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    • br Glucocorticoid receptor and metabolic syndrome GCs acting

    2022-04-14


    Glucocorticoid receptor and metabolic syndrome GCs acting through the GR regulate key enzymes of glucose metabolism in the liver, skeletal muscle, adipose tissue and the pancreas. In the liver, GCs regulate the expression of major gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase, glucose-6-phosphatase and tyrosine aminotransferase. In skeletal muscle, GCs play a major role in peripheral glucose utilization by interfering with translocation of glucose transporter type 4. In the pancreas, GCs provoke hyperglycemia by inhibiting glucose-stimulated insulin secretion from β-cells. Metabolic syndrome, an important risk factor for coronary artery disease, is a compilation of multiple metabolic abnormalities such as insulin resistance, hyperglycemia, dyslipidemia, obesity, and hypertension. The resemblance of the symptoms and biochemical findings between Cushing’s syndrome and metabolic syndrome suggest that CEP-18770 plays a central role in the pathogenesis and the evolution of both of these medical conditions. The vast majority of obese subjects have cortisol levels currently considered to be in the normal range, indicating that cortisol might exert a portion of its deleterious effects at the tissue level because of abnormalities of the GR and the intracellular cortisol metabolism. Therefore, mutations of the GR gene, interfering with the sensitivity of the GR to cortisol may be responsible for its varying effects in different individuals. For example, patients can develop the phenotype typically seen in Cushing’s syndrome despite normal or even low serum cortisol levels. This has been described in the literature as “cortisol hyper-reactive syndrome”, “glucocorticoid hypersensitivity syndrome”, and “normocortisolemic Cushing’s syndrome.” [18] Cortisol hypersensitivity was confirmed by Iida et al. when they conducted an ex vivo study of the peripheral tissues from a patient with the manifestations of Cushing’s syndrome who had extremely low cortisol levels [19]. Patients carrying polymorphisms associated with decreased receptor sensitivity to cortisol, as described later in the manuscript, have increased insulin sensitivity, lower BMI, waist circumference and LDL. Although, those polymorphisms are associated with a favorable metabolic profile, an increased incidence of autoimmune disorders is anticipated. However, studies failed to demonstrate an association with autoimmune disorders but found an increased rates of nasal Staph. Aureus [20]. Only the 9β polymorphism of the GR gene was found to have a positive association with autoimmune disorders but, despite the favorable effects of that variant on cardiometabolic parameters, carriers were found to have increased intima-media thickness and a three-fold increased rate of cardiovascular disease most likely due to a chronic pro-inflammatory state seen in those subjects as supported by the elevated levels of IL-6 and hsCRP. An association between GR gene mutations and the manifestations of metabolic syndrome was first reported in 1992 by Weaver et al. who demonstrated that homozygous carriers of the BclI variant of GR had elevated fasting insulin and HOMA insulin resistance index [21]. Another study also found a statistically significant increase in body weight, BMI, abdominal obesity, fasting plasma glucose, insulin, and HOMA among homozygous carriers of the BclI variant [22]. GR BclI polymorphism was found in a familial linkage study of obese (BMI>27kg/m2) sibling pairs and some variants were associated with higher abdominal visceral adiposity [23]. In a study of middle-aged men, the 4.5-kb BclI allele was associated with elevated waist to hip ratio, BMI and abdominal sagittal diameter [24]. However, this polymorphism did not demonstrate an association with either BMI or percent body fat in younger men (age 18–40 years old) [25]. A study of identical twins showed that the 2.3-kb homozygotes exhibit the greatest increase in body weight, abdominal adiposity and plasma cholesterol in response to overfeeding [26]. In a prospective study with a prolonged follow-up period, women with the GR BclI polymorphism showed a substantial increase in body weight, subcutaneous adiposity, and total body fat mass [27].