between prenatal stress, low birth weight and adult stress-associated disorders, e.g. hypertension and type 2 diabetes, increased hypothalamic-pituitary-adrenal (HPA) activity and affective dysfunction. Normally, 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) rapidly inactivates glucocorticoids in placenta and many foetal tissues, thus acting as a 'barrier' to maternal steroids. We investigated the effect of inhibiting foeto-placental 11beta-HSD in rats, using carbenoxolone (CBX), on subsequent HPA activity and regulation and stress-induced behaviour in adult offspring. Pregnant Wistar rats were injected with CBX (12.5 mg s.c.) or vehicle daily throughout pregnancy. CBX treatment reduced birth weight. Adult offspring of CBX-treated dams had persistently reduced body weight, increased basal corticosterone (CORT) levels, increased corticotropin-releasing hormone (CRH) and reduced glucocorticoid receptor (GR) mRNA in the hypothalamic paraventricular nucleus, though hippocampal GR and mineralocorticoid receptor (MR) mRNA expression were unaltered. In addition, these animals showed less grooming and rearing in an open field and reduced immobility in a forced swim test, and had increased GR mRNA expression in the basolateral (BLA), central (CEA) and medial (MEA) nuclei of the amygdala, with unaltered MR mRNA. These data suggest that disturbance of the foeto-placental enzymatic barrier to maternal glucocorticoids reduces birth and body weight, and produces permanent alterations of the HPA axis and anxiety-like behaviour in aversive situations. The behavioural and HPA effects may reflect GR gene programming in amygdala and hypothalamus, respectively. Foetal overexposure to endogenous glucocorticoids (prenatal stress or reduced activity of foeto-placental 11beta-HSD) may represent a common link between the prenatal environment, foetal growth and adult neuroendocrine and affective disorders.
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PMID:Inhibition of 11beta-hydroxysteroid dehydrogenase, the foeto-placental barrier to maternal glucocorticoids, permanently programs amygdala GR mRNA expression and anxiety-like behaviour in the offspring. 1076 36

11beta-hydroxysteroid dehydrogenases (11beta-HSDs) catalyze the interconversion of active glucocorticoids (cortisol, corticosterone) and inert 11-keto forms (cortisone, 11-dehydrocorticosterone). 11beta-HSD type 2 has a well recognized function as a potent dehydrogenase that rapidly inactivates glucocorticoids, thus allowing aldosterone selective access to otherwise nonselective mineralocorticoid receptors in the distal nephron. In contrast, the function of 11beta-HSD type 1 has, until recently, been little understood. 11beta-HSD1 is an ostensibly reversible oxidoreductase in vitro, which is expressed in liver, adipose tissue, brain, lung, and other glucocorticoid target tissues. However, increasing data suggest that 11beta-HSD1 acts as a predominant 11beta-reductase in many intact cells, whole organs, and in vivo. This reaction direction locally regenerates active glucocorticoids within expressing cells, exploiting the substantial circulating levels of inert 11-keto steroids. While the biochemical determinants of the reaction direction are not fully understood, insights to its biological importance have been afforded by use of inhibitors in vivo, including in humans, and the generation of knockout mice. Such studies suggest 11beta-HSD1 effectively amplifies glucocorticoid action at least in the liver, adipose tissue, and the brain. Inhibition of 11beta-HSD1 represents a potential target for therapy of disorders that might be ameliorated by local reduction of glucocorticoid action, including type 2 diabetes, obesity, and age-related cognitive dysfunction.
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PMID:Minireview: 11beta-hydroxysteroid dehydrogenase type 1- a tissue-specific amplifier of glucocorticoid action. 1125 Sep 14

Recent evidence suggests that increased cortisol secretion, altered cortisol metabolism, and/or increased tissue sensitivity to cortisol may link insulin resistance, hypertension, and obesity. Whether these changes are important in type 2 diabetes mellitus (DM) is unknown. We performed an integrated assessment of glucocorticoid secretion, metabolism, and action in 25 unmedicated lean male patients with hyperglycemia (20 with type 2 diabetes and 5 with impaired glucose intolerance by World Health Organization criteria) and 25 healthy men, carefully matched for body mass index, age, and blood pressure. Data are mean +/- SE. Patients with hyperglycemia (DM) had higher HbA(1c) (6.9 +/- 0.2% vs. 6.0 +/- 0.1%, P < 0.0001) and triglycerides. Cortisol secretion was not different, as judged by 0900 h plasma cortisol and 24 h total urinary cortisol metabolites. However, the proportion of cortisol excreted as 5alpha- and 5beta-reduced metabolites was increased in DM patients. Following an oral dose of cortisone 25 mg, generation of plasma cortisol by hepatic 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD 1) was impaired in DM patients (area under the curve, 3617 +/- 281 nM.2 h vs. 4475 +/- 228; P < 0.005). In contrast, in sc gluteal fat biopsies from 17 subjects (5 DM and 12 controls) in vitro 11beta-HSD 1 activity was not different (area under the curve, 128 +/- 56% conversion.30 h DM vs. 119 +/- 21, P = 0.86). Sensitivity to glucocorticoids was increased in DM patients both centrally (0900 h plasma cortisol after overnight 250 micro g oral dexamethasone 172 +/- 16 nM vs. 238 +/- 20 nM, P < 0.01) and peripherally (more intense forearm dermal blanching following overnight topical beclomethasone; 0.56 +/- 0.92 ratio to vehicle vs. 0.82 +/- 0.69, P < 0.05). In summary, in patients with glucose intolerance, cortisol secretion, although normal, is inappropriately high given enhanced central and peripheral sensitivity to glucocorticoids. Normal 11beta-HSD 1 activity in adipose tissue with impaired hepatic conversion of cortisone to cortisol suggests that tissue-specific changes in 11beta-HSD 1 activity in hyperglycemia differ from those in primary obesity but may still be susceptible to pharmacological inhibition of the enzyme to reduce intracellular cortisol concentrations. Thus, altered cortisol action occurs not only in obesity and hypertension but also in glucose intolerance, and could therefore contribute to the link between these multiple cardiovascular risk factors.
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PMID:Abnormal cortisol metabolism and tissue sensitivity to cortisol in patients with glucose intolerance. 1278 12

11 beta-Hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) regenerates cortisol from inactive cortisone in liver and adipose tissue. Inhibition of 11 beta-HSD1 offers a novel potential therapy to lower intracellular cortisol concentrations and thereby enhance insulin sensitivity and hepatic lipid catabolism in type 2 diabetes, obesity, and hyperlipidemia. We evaluated this approach using the nonselective 11 beta-HSD inhibitor, carbenoxolone, in healthy men and lean male patients with type 2 diabetes. Six diet-controlled nonobese diabetic patients with hemoglobin A(1c) less than 8%, and six matched controls participated in a double-blind, cross-over comparison of carbenoxolone (100 mg every 8 h, orally, for 7 d) and placebo. They were admitted overnight for infusions of insulin (as required to maintain arterialized plasma glucose of 5.0 mM) and [13C6]glucose. Glucose kinetics were measured in the fasted state from 0700-0730 h, during a 3-h euglycemic hyperinsulinemic clamp (including somatostatin infusion and replacement of physiological GH and glucagon levels), and during a 2-h euglycemic hyperinsulinemic clamp with a 4-fold increase in glucagon levels. Data are the mean +/- SEM. Carbenoxolone had the expected effects of raising blood pressure and lowering plasma potassium. Carbenoxolone reduced total cholesterol in healthy subjects (5.25 +/- 0.34 vs. 4.78 +/- 0.40 mM; P < 0.01), but had no effect on other serum lipids or on cholesterol in diabetic patients. Carbenoxolone did not affect the rate of glucose disposal or the suppression of free fatty acids during hyperinsulinemia. However, carbenoxolone reduced the glucose production rate during hyperglucagonemia in diabetic patients (1.90 +/- 0.2 vs. 1.53 +/- 0.3 mg/kg x min; P < 0.05). This was attributable to reduced glycogenolysis (1.31 +/- 0.2 vs. 1.01 +/- 0.2 mg/kg x min; P < 0.005) rather than altered gluconeogenesis. These observations reinforce the potential metabolic benefits of inhibiting 11 beta-HSD1 in the liver of patients with type 2 diabetes. Further studies in obesity and hyperlipidemia are now warranted. However, clinically useful therapeutic effects will probably require selective 11 beta-HSD1 inhibitors that lower intraadipose cortisol levels and enhance peripheral glucose uptake.
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PMID:Effects of the 11 beta-hydroxysteroid dehydrogenase inhibitor carbenoxolone on insulin sensitivity in men with type 2 diabetes. 1251 67

In aging humans and rodents, inter-individual differences in cognitive function have been ascribed to variations in long-term glucocorticoid exposure. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) regenerates the active glucocorticoid cortisol from circulating inert cortisone, thus amplifying intracellular glucocorticoid levels in some tissues. We show that 11beta-HSD1, but not 11beta-HSD2, mRNA is expressed in the human hippocampus, frontal cortex, and cerebellum. In two randomized, double-blind, placebo-controlled crossover studies, administration of the 11beta-HSD inhibitor carbenoxolone (100 mg three times per day) improved verbal fluency (P < 0.01) after 4 weeks in 10 healthy elderly men (aged 55-75 y) and improved verbal memory (P < 0.01) after 6 weeks in 12 patients with type 2 diabetes (52-70 y). Although carbenoxolone has been reported to enhance hepatic insulin sensitivity in short-term studies, there were no changes in glycemic control or serum lipid profile, nor was plasma cortisol altered. 11beta-HSD1 inhibition may be a new approach to prevent/ameliorate cognitive decline.
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PMID:11Beta-hydroxysteroid dehydrogenase inhibition improves cognitive function in healthy elderly men and type 2 diabetics. 1509 96

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.
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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

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.
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PMID:Cameroon local diet-induced glucose intolerance and dyslipidemia in adult Wistar rat. 1609 18

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

This study evaluated the effects of fiber nets and application techniques and flowable composites as a liner on microleakage and the effects of fiber nets on polymerization shrinkage in Class II MOD cavities. Standard MOD cavities were performed in 80 extracted third molars. The teeth were randomly divided into eight groups (n=10). Group 1: Filtek Supreme XT (bulk technique) (FSB); Group 2: Filtek Supreme XT (incremental technique) (FSI); Group 3: Filtek Supreme XT Flow (FS Flow)+FSB; Group 4: FS Flow+FSI; Group 5: FS Flow+Ribbond (R)+FSB; Group 6: FS Flow+R+FSI; Group 7: FS Flow+everStick NET (E)+FSB; Group 8: FS Flow+(E)+FSI. All the teeth were then immersed in 0.5% basic fuchsin solution for 24 hours after thermocycling for 1000 cycles (5 degrees C and 55 degrees C). The teeth were sectioned longitudinally and observed under a stereomicroscope. In order to determine the polymerization shrinkage, another study was designed. In Group A, composite was applied as a bulk. In Group B, the resin composite was divided into two parts and Ribbond fiber was placed in the middle of the mass. In Group C, everStick NET fiber was placed inside the composite, as in Group B. Statistical analysis were performed by using one-way ANOVA and Tukey HSD tests for both microleakage and polymerization shrinkage (p < 0.05). Less microleakage was observed in groups where composites were applied by the incremental technique compared with those where the bulk technique was used (p < 0.05). The groups that used flowable composites showed significantly lower microleakage (p < 0.05). In groups where fiber nets were used, a significant decrease was determined in terms of microleakage (p < 0.05). Groups with fiber nets exhibited lower polymerization shrinkage (p < 0.05). Fiber nets decreased both microleakage and polymerization shrinkage. The incremental technique is an effective method for Class II composite restorations.
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PMID:Effect of fiber nets, application techniques and flowable composites on microleakage and the effect of fiber nets on polymerization shrinkage in class II MOD cavities. 1936 73


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