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

---

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

Considerable evidence suggests that diabetes mellitus and hypertension are influenced by genetic factors. Studies in humans have associated glucocorticoid receptor (GR) polymorphisms with high blood pressure, insulin sensitivity, body mass index, increased visceral fat, and variations in tissue-specific steroid sensitivity. The N363S polymorphism of the GR results in an asparagine to serine amino acid substitution in a modulatory region of the receptor. Phosphorylation of serine residues in this region has been shown to enhance transactivation of GR responsive genes. The aim of this study was to investigate the association between the 363S allele and risk factors for coronary heart disease and diabetes mellitus in a population of European origin living in the northeast of the United KINGDOM: Blood samples from 135 males and 240 females were characterized for 363 allele status. The overall frequency of the 363S allele was 3.0%, 23 heterozygotes (7 males and 16 females) but no 363S homozygotes were identified. The data show a significant association of the 363S allele with increased waist to hip ratio in males but not females. This allele was not associated with blood pressure, body mass index, serum cholesterol, triglycerides, low-density lipoprotein and high-density lipoprotein cholesterol levels, and glucose tolerance status. The results of this study suggest that this GR polymorphism may contribute to central obesity in men. Further studies are required to elucidate the properties of GR(363S) at a molecular level.
...
PMID:The N363S polymorphism of the glucocorticoid receptor: potential contribution to central obesity in men and lack of association with other risk factors for coronary heart disease and diabetes mellitus. 1134 38

Blood glucose levels are maintained by the balance between glucose uptake by peripheral tissues and glucose secretion by the liver. Gluconeogenesis is strongly stimulated during fasting and is aberrantly activated in diabetes mellitus. Here we show that the transcriptional coactivator PGC-1 is strongly induced in liver in fasting mice and in three mouse models of insulin action deficiency: streptozotocin-induced diabetes, ob/ob genotype and liver insulin-receptor knockout. PGC-1 is induced synergistically in primary liver cultures by cyclic AMP and glucocorticoids. Adenoviral-mediated expression of PGC-1 in hepatocytes in culture or in vivo strongly activates an entire programme of key gluconeogenic enzymes, including phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, leading to increased glucose output. Full transcriptional activation of the PEPCK promoter requires coactivation of the glucocorticoid receptor and the liver-enriched transcription factor HNF-4alpha (hepatic nuclear factor-4alpha) by PGC-1. These results implicate PGC-1 as a key modulator of hepatic gluconeogenesis and as a central target of the insulin-cAMP axis in liver.
...
PMID:Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1. 1155 65

Insulin resistance is a condition of central importance in a cluster of clinical disorders including diabetes mellitus, hypertension, dyslipidemia, central obesity and coronary heart disease. Despite its association with numerous health problems, the mechanism responsible for the development of this phenomenon remains to be established. A novel theory has proposed that insulin resistance in diabetes stems, at least in part, from enhanced free fatty acid (FFA) oxidation and/or excessive production of glucocorticoids (GCs). Several key predictions of this premise were subjected to experimental testing using streptozotocin (STZ)-treated rats as a model for insulin-dependent diabetes mellitus and euglycemic-hyperinsulinemic clamp technique for the in vivo measurement of insulin actions. Euglycemic clamp studies with an insulin infusion index of 5 mU/kg/min were used to measure endogenous glucose production (EGP), glucose infusion rate (GIR), glucose disposal rate (GDR) and skeletal muscle glucose utilization index (GUI). Post-absorptive basal EGP and plasma levels of glucose and free fatty acids (FFA) were elevated in the STZ diabetic rats compared to their corresponding control values. In contrast, hypoinsulinemia was evident in these animals. Steady-state GIR and GDR during euglycemic-hyperinsulinemic clamp were markedly decreased in the STZ diabetic rats. Similarly, insulin-mediated suppression of EGP and plasma FFA concentration was also impaired in these animals. GUI, a measure of 2-deoxyglucose (2-DG) uptake, was increased in response to insulin in the order of white gastrocnemus (WG), red gastrocnemus (RG), extensor digitorum longus and soleus muscles. This parallels the percentage of red fibers in these muscles. Diabetes interferes with insulin's ability to increase 2-DG uptake in all of the above muscles with the exception of WG. Nullification of the associated hyperlipidemic and hypercortisolemic states of diabetes with etomoxir (hyperlipidemic) and the glucocorticoid receptor blocker RU-486 (hypercortisolemic) ameliorated the diabetes-related impairment of the in vivo insulin action. Overall these results together with those garnered from the literature support the notion that hypercortisolemia and the enhancement of FFA oxidation are involved, at least in part, in the development of hepatic and skeletal muscle insulin resistance in poorly controlled type I diabetes.
...
PMID:Co-administration of etomoxir and RU-486 mitigates insulin resistance in hepatic and muscular tissues of STZ-induced diabetic rats. 1160 76

To test the hypothesis that changes in the expression of the glucocorticoid receptor (GCR) and the beta(2)-adrenoceptor (beta(2)-AR) contribute significantly to the abnormal glucose metabolism in skeletal muscle from patients with Type II diabetes, we have examined (1) the levels of total GCR (alpha+beta isoforms), the alpha/alpha 2 isoform of GCR and beta(2)-AR mRNAs in skeletal muscle from insulin-resistant patients with Type II diabetes (n=10) and healthy controls (n=15), and (2) the effects of 8 weeks of intensive treatment on the whole-body glucose disposal rate and on total GCR, alpha/alpha 2 GCR and beta(2)-AR mRNA levels in diabetic patients. The total glucose disposal rate was measured by the euglycaemic hyperinsulinaemic (2 m-units x min(-1) x kg(-1)) clamp technique, and mRNA levels were assessed by reverse transcriptase-PCR and HPLC for separation of standard and unknown and quantification. Mean levels of total GCR and alpha/alpha 2 GCR mRNAs were increased in patients with Type II diabetes when compared with control subjects [total GCR, 2.06+/-0.30 and 1.47+/-0.10 amol/microg of total RNA respectively (P=0.09); alpha/alpha 2 GCR mRNA, 1.69+/-0.31 and 0.92+/-0.09 amol/microg of total RNA respectively (P=0.02)], whereas mRNA levels of the beta isoform of GCR (total GCR minus alpha/alpha 2 GCR) were decreased (P=0.006). beta(2)-AR mRNA levels were comparable in diabetic patients and control subjects (0.53+/-0.05 and 0.45+/-0.02 amol/microg of total RNA respectively; P=0.2). Intensive treatment for 8 weeks was associated with improved glycaemic control (P=0.019), and during the clamp a 75% (P=0.001) increase in the whole-body insulin-stimulated glucose disposal rate was demonstrated. Total GCR (P=0.005), alpha/alpha 2 GCR (P=0.005) and beta(2)-AR (P=0.03) mRNA levels all decreased significantly after intensive insulin treatment. A close correlation was found between increments in glucose uptake during intensive treatment and decrements in skeletal muscle total GCR mRNA (r=0.95, P<0.001; multiple regression analysis), and between glucose uptake and alpha/alpha 2 GCR m RNA levels (r=0.88, P<0.001; simple correlation). In conclusion, the abnormal regulation of GCR mRNA is likely to play a significant role in the insulin resistance observed in obese patients with Type II diabetes.
...
PMID:Increments in insulin sensitivity during intensive treatment are closely correlated with decrements in glucocorticoid receptor mRNA in skeletal muscle from patients with Type II diabetes. 1167 59

Altered glucocorticoid hormone action may contribute to the etiology of the metabolic syndrome, but the molecular mechanisms are poorly defined. Tissue sensitivity to glucocorticoid is regulated by expression of the glucocorticoid receptor (GR)-alpha and 11beta-hydroxysteroid dehydrogenase type I (11beta-HSD1)-mediated intracellular synthesis of active cortisol from inactive cortisone. We have analyzed GRalpha and 11beta-HSD1 expression in skeletal myoblasts from men (n = 14) with contrasting levels of insulin sensitivity (euglycemic clamp measurements of insulin-dependent glucose disposal rate), blood pressure, and adiposity. Positive associations were evident between myoblast expression of GRalpha under basal conditions and levels of insulin resistance (r(2) = 0.34, P < 0.05), BMI (r(2) = 0.49, P < 0.01), percent body fat (r(2) = 0.34, P < 0.02), and blood pressure (r(2) = 0.86, P < 0.001). Similar associations were evident when myoblasts were incubated with physiological levels of cortisol (P < 0.01 for all). Importantly, GRalpha expression was unaffected by variations in in vivo concentrations of insulin, IGF-1, or glucose concentrations. In common with the GR, 11beta-HSD1 expression in myoblasts incubated with physiological concentrations of cortisol in vitro was positively associated with levels of insulin resistance (r(2) = 0.68, P < 0.001), BMI (r(2) = 0.63, P < 0.005), and blood pressure (r(2) = 0.27, P < 0.05). Regulation of GRalpha and 11beta-HSD1 by cortisol was abolished by the GR antagonist RU38486. In summary, our data suggest that raised skeletal muscle cell expression of GRalpha and 11beta -HSD1-mediated regulation of intracellular cortisol may play a fundamental role in mechanisms contributing to the pathogenesis of the metabolic syndrome.
Diabetes 2002 Apr
PMID:Increased glucocorticoid receptor expression in human skeletal muscle cells may contribute to the pathogenesis of the metabolic syndrome. 1191 27

We recently established that in addition to plasma adrenocorticotrophic hormone (ACTH) and corticosterone, hypothalamic corticotrophin-releasing hormone (CRH) mRNA and hippocampal type 1 glucocorticoid receptor (GR1) mRNA were also upregulated in uncontrolled streptozotocin-induced diabetes. In the current study, control, diabetic, and insulin-treated diabetic rats underwent a hyperinsulinemic-hypoglycemic glucose clamp to evaluate central mechanisms of hypothalamo-pituitary-adrenal (HPA) and counterregulatory responses to insulin-induced hypoglycemia. Increases in plasma ACTH, corticosterone, and epinephrine were significantly lower in diabetic rats versus controls. Insulin treatment restored ACTH and corticosterone but not epinephrine responses to hypoglycemia in diabetic rats. Glucagon and norepinephrine responses to hypoglycemia were not affected by diabetes or insulin treatment. In response to hypoglycemia, hypothalamic CRH mRNA and pituitary proopiomelanocortin mRNA expression increased in control and insulin-treated but not in untreated diabetic rats. Arginine vasopressin mRNA was unaltered by hypoglycemia in all groups. Interestingly, hypoglycemia decreased hippocampal GR1 mRNA expression in control and insulin-treated diabetic rats but not in diabetic rats. In contrast, type 2 glucocortoid receptor (GR2) mRNA was not altered by hypoglycemia. In conclusion, despite increased basal HPA activity, HPA responses to hypoglycemia were markedly reduced in uncontrolled diabetes. We speculate that the defect in CRH response could be related to the defective GR1 response. It is intriguing that insulin treatment restored the HPA response to hypoglycemia but, surprisingly, not the deficient epinephrine response. This is important because during severe hypoglycemia, epinephrine is an important counterregulatory hormone.
Diabetes 2002 Jun
PMID:Diabetes impairs hypothalamo-pituitary-adrenal (HPA) responses to hypoglycemia, and insulin treatment normalizes HPA but not epinephrine responses. 1203 53

Glucocorticoids play a crucial role in the regulation of carbohydrate metabolism and in the immune response, and can influence the development of diabetes in certain animal models including autoimmune type 1 diabetes in the non-obese diabetic (NOD) mouse. In these animals, the onset of destructive autoimmune pancreatic changes (insulitis) occurs at around 3 weeks of age. Moreover, the incidence of diabetes is significantly higher in females compared to males. However, the underlying mechanisms for this sex-specificity are unknown. Therefore, the present study was undertaken to examine the expression of the glucocorticoid receptor (GR) in pancreatic islets of Langerhans of the NOD mouse during the first 3 weeks of postnatal development. Immunohistochemistry was used to determine pancreatic GR expression and to identify insulin-secreting beta cells in postnatal (1-, 2-, and 3-week-old) NOD mice. Age-matched NOD.SCID mice (immunodeficient animals with the same NOD genetic background) were used as control animals. In both strains, regardless of sex or age, GR staining was found predominantly in the cytoplasm of beta cells but was also present in other cell types within the islets. At all ages, the percentage of islet cells containing GR was similar between male and female animals of the same strain. In control mice, the percentage of islet cells containing GR increased progressively from 80% at 1 week of age to 100% at 3 weeks of age. In marked contrast, in the NOD mice, the proportion of islets containing GR decreased from 95% at week 1 to only 60% at 3 weeks of age. We conclude that sex-specific differences in the incidence of diabetes are not associated with altered pancreatic GR expression in NOD mice during early postnatal development. However, the distinct and remarkable decrease in islet GR levels at 3 weeks of age may contribute to the onset of insulitis, and potentially to the ontology of diabetes in NOD mice, as a result of the loss of protective immunosuppressive effects of glucocorticoids.
...
PMID:Glucocorticoid receptor expression is altered in pancreatic beta cells of the non-obese diabetic mouse during postnatal development. 1203 32

Epidemiological studies have led to the hypothesis that a major component of the risk of diseases such as hypertension, coronary heart disease and non-insulin-dependent diabetes (the 'metabolic syndrome') is established before birth. Although the underlying mechanisms of this 'programming' of disease have not yet been conclusively determined, a reduced fetal nutrient supply as a consequence of poor placental function or unbalanced maternal nutrition is strongly implicated. It has been proposed that one outcome of suboptimal nutrition is exposure of the fetus to excess glucocorticoids, which restrict fetal growth and programme permanent alterations in its cardiovascular, endocrine and metabolic systems. This review focuses on the effects of endogenous and exogenous glucocorticoid exposure in utero on postnatal hypothalamo-pituitary-adrenal (HPA) axis activity, both in humans and experimental animals. The physiological consequences and proposed underlying molecular and cellular mechanisms are discussed. Current data indicate that key targets for programming may include not only the HPA axis but also glucocorticoid receptor gene and 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) gene expression in a range of tissues.
...
PMID:Prenatal programming of postnatal endocrine responses by glucocorticoids. 1236 63

Cushing's syndrome results from prolonged exposure to excessive circulating glucocorticosteroids, and is associated with significant morbidity and mortality. While the treatment of choice in most patients is surgical, the metabolic consequences of the syndrome, including increased tissue fragility, poor wound healing, hypertension, and diabetes mellitus, increase the risks of such surgery. The hypercortisolemia and its sequelae can be efficiently reversed using medical therapy, either as a temporary measure prior to definitive treatment, or longer term in more difficult cases. Drug treatment has been targeted at the hypothalamic/pituitary level, the adrenal glands, and also at the glucocorticoid receptor level. In this review we discuss the pharmacotherapeutic agents that have been used in Cushing's syndrome, and their efficacy, the monitoring of treatment, and potential therapies that may prove useful in the future in this complex endocrinological disorder.
...
PMID:The medical management of Cushing's syndrome. 1238 47

The metabolic syndrome X and Cushing's syndrome show similar symptoms but one major difference: Plasma cortisol is not elevated in the metabolic syndrome. Evidence is presented, that by the action of 11 beta-hydroxysteroid dehydrogenase 1 (11 beta HSD1) higher intracellular cortisol concentration may be created that may be relevant to induce insulin resistance and metabolic disturbances. Regulation of 11 beta HSD1 expression by hormones, growth factors, cytokines and transcription factors enables tissue specific adjustments of glucocorticoid receptor activation by cortisol. Specific inhibition of 11 beta HSD1 would help to understand aspects of the pathogenesis of syndrome X and to develop new therapeutic perspectives.
Exp Clin Endocrinol Diabetes 2002 Oct
PMID:The metabolic syndrome X and peripheral cortisol synthesis. 1239 28


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

---