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Pathophysiology of Glucocorticoid Signaling.
Vitellius, G, Trabado, S, Bouligand, J, Delemer, B, Lombès, M
Annales d'endocrinologie. 2018;(3):98-106
Abstract
Glucocorticoids (GC), such as cortisol or dexamethasone, control various physiological functions, notably those involved in development, metabolism, inflammatory processes and stress, and exert most of their effects upon binding to the glucocorticoid receptor (GR, encoded by NR3C1 gene). GC signaling follows several consecutive steps leading to target gene transactivation, including ligand binding, nuclear translocation of ligand-activated GR complexes, DNA binding, coactivator interaction and recruitment of functional transcriptional machinery. Any step may be impaired and may account for altered GC signaling. Partial or generalized glucocorticoid resistance syndrome may result in a reduced level of functional GR, a decreased hormone affinity and binding, a defect in nuclear GR translocation, a decrease or lack of DNA binding and/or post-transcriptional GR modifications. To date, 26 loss-of-function NR3C1 mutations have been reported in the context of hypertension, hirsutism, adrenal hyperplasia or metabolic disorders. These clinical signs are generally associated with biological features including hypercortisolism without negative regulatory feedback loop on the hypothalamic-pituitary-adrenal axis. Patients had often low plasma aldosterone and renin levels despite hypertension. Only one GR gain-of-function mutation has been described associating Cushing's syndrome phenotype with normal urinary-free cortisol. Some GR polymorphisms (ER22/23EK, GR-9β) have been linked to glucocorticoid resistance and a healthier metabolic profile whereas some others seemed to be associated with GC hypersensitivity (N363S, BclI), increasing cardiovascular risk (diabetes type 2, visceral obesity). This review focuses on the earlier findings on the pathophysiology of GR signaling and presents criteria facilitating identification of novel NR3C1 mutations in selected patients.
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2.
Fructose, Glucocorticoids and Adipose Tissue: Implications for the Metabolic Syndrome.
Legeza, B, Marcolongo, P, Gamberucci, A, Varga, V, Bánhegyi, G, Benedetti, A, Odermatt, A
Nutrients. 2017;(5)
Abstract
The modern Western society lifestyle is characterized by a hyperenergetic, high sugar containing food intake. Sugar intake increased dramatically during the last few decades, due to the excessive consumption of high-sugar drinks and high-fructose corn syrup. Current evidence suggests that high fructose intake when combined with overeating and adiposity promotes adverse metabolic health effects including dyslipidemia, insulin resistance, type II diabetes, and inflammation. Similarly, elevated glucocorticoid levels, especially the enhanced generation of active glucocorticoids in the adipose tissue due to increased 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1) activity, have been associated with metabolic diseases. Moreover, recent evidence suggests that fructose stimulates the 11β-HSD1-mediated glucocorticoid activation by enhancing the availability of its cofactor NADPH. In adipocytes, fructose was found to stimulate 11β-HSD1 expression and activity, thereby promoting the adipogenic effects of glucocorticoids. This article aims to highlight the interconnections between overwhelmed fructose metabolism, intracellular glucocorticoid activation in adipose tissue, and their metabolic effects on the progression of the metabolic syndrome.
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3.
Efficacy of calcitriol in treating glucocorticoidinduced osteoporosis in patients with nephrotic syndrome: an open-label, randomized controlled study.
Chen, Y, Wan, JX, Jiang, DW, Fu, BB, Cui, J, Li, GF, Chen, CM
Clinical nephrology. 2015;(5):262-9
Abstract
OBJECTIVE To evaluate the efficacy and safety of calcitriol in the prevention and treatment of glucocorticoid-induced osteoporosis. METHODS 66 patients treated with glucocorticoids (GC) for primary nephrotic syndrome (NS) were randomly assigned to 3 groups. Groups were designated as follows: calcitriol alone (n = 22), calcitriol plus calcium carbonate (n = 23), or calcium carbonate alone (n = 21). Serum markers of bone metabolism and bone mineral density (BMD) were tested at 3 different time points: the initiation of GC treatment (baseline), 12 weeks, and 24 weeks after the initiation of treatment. RESULTS Levels of serum 25-hydroxy vitamin D, serum osteocalcin, and total serum collagen type N-terminal extension of the peptide were significantly decreased following GC therapy (p < 0.05). β-collagen serum-specific sequences were significantly increased following GC therapy. The above-mentioned changes were less dramatic in patients treated with calcitriol, although the differences were significant (p < 0.05). Changes in serum levels of calcium, phosphorus, alkaline phosphatase, and parathyroid hormone (PTH) were not significant. 24 weeks after the initiation of treatment, BMD of the lumbar spine and femoral bone significantly decreased in all of 3 groups. However, patients who received calcitriol had significantly higher BMD of the lumbar spine than patients who received calcium carbonate alone (calcitriol plus calcium carbonate vs. calcium carbonate alone: 0.82 ± 0.19 g/cm2 vs. 0.62 ± 0.23 g/cm2 p < 0.05; calcitriol vs. calcium carbonate alone 0.805 ± 0.203 g/cm2 vs. 0.615 ± 0.225 g/cm2 p < 0.05), respectively. No serious adverse events were observed. CONCLUSION Calcitriol may be more effective than calcium carbonate in preventing and treating GC-induced osteoporosis in patients with NS.
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4.
[New insights in steroid diabetes].
Kurir, TT, Bozić, J, Markotić, A, Novak, A
Acta medica Croatica : casopis Hravatske akademije medicinskih znanosti. 2012;(4):303-10
Abstract
Glucocorticoids (GC) are the cornerstone in the treatment of numerous chronic autoimmune and inflammatory diseases. GC treatment is accompanied by significant metabolic adverse effects, including insulin resistance, glucose intolerance and diabetes, visceral adiposity, dyslipidemia and skeletal muscle atrophy. GCs are the most common cause of drug-induced diabetes mellitus. However, not everyone treated with glucocorticoids develops diabetes. Predictors of development of diabetes are age, weight, family history of diabetes mellitus, or personal history of gestational diabetes. There is evidence that patients with decreased insulin secretory reserve are much more likely to develop diabetes. Diabetes from topical steroid use is uncommon, but high-dose steroids have been associated with significant hyperglycemia, including development of hyperglycemic hyperosmolar syndrome and even diabetic ketoacidosis in patients with type 1 diabetes mellitus. Several mechanisms contribute to the development of hyperglycemia and steroid-induced diabetes, including decreased peripheral insulin sensitivity, increased hepatic glucose production, and inhibition of pancreatic insulin production and secretion. Physicians treating patients with GCs should be aware of the induction of metabolic disturbances and should not solely rely on fasting measurements. In addition, our review indicates that insulin therapy could be considered when treating patients on GC therapy.
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5.
Effects of hyperlipidaemia on glucocorticoid metabolism: results of a randomized controlled trial in healthy young women.
Mai, K, Reinecke, F, Andres, J, Bobbert, T, Kraatz, J, Wudy, SA, Hartmann, MF, Maser-Gluth, C, Pfeiffer, AF, Spranger, J
Clinical endocrinology. 2011;(5):551-7
Abstract
OBJECTIVE It is well established that the hypothalamic-pituitary-adrenal (HPA) axis is altered in obese individuals. Hyperlipidaemia with elevated levels of free fatty acids (FFAs) is also frequently seen in obesity and in the metabolic syndrome. We hypothesized, therefore, that hyperlipidaemia may alter the activity of the HPA axis. PATIENTS AND METHODS The effects of hyperlipidaemia, including increased circulating FFAs, on ACTH secretion and cortisol metabolism were analysed in 13 healthy young women during the early follicular phase of two subsequent cycles. We administered a 20% lipid/heparin (LHI) or a saline/heparin infusion (SHI) using a crossover design in random order for 330 min. A detailed characterization of glucocorticoid metabolism was performed by measurement of plasma ACTH, cortisol and urinary excretion rates of adrenal glucocorticoids and the glucocorticoid metabolites. RESULTS We observed that LHI-induced hyperlipidaemia elevated serum cortisol levels compared to SHI. No changes in plasma ACTH levels, daily urinary excretion rates of adrenal glucocorticoids, glucocorticoid precursors/metabolites and the calculated activities of the 5α-reductase, 3β-hydroxysteroid dehydrogenase (HSD), 11-, 17-, 21-hydroxylase and 11β-HSD 1 or 2 were found. CONCLUSION Our randomized controlled trial suggests that the adrenal sensitivity to ACTH may be enhanced by LHI-induced hyperlipidaemia in normal-weight healthy young women. This effect might contribute to the disturbances of the HPA axis described in women with abdominal obesity and impaired lipid metabolism.
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6.
Glucocorticoids and the insulin resistance syndrome.
Siminialayi, IM, Emem-Chioma, PC
Nigerian journal of medicine : journal of the National Association of Resident Doctors of Nigeria. 2004;(4):330-5
Abstract
BACKGROUND Insulin regulates the uptake, utilization and storage of cellular nutrients. An attenuated responsiveness of tissues to insulin (insulin resistance), results in the metabolic or insulin resistance syndrome, polycystic ovary disease, lipodystrophic states and leprechaunism. Type 2 diabetes mellitus, a consequence of insulin resistance and a major component of the insulin resistance syndrome, currently affects 177 million people worldwide and is predicted to rise to over 300 million by 2025 (the majority of cases in Africa). METHODS We reviewed currently available literature on the role of glucocorticoids in the pathogenesis and clinical management of the insulin resistance syndrome. RESULTS The epidemiology of insulin resistance, the components of insulin resistance syndrome, factors responsible for insulin resistance, the role of glucocorticoids, and the treatment of gluocorticoid induced insulin resistance have been discussed. CONCLUSION Chronically elevated serum glucocorticoid levels contribute to diabetes and removal of glucocorticoid excess improves insulin sensitivity. Because insulin regulates 11beta-hydroxysteroid dehydrogenase enzyme type-1 (11betaHSD-1) activity, it has been suggested that dysregulation of (11betaHSD-1) may underlie the pathogenesis of glucocorticoid-dependent insulin-resistance. Indeed, 11beta-HSD1 has been proposed as a new target for type 2 diabetes drugs.