BclI glucocorticoid receptor polymorphism in relation to cardiovascular variables: the Hoorn and CODAM studies

Moorsel, Dirk van; Greevenbroek, Marleen M.J. van; Schaper, Nicolaas C.; Henry, Ronald M.A.; Geelen, C.C.; Rossum, Elisabeth F.C. van; Nijpels, Giel; Hart, Leen M ’t; Schalkwijk, Casper G.; Kallen, Carla; Sauerwein, Hans P.; Dekker, Joost; Stehouwer, Coen D. A.; Havekes, Bas

doi:10.1530/eje-15-0381

Cited by 15 publications

(7 citation statements)

References 45 publications

(68 reference statements)

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“…The Bcl I polymorphism (rs41423247), located in Intron 2, influences GR expression and modulates the GR transcriptional activity of genes responsible for glucose and insulin homeostasis 70 . Homozygous carriers of the Bcl I polymorphism have, compared with noncarriers, more total body fat and insulin resistance, as well as higher blood pressure 71–73 . Carriers of both the Bcl I and N363S polymorphisms had higher blood pressure and higher LDL cholesterol compared with carriers of the N363S polymorphism alone 64 …”

Section: Genetic Mutations and Polymorphisms In Association With Gc Sensitivitymentioning

confidence: 99%

Variation in glucocorticoid sensitivity and the relation with obesity

et al. 2021

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Summary Increasing evidence points to a relation between increased glucocorticoid (GC) exposure and weight gain. In support, long‐term cortisol measurements using hair analysis revealed that many individuals with obesity appear to have cortisol values in the high physiological range. The mechanisms behind this relationship need to be determined in order to develop targeted therapy to reach sustainable weight loss in these subgroups. The effect of GCs is not only determined by the plasma concentration of GCs but also by individual differences in GC sensitivity and the target tissue, which can be analyzed by functional GC assays. GC sensitivity is influenced by multiple genetic and acquired (e.g., disease‐related) factors, including intracellular GC availability, hormone binding affinity, and expression levels of the GC receptors and their isoforms, as well as factors involved in the modulation of gene transcription. Interindividual differences in GC sensitivity also play a role in the response to exogenous GCs, with respect to both therapeutic and adverse effects. Accordingly, in this review, we summarize current knowledge on mechanisms that influence GC sensitivity and their relationships with obesity and discuss personalized treatment options targeting the GC receptor.

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Section: Genetic Mutations and Polymorphisms In Association With Gc Sensitivitymentioning

confidence: 99%

Variation in glucocorticoid sensitivity and the relation with obesity

et al. 2021

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“…In addition to the N363S polymorphism, the BclI polymorphism of the NR3C1 gene has also been associated with increased glucocorticoid sensitivity [43]. Subjects with this polymorphism are obese and more susceptible to chronic diseases, such as hypertension, bronchial asthma, and mood disorders [44,45]. Furthermore, one point mutation in the NR3C1 gene has been associated with primary generalized glucocorticoid hypersensitivity.…”

Section: Discussionmentioning

confidence: 99%

Untargeted Plasma Metabolomics Unravels a Metabolic Signature for Tissue Sensitivity to Glucocorticoids in Healthy Subjects: Its Implications in Dietary Planning for a Healthy Lifestyle

et al. 2021

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In clinical practice, differences in glucocorticoid sensitivity among healthy subjects may influence the outcome and any adverse effects of glucocorticoid therapy. Thus, a fast and accurate methodology that could enable the classification of individuals based on their tissue glucocorticoid sensitivity would be of value. We investigated the usefulness of untargeted plasma metabolomics in identifying a panel of metabolites to distinguish glucocorticoid-resistant from glucocorticoid-sensitive healthy subjects who do not carry mutations in the human glucocorticoid receptor (NR3C1) gene. Applying a published methodology designed for the study of glucocorticoid sensitivity in healthy adults, 101 healthy subjects were ranked according to their tissue glucocorticoid sensitivity based on 8:00 a.m. serum cortisol concentrations following a very low-dose dexamethasone suppression test. Ten percent of the cohort, i.e., 11 participants, on each side of the ranking, with no NR3C1 mutations or polymorphisms, were selected, respectively, as the most glucocorticoid-sensitive and most glucocorticoid-resistant of the cohort to be analyzed and compared with untargeted blood plasma metabolomics using gas chromatography–mass spectrometry (GC–MS). The acquired metabolic profiles were evaluated using multivariate statistical analysis methods. Nineteen metabolites were identified with significantly lower abundance in the most sensitive compared to the most resistant group of the cohort, including fatty acids, sugar alcohols, and serine/threonine metabolism intermediates. These results, combined with a higher glucose, sorbitol, and lactate abundance, suggest a higher Cori cycle, polyol pathway, and inter-tissue one-carbon metabolism rate and a lower fat mobilization rate at the fasting state in the most sensitive compared to the most resistant group. In fact, this was the first study correlating tissue glucocorticoid sensitivity with serine/threonine metabolism. Overall, the observed metabolic signature in this cohort implies a worse cardiometabolic profile in the most glucocorticoid-sensitive compared to the most glucocorticoid-resistant healthy subjects. These findings offer a metabolic signature that distinguishes most glucocorticoid-sensitive from most glucocorticoid-resistant healthy subjects to be further validated in larger cohorts. Moreover, they support the correlation of tissue glucocorticoid sensitivity with insulin resistance and metabolic syndrome-associated pathways, further emphasizing the need for nutritionists and doctors to consider the tissue glucocorticoid sensitivity in dietary and exercise planning, particularly when these subjects are to be treated with glucocorticoids.

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“…Patients with Addison’s disease carrying the polymorphic BclI allele in a homozygous variant had a higher prevalence of central adiposity, impaired glucose tolerance, diabetes mellitus and dyslipidemia [ 149 ]. Studies have also shown greater susceptibility to cardiovascular disease in men with the BclI haplotype [ 150 , 151 ].…”

Section: Glucocorticoid Receptor Polymorphisms In Type 2 Diabetes Mellitusmentioning

confidence: 99%

Glucocorticoid Receptor Signaling in Diabetes

Kokkinopoulou

Diakoumi

Moutsatsou

2021

IJMS

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Stress and depression increase the risk of Type 2 Diabetes (T2D) development. Evidence demonstrates that the Glucocorticoid (GC) negative feedback is impaired (GC resistance) in T2D patients resulting in Hypothalamic-Pituitary-Adrenal (HPA) axis hyperactivity and hypercortisolism. High GCs, in turn, activate multiple aspects of glucose homeostasis in peripheral tissues leading to hyperglycemia. Elucidation of the underlying molecular mechanisms revealed that Glucocorticoid Receptor (GR) mediates the GC-induced dysregulation of glucose production, uptake and insulin signaling in GC-sensitive peripheral tissues, such as liver, skeletal muscle, adipose tissue, and pancreas. In contrast to increased GR peripheral sensitivity, an impaired GR signaling in Peripheral Blood Mononuclear Cells (PBMCs) of T2D patients, associated with hyperglycemia, hyperlipidemia, and increased inflammation, has been shown. Given that GR changes in immune cells parallel those in brain, the above data implicate that a reduced brain GR function may be the biological link among stress, HPA hyperactivity, hypercortisolism and hyperglycemia. GR polymorphisms have also been associated with metabolic disturbances in T2D while dysregulation of micro-RNAs—known to target GR mRNA—has been described. Collectively, GR has a crucial role in T2D, acting in a cell-type and context-specific manner, leading to either GC sensitivity or GC resistance. Selective modulation of GR signaling in T2D therapy warrants further investigation.

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BclI glucocorticoid receptor polymorphism in relation to cardiovascular variables: the Hoorn and CODAM studies

Cited by 15 publications

References 45 publications

Variation in glucocorticoid sensitivity and the relation with obesity

Variation in glucocorticoid sensitivity and the relation with obesity

Untargeted Plasma Metabolomics Unravels a Metabolic Signature for Tissue Sensitivity to Glucocorticoids in Healthy Subjects: Its Implications in Dietary Planning for a Healthy Lifestyle

Glucocorticoid Receptor Signaling in Diabetes

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