Improvement in insulin sensitivity during mifepristone treatment of Cushing syndrome: early and late effects.
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ABSTRACT:
SUBMITTER: Wallia A
PROVIDER: S-EPMC3747910 | biostudies-literature | 2013 Sep
REPOSITORIES: biostudies-literature
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Improvement in insulin sensitivity during mifepristone treatment of Cushing syndrome: early and late effects.
Wallia Amisha A Colleran Kathleen K Purnell Jonathan Q JQ Gross Coleman C Molitch Mark E ME
Diabetes care 20130901 9
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Project description:BackgroundIncreased tissue cortisol availability has been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes (T2DM). Our objective was to evaluate whether blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance (IR) in overweight/obese subjects with glucose intolerance.MethodsWe conducted a randomized, double-blinded, placebo-controlled, crossover study in overweight/obese individuals (n = 16, 44% female) with prediabetes or mild T2DM but not clinical hypercortisolism. Mifepristone (50 mg every 6 h) or placebo was administered for 9 days, followed by crossover to the other treatment arm after a washout period of 6 to 8weeks. At baseline and following each treatment, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Insulin sensitivity was measured using FSIVGTT [primary outcome: insulin sensitivity index (SI)] and OGTT [Matsuda index (MI) and oral glucose insulin sensitivity index (OGIS)]. Hepatic and adipose insulin resistance were assessed using hepatic insulin resistance index (HIRI), and adipose tissue insulin sensitivity index (Adipo-SI) and adipo-IR, derived from the FSIVGTT.ResultsMifepristone administration did not alter whole-body glucose disposal indices of insulin sensitivity (SI, MI, and OGIS). GR blockade significantly improved Adipo-SI (61.7 ± 32.9 vs 42.8 ± 23.9; P = 0.002) and reduced adipo-IR (49.9 ± 45.9 vs 65.5 ± 43.8; P = 0.004), and HIRI (50.2 ± 38.7 vs 70.0 ± 44.3; P = 0.08). Mifepristone increased insulin clearance but did not affect insulin secretion or β-cell glucose sensitivity.ConclusionShort-term mifepristone administration improves adipose and hepatic insulin sensitivity among obese individuals with hyperglycemia without hypercortisolism.
| S-EPMC8063260 | biostudies-literature
Project description:PurposeLiterature regarding endogenous Cushing syndrome (CS) largely focuses on the challenges of diagnosis, subtyping, and treatment. The enigmatic phenomenon of glucocorticoid withdrawal syndrome (GWS), due to rapid reduction in cortisol exposure following treatment of CS, is less commonly discussed but also difficult to manage. We highlight the clinical approach to navigating patients from GWS and adrenal insufficiency to full hypothalamic-pituitary-adrenal (HPA) axis recovery.MethodsWe review the literature on the pathogenesis of GWS and its clinical presentation. We provide strategies for glucocorticoid dosing and tapering, HPA axis testing, as well as pharmacotherapy and ancillary treatments for GWS symptom management.ResultsGWS can be difficult to differentiate from adrenal insufficiency and CS recurrence, which complicates glucocorticoid dosing and tapering regimens. Monitoring for HPA axis recovery requires both clinical and biochemical assessments. The most important intervention is reassurance to patients that GWS symptoms portend a favorable prognosis of sustained remission from CS, and GWS typically resolves as the HPA axis recovers. GWS also occurs during medical management of CS, and gradual dose titration based primarily on symptoms is essential to maintain adherence and to eventually achieve disease control. Myopathy and neurocognitive dysfunction can be chronic complications of CS that do not completely recover.ConclusionsDue to limited data, no guidelines have been developed for management of GWS. Nevertheless, this article provides overarching themes derived from published literature plus expert opinion and experience. Future studies are needed to better understand the pathophysiology of GWS to guide more targeted and optimal treatments.
| S-EPMC9170649 | biostudies-literature
Project description:A growing body of research indicates that cortisol, the glucocorticoid product of the activation of the hypothalamic-pituitary-adrenal axis, plays a role in the pathophysiology of metabolic syndrome. In this regard, chronic exposure to cortisol is associated with risk factors related to metabolic syndrome like weight gain, type 2 diabetes, hypertension, among others. Mifepristone is the only FDA-approved drug with antiglucocorticoids properties for improved the glycemic control in patients with type 2 patients secondary to endogenous Cushing's syndrome. Mifepristone also have been shown positive effects in rodents models of diabetes and patients with obesity due to antipsychotic treatment. However, the underlying molecular mechanisms are not fully understood. In this perspective, we summarized the literature regarding the beneficial effects of mifepristone in metabolic syndrome from animal studies to clinical research. Also, we propose a potential mechanism for the beneficial effects in insulin sensitivity which involved the regulation of mitochondrial function in muscle cells.
| S-EPMC7193078 | biostudies-literature
Project description:Late chronotype (LC) correlates with reduced metabolic insulin sensitivity and cardiovascular disease. It is unclear if insulin action on aortic waveforms and inflammation is altered in LC versus early chronotype (EC). Adults with metabolic syndrome (n = 39, MetS) were classified as either EC (Morning-Eveningness Questionnaire [MEQ] = 63.5 ± 1.2) or LC (MEQ = 45.5 ± 1.3). A 120 min euglycemic clamp (40 mU/m2 /min, 90 mg/dL) with indirect calorimetry was used to determine metabolic insulin sensitivity (glucose infusion rate [GIR]) and nonoxidative glucose disposal (NOGD). Aortic waveforms via applanation tonometry and inflammation by blood biochemistries were assessed at 0 and 120 min of the clamp. LC had higher fat-free mass and lower VO2 max, GIR, and NOGD (between groups, all p ≤ 0.05) than EC. Despite no difference in 0 min waveforms, both groups had insulin-stimulated elevations in pulse pressure amplification with reduced AIx75 and augmentation pressure (AP; time effect, p ≤ 0.05). However, EC had decreased forward pressure (Pf; interaction effect, p = 0.007) with insulin versus rises in LC. Although LC had higher tumor necrosis factor-α (TNF-α; group effect, p ≤ 0.01) than EC, both LC and EC had insulin-stimulated increases in TNF-α and decreases in hs-CRP (time effect, both p ≤ 0.01). Higher MEQ scores related to greater insulin-stimulated reductions in AP (r = -0.42, p = 0.016) and Pf (r = -0.41, p = 0.02). VO2 max correlated with insulin-mediated reductions in AIx75 (r = -0.56, p < 0.01) and AP (r = -0.49, p < 0.01). NOGD related to decreased AP (r = -0.44, p = 0.03) and Pf (r = -0.43, p = 0.04) during insulin infusion. LC was depicted by blunted forward pressure waveform responses to insulin and higher TNF-α in MetS. More work is needed to assess endothelial function across chronotypes.
| S-EPMC9612142 | biostudies-literature
Project description:The purpose of this study was to conduct a randomized-controlled trial to evaluate the effect of a high-protein (HP) diet weight loss (WL) on changes in body composition, insulin sensitivity and skeletal muscle gene expression profile in postmenopausal women who were obese and randomized to one of three dietary intervention groups: 1) a weight maitenance group, 2) a weight loss group (normal protein intake, 0.8 g protein/kg body weight per day) and 3) a weight loss group (high protein intake, 1.2 g protein/kg body weight per day) and studies before and after they lost 10% of their body weight (WL groups) or a time-matched weight maintenacne period.
2016-12-01 | GSE73525 | GEO
Project description:The steroid receptor antagonist mifepristone is used as an anti-cancer agent, eliciting both cytostatic and cytotoxic effects on malignant cells. However, the metabolic effects of long-term treatment with mifepristone have remained unclear. The effects of mifepristone on insulin sensitivity and adiponectin secretion were evaluated both in in vivo and in vitro. First, we explored the effects of mifepristone, on metabolic functions in obese mice receiving a high-fat diet. When these mice were fed mifepristone, they exhibited a marked improvement in insulin sensitivity, attenuated hepatic injury, and decreased adipocyte size, compared with mice that received only the high-fat diet. Intriguingly, mifepristone-treated mice showed significantly elevated plasma adiponectin levels. Second, we tested the effects of mifepristone on differentiated 3T3-L1 adipocytes in vitro. When differentiated adipocytes were treated with mifepristone for 48 h, adiponectin was upregulated at both mRNA and protein levels. Collectively, these results reveal novel actions of mifepristone on metabolic functions, in vivo and in vitro, in which the drug exerts antidiabetic effects associated with an upregulation in adiponectin-secretion.
| S-EPMC3819252 | biostudies-literature
Project description:BACKGROUND & AIMS:Children with Cushing syndrome present with growth delay and excess adiposity that tends to be generalized rather than centripetal. There are no prospective studies of this phenotype as it evolves before and after treatment in children. The aims of this study were to evaluate children prior to and one-year after surgical cure compared to controls and to determine fasting insulin levels and their possible association with waist circumference and waist-height ratio, pre- and post-cure of Cushing syndrome. METHODS:30 children with Cushing syndrome were evaluated prior to and one-year post-treatment and compared to 14 age and body mass index-matched controls. RESULTS:Only triceps skin fold z- score showed a significant difference between patients with active Cushing syndrome and controls. A positive correlation between fasting insulin levels and waist circumference z- score was found for children with Cushing syndrome; this association persisted one-year following cure. CONCLUSIONS:Unlike adults affected with Cushing syndrome, upper arm muscle area of children with Cushing syndrome did not differ from obese children without Cushing syndrome. The persistence of a positive correlation between waist circumference and fasting insulin despite remission of Cushing syndrome suggests that children with a history of Cushing syndrome may have an increased risk for adverse long-term effects of increased abdominal fat mass.
| S-EPMC3319516 | biostudies-literature
Project description:ContextCushing syndrome (CS) is a rare but potentially fatal feature of McCune-Albright syndrome (MAS). Optimal management, prognostic features, and long-term follow-up of this disorder have not been described.SettingThe study was conducted at an academic tertiary care center.PatientsA total of 112 patients participating in a natural history study at the National Institutes of Health (NIH) were evaluated, and 21 published cases were reviewed.InterventionsSubjects received observation, medical management, or bilateral adrenalectomy.Main outcome measuresWe measured prevalence, prognostic factors, and natural history.ResultsThe prevalence of CS among NIH patients was 7.1%. The median age at diagnosis was 3 months. Clinical features included "Cushingoid facies" (66.7%), failure to thrive (60.0%), low birth weight (50.0%), liver disease (36.7%), and heart disease (26.7%). Six patients (20.0%) died, four after adrenalectomy. Death was more likely in patients with comorbid heart disease (odds ratio, 13.3; P < 0.05). Of 23 survivors, 13 underwent adrenalectomy, and 10 exhibited spontaneous resolution. Two patients with spontaneous resolution who were tested later in life (3 and 15 yr after resolution) continued to have low-level, autonomous adrenal function with biochemical adrenal insufficiency. Compared to MAS patients without CS, patients with CS were more likely to have a cognitive/developmental disorder (44.4 vs. 4.8%; P < 0.001; odds ratio, 8.8).ConclusionsComorbid heart and liver disease were poor prognostic markers and may indicate the need for prompt adrenalectomy. The high incidence of cognitive disorders indicates a need for close developmental follow-up and parental counseling. Patients with spontaneous resolution of CS may develop adrenal insufficiency, and they require long-term monitoring.
| S-EPMC2853983 | biostudies-literature
Project description: Not available
| S-EPMC2845687 | biostudies-literature
Project description:BackgroundData suggest that estrogen-containing hormone therapy is associated with beneficial effects with regard to cardiovascular disease when the therapy is initiated temporally close to menopause but not when it is initiated later. However, the hypothesis that the cardiovascular effects of postmenopausal hormone therapy vary with the timing of therapy initiation (the hormone-timing hypothesis) has not been tested.MethodsA total of 643 healthy postmenopausal women were stratified according to time since menopause (<6 years [early postmenopause] or ≥10 years [late postmenopause]) and were randomly assigned to receive either oral 17β-estradiol (1 mg per day, plus progesterone [45 mg] vaginal gel administered sequentially [i.e., once daily for 10 days of each 30-day cycle] for women with a uterus) or placebo (plus sequential placebo vaginal gel for women with a uterus). The primary outcome was the rate of change in carotid-artery intima-media thickness (CIMT), which was measured every 6 months. Secondary outcomes included an assessment of coronary atherosclerosis by cardiac computed tomography (CT), which was performed when participants completed the randomly assigned regimen.ResultsAfter a median of 5 years, the effect of estradiol, with or without progesterone, on CIMT progression differed between the early and late postmenopause strata (P=0.007 for the interaction). Among women who were less than 6 years past menopause at the time of randomization, the mean CIMT increased by 0.0078 mm per year in the placebo group versus 0.0044 mm per year in the estradiol group (P=0.008). Among women who were 10 or more years past menopause at the time of randomization, the rates of CIMT progression in the placebo and estradiol groups were similar (0.0088 and 0.0100 mm per year, respectively; P=0.29). CT measures of coronary-artery calcium, total stenosis, and plaque did not differ significantly between the placebo group and the estradiol group in either postmenopause stratum.ConclusionsOral estradiol therapy was associated with less progression of subclinical atherosclerosis (measured as CIMT) than was placebo when therapy was initiated within 6 years after menopause but not when it was initiated 10 or more years after menopause. Estradiol had no significant effect on cardiac CT measures of atherosclerosis in either postmenopause stratum. (Funded by the National Institute on Aging, National Institutes of Health; ELITE ClinicalTrials.gov number, NCT00114517.).
| S-EPMC4921205 | biostudies-literature