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)

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.
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PMID:Effect of glycyrrhizine on hyperkalemia due to hyporeninemic hypoaldosteronism in diabetes mellitus. 833 14

There are striking similarities between Cushing's syndrome and the 'metabolic syndrome X' since both are characterised by hypertension, insulin resistance, glucose intolerance, hyperlipidaemia, and central obesity. The possibility that cortisol contributes to the associations between multiple risk factors for cardiovascular disease was rejected when it was demonstrated that there was no elevation in cortisol secretion or circulating concentration in patients with essential hypertension or type 2 diabetes mellitus. However, in recent years the enormous variability in tissue sensitivity to cortisol has become apparent. We have measured tissue sensitivity to glucocorticoids using an assay of skin vasoconstriction and have demonstrated its relationship with high blood pressure, insulin resistance, glucose intolerance, and hypertriglyceridaemia. Our data suggest that the increase in dermal glucocorticoid sensitivity is not a secondary phenomenon and may be explained by increased glucocorticoid receptor affinity together with impaired inactivation of cortisol by 11 beta-hydroxysteroid dehydrogenase. Importantly, we have not found that enhanced peripheral glucocorticoid sensitivity is associated with compensatory suppression of cortisol secretion, so that the maintenance of normal circulating cortisol concentrations in patients with cardiovascular risk factors may be paradoxical and inappropriate.
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PMID:Abnormal glucocorticoid activity in subjects with risk factors for cardiovascular disease. 896 30

Novel antidiabetic arylsulfonamidothiazoles are presented that exert action through selective inhibition of the 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) enzyme, thereby attenuating hepatic gluconeogenesis. The diethylamide derivative 2a was shown to potently inhibit human 11beta-HSD1 (IC(50) = 52 nM), whereas the N-methylpiperazinamide analogue 2b only inhibited murine 11beta-HSD1 (IC(50) = 96 nM). Both compounds showed >200-fold selectivity over human and murine 11beta-HSD2. 2b was subsequently shown to reduce glucose levels in diabetic KKA(y) mice, substantiating the 11beta-HSD1 enzyme as a target for the treatment of type 2 diabetes.
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PMID:Arylsulfonamidothiazoles as a new class of potential antidiabetic drugs. Discovery of potent and selective inhibitors of the 11beta-hydroxysteroid dehydrogenase type 1. 1219 Mar 2

The major risk factor for the development of insulin resistance and type 2 diabetes is obesity. A key role is the new understanding of adipocytes as an endocrine system. Adipocytes secrete numerous substances that contribute to peripheral insulin resistance, including adiponectin, resistin, TNF-alpha and interleukin 6. There is also a role of free fatty acids by blocking directly intracellular metabolism of glucose and by their lipotoxicity. The pre-receptor metabolism of cortisol may be enhanced in visceral adipose tissue by activation of 11 beta-hydroxysteroid dehydrogenase type 1. The new class of thiazolidinediones (glitazones), binding to the peroxisome proliferator activated receptor (PPAR-gamma) lowers the levels of resistin and increases adiponectin, resulting in an improvement of glucose homeostasis. However, the first step to avoid insulin resistance should be an attempt to reduce body weight and to increase physical activity. These are successful means to avoid the development of type 2 diabetes from prediabetic states, as shown recently in 3 independent intervention trials.
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PMID:[From obesity to diabetes]. 1223 30

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

The discovery of antidiabetic agents that inhibit hepatic glucose production is a popular and potentially fruitful research area for the pharmaceutical research community. Metformin, a marketed agent with this mechanism of action, is widely used for the treatment of type 2 diabetes, however, more efficacious agents are sought. A number of promising proteins are being targeted for modulation by new compounds, including the glucagon receptor, glycogen phosphorylase, glucocorticoid receptor, 11 beta-hydroxysteroid dehydrogenase-1, fructose-1,6-bisphosphatase, carnitine palmitoyltransferase-1, glycogen synthase kinase-3, glucose-6-phosphate T1 translocase and the A2B receptor. Compounds designed to work against these targets are at the early clinical or preclinical phase of study. Glucagon receptor antagonists, glycogen phosphorylase inhibitors, 11 beta-hydroxysteroid dehydrogenase-1 inhibitors, carnitine palmitoyltransferase-1 inhibitors and fructose-1,6-bisphosphatase inhibitors are, or have been, clinically evaluated. Preclinical studies against the other targets have yielded compounds that demonstrate efficacy in diabetic animal models and clinical activity will continue.
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PMID:Pharmacological regulation of hepatic glucose production. 1280 81

Obesity and Type 2 diabetes mellitus are associated with abnormal regulation of glucocorticoid metabolism that are highlighted by clinical similarities between the sequelae of insulin resistance and Cushing's syndrome, as well as glucocorticoids' functional antagonism to insulin. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activates functionally inert glucocorticoid precursors (cortisone) to active glucocorticoids (cortisol) within insulin target tissues, such as adipose tissue, thereby regulating local glucocorticoid action. Recent data, mainly from rodents, provide considerable evidence for a causal role of 11beta-HSD1 for the development of visceral obesity and Type 2 diabetes though data in humans are not unequivocal. This review summarizes current evidence on a possible role of 11beta-HSD1 for development of the metabolic syndrome, raising the possibility of novel therapeutic options for the treatment of Type 2 diabetes by inhibition or down-regulation of 11beta-HSD1 activity.
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PMID:11beta-Hydroxysteroid dehydrogenase Type 1 in obesity and Type 2 diabetes. 1465 20

The highly prevalent metabolic syndrome (insulin resistance, type 2 diabetes, dyslipidemia, hypertension, along with abdominal obesity) resembles Cushing's syndrome. However, in simple obesity, plasma cortisol levels are not elevated. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), at least in mature adipocytes and hepatocytes, converts inactive circulating 11-keto steroids into active glucocorticoids, amplifying local glucocorticoid action. 11beta-HSD1 is elevated in adipose tissue in obese humans and rodents, suggesting that adipose tissue glucocorticoid excess may explain the conundrum. Indeed, transgenic mice overexpressing 11beta-HSD1 in adipose tissue faithfully replicate the metabolic syndrome. Conversely, 11beta-HSD1(-/-) mice resist the metabolic consequences of stress and high-fat feeding via insulin sensitisation and other advantageous effects in the liver and adipose tissue. Adipose 11beta-HSD1 deficiency contributes to a protective metabolic phenotype, supporting its role as a therapeutic target for the metabolic syndrome.
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PMID:Glucocorticoids and 11beta-hydroxysteroid dehydrogenase in adipose tissue. 1474 10

The metabolic syndrome (visceral obesity, insulin resistance, type 2 diabetes, and dyslipidemia) resembles Cushing's Syndrome, but without elevated circulating glucocorticoid levels. An emerging concept suggests that the aberrantly elevated levels of the intracellular glucocorticoid reamplifying enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD-1) found in adipose tissue of obese humans and rodents underlies the phenotypic similarities between idiopathic and "Cushingoid" obesity. Transgenic overexpression of 11 beta-HSD-1 in adipose tissue reproduces a metabolic syndrome in mice, whereas 11 beta-HSD-1 deficiency or inhibition has beneficial metabolic effects, at least on liver metabolism. Here we report novel protective effects of 11 beta-HSD-1 deficiency on adipose function, distribution, and gene expression in vivo in 11 beta-HSD-1 nullizygous (11 beta-HSD-1(-/-)) mice. 11 beta-HSD-1(-/-) mice expressed lower resistin and tumor necrosis factor-alpha, but higher peroxisome proliferator-activated receptor-gamma, adiponectin, and uncoupling protein-2 mRNA levels in adipose, indicating insulin sensitization. Isolated 11 beta-HSD-1(-/-) adipocytes exhibited higher basal and insulin-stimulated glucose uptake. 11 beta-HSD-1(-/-) mice also exhibited reduced visceral fat accumulation upon high-fat feeding. High-fat-fed 11 beta-HSD-1(-/-) mice rederived onto the C57BL/6J strain resisted diabetes and weight gain despite consuming more calories. These data provide the first in vivo evidence that adipose 11 beta-HSD-1 deficiency beneficially alters adipose tissue distribution and function, complementing the reported effects of hepatic 11 beta-HSD-1 deficiency or inhibition.
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PMID:Novel adipose tissue-mediated resistance to diet-induced visceral obesity in 11 beta-hydroxysteroid dehydrogenase type 1-deficient mice. 1504 7

Glucocorticoids play an important role in the pathogenesis of obesity and insulin resistance. Impaired conversion of cortisone (E) to cortisol (F) by the type 1 isoenzyme of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) in obesity may represent a protective mechanism preventing ongoing weight gain and glucose intolerance. We have studied glucocorticoid metabolism in 33 male subjects with type 2 diabetes mellitus [age, 44.2 +/- 13 yr; body mass index (BMI), 31.1 +/- 7.5 kg/m(2) (mean +/- sd)] and 38 normal controls (age, 41.4 +/- 14 yr; BMI, 38.2 +/- 12.8 kg/m(2)). Circulating F:E ratios were elevated in the diabetic group and correlated with serum cholesterol and homeostasis model assessment-S. There was no difference in 11beta-HSD1 activity between diabetic subjects and controls. In addition, 11beta-HSD1 activity was unaffected by BMI in diabetic subjects. However, in control subjects, increasing BMI was associated with a reduction in the urinary tetrahydrocortisol+5alpha-tetrahydrocortisol:tetrahydrocortisone ratio (P < 0.05) indicative of impaired 11beta-HSD1 activity. The degree of inhibition correlated tightly with visceral fat mass. Changes in 11beta-HSD1 activity could not be explained by circulating levels of adipocytokines. Impaired E to F metabolism in obesity may help preserve insulin sensitivity and prevent diabetes mellitus. Failure to down-regulate 11beta-HSD1 activity in patients with diabetes may potentiate dyslipidemia, insulin resistance, and obesity. Inhibition of 11beta-HSD1 may therefore represent a therapeutic strategy in patients with type 2 diabetes mellitus and obesity.
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PMID:11beta-hydroxysteroid dehydrogenase type 1 activity in lean and obese males with type 2 diabetes mellitus. 1535 90


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