Syndromes of glucocorticoid and mineralocorticoid resistance

Zennaro, Maria-Christina

doi:10.1530/eje.0.1390127

Cited by 13 publications

(8 citation statements)

References 116 publications

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“…Previous studies have demonstrated that excess cortisol induces hepatic and extrahepatic insulin resistance (3,18,20,28,41,42,48). Metabolic effects may be induced by the normal circadian variation in cortisol secretion (10,11).…”

Section: Discussionmentioning

confidence: 99%

Impaired basal glucose effectiveness but unaltered fasting glucose release and gluconeogenesis during short-term hypercortisolemia in healthy subjects

Nielsen¹,

Caumo²,

Chandramouli³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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, September , 2011; 34 (9): 1959-1964 has been demonstrated to impair hepatic and extrahepatic insulin action. To determine whether glucose effectiveness and, in terms of endogenous glucose release (EGR), gluconeogenesis, also are altered by hypercortisolemia, eight healthy subjects were studied after overnight infusion with hydrocortisone or saline. Glucose effectiveness was assessed by a combined somatostatin and insulin infusion protocol to maintain insulin concentration at basal level in the presence of prandial glucose infusions. Despite elevated insulin concentrations (P Ͻ 0.05), hypercortisolemia resulted in higher glucose (P Ͻ 0.05) and free fatty acid concentrations (P Ͻ 0.05). Furthermore, basal insulin concentrations were higher during hydrocortisone than during saline infusion (P Ͻ 0.01), indicating the presence of steroidinduced insulin resistance. Postabsorptive glucose production (P ϭ 0.64) and the fractional contribution of gluconeogenesis to EGR (P ϭ 0.33) did not differ on the two study days. During the prandial glucose infusion, the integrated glycemic response above baseline was higher in the presence of hydrocortisone than during saline infusion (P Ͻ 0.05), implying a decrease in net glucose effectiveness (4.42 Ϯ 0.52 vs. 6.65 Ϯ 0.83 ml⅐kg Ϫ1 ⅐min Ϫ1 ; P Ͻ 0.05). To determine whether this defect is attributable to an impaired ability of glucose to suppress glucose production, to stimulate its own uptake, or both, glucose turnover and "hot" (labeled) indexes of glucose effectiveness (GE) were calculated. Hepatic GE was lower during cortisol than during saline infusion (2.39 Ϯ 0.24 vs. 3.82 Ϯ 0.51 ml⅐kg Ϫ1 ⅐min Ϫ1 ; P Ͻ 0.05), indicating a defect in the ability of glucose to restrain its own production. In addition, in the presence of excess cortisol, glucose disappearance was inappropriate for the prevailing glucose concentration, implying a decrease in glucose clearance (P Ͻ 0.05). The decrease in glucose clearance was confirmed by the higher increment in [3-3 H]glucose during hydrocortisone than during saline infusion (P Ͻ 0.05), despite the administration of identical tracer infusion rates. In conclusion, short-term hypercortisolemia in healthy individuals with normal ␤-cell function decreases insulin action but does not alter rates of EGR and gluconeogenesis. In addition, cortisol impairs the ability of glucose to suppress its own production, which due to accumulation of glucose in the glucose space results in impaired peripheral glucose clearance. These results suggest that cortisol excess

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Section: Discussionmentioning

confidence: 99%

Impaired basal glucose effectiveness but unaltered fasting glucose release and gluconeogenesis during short-term hypercortisolemia in healthy subjects

Nielsen¹,

Caumo²,

Chandramouli³

et al. 2004

American Journal of Physiology-Endocrinology and Metabolism

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“…While mineralocorticoids are major regulators of sodium homeostasis (Booth et al 2002), glucocorticoids are involved in lipid and carbohydrate metabolism, as well as in the modulation of immune and stress responses (Hasselgren 1999, Cavagnini et al 2000, Engelhardt 2000. Mineralocorticoid resistance, known as pseudohypoaldosteronism type 1, and generalized inherited glucocorticoid resistance lead to several consequences such as hyponatremia, hyperkalemia, and metabolic acidosis (Cheek & Perry, Malchoff et al 1990, Lamberts et al 1992, Zennaro 1998. Furthermore, the abnormal production of glucocorticoids or mineralocorticoids results in several disease states, such as Cushing's or Conn's syndrome, respectively (Grell et al 1984, Miyachi 2000, which are in particular characterized clinically by hypertension.…”

Section: Discussionmentioning

confidence: 99%

The transcriptional regulating protein of 132 kDa (TReP-132) differentially influences steroidogenic pathways in human adrenal NCI-H295 cells

Gizard

Teissier²,

Dufort³

et al. 2004

Journal of Molecular Endocrinology

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Steroid hormones synthesized from cholesterol in the adrenal gland are important regulators of many physiological processes. It is now well documented that the expression of many genes required for steroid biosynthesis is dependent on the coordinated expression of the nuclear receptor steroidogenic factor-1 (SF-1). However, transcriptional mechanisms underlying the species-specific, developmentally programmed and hormone-dependent modulation of the adrenal steroid pathways remain to be elucidated. Recently, we demonstrated that the transcriptional regulating protein of 132 kDa (TReP-132) acts as a coactivator of SF-1 to regulate human P450scc gene transcription in human adrenal NCI-H295 cells. The present study shows that overexpression of TReP-132 increases the level of active steroids produced in NCI-H295 cells. The conversion of pregnenolone to downstream steroids following TReP-132 expression showed increased levels of glucocorticoids, C 19 steroids and estrogens. Correlating with these data, TReP-132 increases P450c17 activities via the induction of transcript levels and promoter activity of the P450c17 gene, an effect that is enhanced in the presence of cAMP or SF-1. In addition, P450aro activity and mRNA levels are highly induced by TReP-132, whereas 3 -hydroxysteroid dehydrogenase type II and P450c11aldo transcript levels are only slightly modulated. Taken together, these results demonstrate that TReP-132 is a trans-acting factor of genes involved in adrenal glucocorticoid, C 19 steroid and estrogen production.

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“…The MR knockout mice, which presented with sodium and water wasting, hyperkaliemia and hyponatremia, died within the first week of life. This phenotype, closely resembling type I pseudohypoaldosteronism (18), can be rescued by intraperitoneal injections of sodium chloride solution (19). A strong activation of the renin-angiotensin-aldosterone axis was noted (20); however the reduction in sodium reabsorption capabilities was surprisingly not accompanied by a concomitant and coordinate decrease in ENaC expression.…”

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confidence: 99%

Alteration of Cardiac and Renal Functions in Transgenic Mice Overexpressing Human Mineralocorticoid Receptor

Menuet¹,

Isnard²,

Bichara³

et al. 2001

Journal of Biological Chemistry

109

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The mineralocorticoid receptor (MR), a ligand-dependent transcription factor, mediates aldosterone actions in a large variety of tissues. To explore the functional implication of MR in pathophysiology, transgenic mouse models were generated using the proximal human MR (hMR) promoter to drive expression of hMR in aldosterone target tissues. Tissue-specific analysis of transgene expression in two independent transgenic animal (TG) lines by ribonuclease protection assays revealed that hMR is expressed in all mineralocorticoid-sensitive tissues, most notably in the kidney and the heart. TG exhibit both renal and cardiac abnormalities. Enlarged kidneys were histologically associated with renal tubular dilation and cellular vacuolization whose prevalence increased with aging. Renal clearance studies also disclosed a significant decrease in urinary potassium excretion rate in TG. hMRexpressing animals had normal blood pressure but developed mild dilated cardiomyopathy (increased left ventricle diameters and decreased shortening fraction), which was accompanied by a significant increase in heart rate. Differential gene expression analysis revealed a 2-to 5-fold increase in cardiac expression of atrial natriuretic peptide, serum-and glucocorticoid-induced kinase, and early growth response gene 1 as detected by microarrays; renal serum-and glucocorticoid-induced kinase was also induced significantly. Altogether, TG exhibited specific alteration of renal and cardiac functions, thus providing useful pathophysiological models to gain new insights into the tissue-specific mineralocorticoid signaling pathways.

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Syndromes of glucocorticoid and mineralocorticoid resistance

Cited by 13 publications

References 116 publications

Impaired basal glucose effectiveness but unaltered fasting glucose release and gluconeogenesis during short-term hypercortisolemia in healthy subjects

Impaired basal glucose effectiveness but unaltered fasting glucose release and gluconeogenesis during short-term hypercortisolemia in healthy subjects

The transcriptional regulating protein of 132 kDa (TReP-132) differentially influences steroidogenic pathways in human adrenal NCI-H295 cells

Alteration of Cardiac and Renal Functions in Transgenic Mice Overexpressing Human Mineralocorticoid Receptor

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