Relacorilant, a Selective Glucocorticoid Receptor Modulator in Development for the Treatment of Patients With Cushing Syndrome, Does Not Cause Prolongation of the Cardiac QT Interval.

OBJECTIVE: To assess the effect of relacorilant, a selective glucocorticoid receptor modulator under investigation for the treatment of patients with endogenous hypercortisolism (Cushing syndrome [CS]), on the heart rate-corrected QT interval (QTc). METHODS: Three clinical studies of relacorilant were included: (1) a first-in-human, randomized, placebo-controlled, ascending-dose (up to 500 mg of relacorilant) study in healthy volunteers; (2) a phase 1 placebo- and positive-controlled thorough QTc (TQT) study of 400 and 800 mg of relacorilant in healthy volunteers; and (3) a phase 2, open-label study of up to 400 mg of relacorilant administered daily for up to 16 weeks in patients with CS. Electrocardiogram recordings were taken, and QTc change from baseline (ΔQTc) was calculated. The association of plasma relacorilant concentration with the effect on QTc in healthy volunteers was assessed using linear mixed-effects modeling. RESULTS: Across all studies, no notable changes in the electrocardiogram parameters were observed. At all time points and with all doses of relacorilant, including supratherapeutic doses, ΔQTc was small, generally negative, and, in the placebo-controlled studies, similar to placebo. In the TQT study, placebo-corrected ΔQTc with relacorilant was small and negative, whereas placebo-corrected ΔQTc with moxifloxacin positive control showed rapid QTc prolongation. These results constituted a negative TQT study. The model-estimated slopes of the concentration-QTc relationship were slightly negative, excluding an association of relacorilant with prolonged QTc. CONCLUSION: At all doses studied, relacorilant consistently demonstrated a lack of QTc prolongation in healthy volunteers and patients with CS, including in the TQT study. Ongoing phase 3 studies will help further establish the overall benefit-risk profile of relacorilant.

Outcomes of Preoperative Medical Therapy for Thyroidectomy in Autoimmune Thyroid Disease.

INTRODUCTION: Thyroidectomy provides definitive treatment for autoimmune thyroid disease (AITD) often resulting in improved quality of life. Historically, patients with AITD undergoing thyroidectomy have increased rates of postoperative hypoparathyroidism and recurrent laryngeal nerve palsy. We investigated the outcomes of preoperative medications in patients with AITD undergoing thyroidectomy. METHODS: We performed a retrospective analysis of patients who underwent thyroidectomy for AITD at a single institution from 2015 to 2021. Surgical outcomes and perioperative laboratory values were analyzed by type of AITD and type of preoperative medical treatment: none, saturated solution of potassium iodide (SSKI), corticosteroids, or both SSKI and corticosteroids. RESULTS: A total of 123 patients underwent thyroidectomy for AITD and were included in analysis: 50 received no preoperative medications, 40 received SSKI, 20 received corticosteroids, and 13 received both. Seventy-six patients had Graves' disease and 47 had Hashimoto's thyroiditis. There were no significant differences in blood loss, operative time, wound complications, hematoma, or recurrent laryngeal nerve injury for patients treated with preoperative corticosteroids compared to those who were not. Patients who received corticosteroids and patients with Graves' disease more commonly had at least one instance of hypocalcemia postoperatively (P < 0.01, P = 0.01), although only on postoperative day 1 was mean calcium < 8.5 mg/dL. There was no difference in rate of transient or permanent hypoparathyroidism. CONCLUSIONS: Patients who received corticosteroids preoperatively had no increased risk of complications. They did have mildly lower calcium levels in the early postoperative period, although no difference in hypoparathyroidism. Further exploration is warranted to investigate the impact of preoperative corticosteroids on operative difficulty, quality of life, and autoantibody clearance.

Corrigendum: Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study.

[This corrects the article DOI: 10.3389/fendo.2021.662865.].

Relacorilant, a Selective Glucocorticoid Receptor Modulator, Induces Clinical Improvements in Patients With Cushing Syndrome: Results From A Prospective, Open-Label Phase 2 Study.

Introduction/Purpose: Relacorilant is a selective glucocorticoid receptor modulator (SGRM) with no progesterone receptor activity. We evaluated the efficacy and safety of relacorilant in patients with endogenous Cushing syndrome (CS). Materials and Methods: A single-arm, open-label, phase 2, dose-finding study with 2 dose groups (NCT02804750, https://clinicaltrials.gov/ct2/show/NCT02804750) was conducted at 19 sites in the U.S. and Europe. Low-dose relacorilant (100-200 mg/d; n = 17) was administered for 12 weeks or high-dose relacorilant (250-400 mg/d; n = 18) for 16 weeks; doses were up-titrated by 50 mg every 4 weeks. Outcome measures included proportion of patients with clinically meaningful changes in hypertension and/or hyperglycemia from baseline to last observed visit. For patients with hypertension, clinical response was defined as a ≥5-mmHg decrease in mean systolic or diastolic blood pressure, measured by a standardized and validated 24-h ABPM. For patients with hyperglycemia, clinical response was defined ad-hoc as ≥0.5% decrease in HbA1c, normalization or ≥50-mg/dL decrease in 2-h plasma glucose value on oral glucose tolerance test, or decrease in daily insulin (≥25%) or sulfonylurea dose (≥50%). Results: 35 adults with CS and hypertension and/or hyperglycemia (impaired glucose tolerance or type 2 diabetes mellitus) were enrolled, of which 34 (24 women/10 men) received treatment and had postbaseline data. In the low-dose group, 5/12 patients (41.7%) with hypertension and 2/13 patients (15.4%) with hyperglycemia achieved response. In the high-dose group, 7/11 patients (63.6%) with hypertension and 6/12 patients (50%) with hyperglycemia achieved response. Common (≥20%) adverse events included back pain, headache, peripheral edema, nausea, pain at extremities, diarrhea, and dizziness. No drug-induced vaginal bleeding or hypokalemia occurred. Conclusions: The SGRM relacorilant provided clinical benefit to patients with CS without undesirable antiprogesterone effects or drug-induced hypokalemia.

Development of an objective tool for the diagnosis of myxedema coma.

Myxedema coma, a rare entity, with a reported 25%-65% mortality had no objective criteria for making the diagnosis when we began our study. We developed an objective screening tool for myxedema coma to more easily identify patients and examine the best treatment method in future prospective studies to reduce the mortality of this entity. We conducted a retrospective chart review to find all patients aged ≥18 years admitted with myxedema coma from January 1, 2005 through June 13, 2010 at Indiana University Health Methodist Hospital. On the basis of both our retrospective chart review and on literature accounts, we identified 6 criteria to diagnose myxedema coma. We identified 10 patients initially diagnosed with myxedema coma and established a control group consisting of 13 patients identified with altered mental status and increased thyroid-stimulating hormone (TSH) levels. The 6 variables we created for the screening tool were heart rate, temperature, Glasgow coma scale, TSH, free thyroxine, and precipitating factors. The screening tool has a sensitivity and specificity of about 80%. We ran a logistic regression model using the 10 study patients and 13 controls with the 6 variables. No variables alone significantly contributed to the model. However, the overall model was highly significant (P = 0.012), providing strong support for a scoring system that uses these variables simultaneously. This screening tool enables physicians to rapidly diagnose myxedema coma to expedite treatment. A more refined diagnostic tool may be used in future clinical studies designed to determine the optimal treatment.

Temporal occurrences and recurrence patterns of hypoglycemia during hospitalization.

OBJECTIVE: To describe the temporal distribution of hypoglycemia and its rate of recurrence during hospitalization to aid in the development of strategies to prevent hypoglycemia in hospitalized patients. METHODS: Retrospective review of hypoglycemia (blood glucose <50 mg/dL) audit data in adult hospitalized patients at 2 academic hospitals. Demographics, timing, and blood glucose values were recorded. Antihyperglycemic medications, number of recurrent events, and change in basal insulin dose following the hypoglycemic event were also extracted. RESULTS: A total of 274 index occurrences of hypoglycemia were analyzed. The mean age of the patients was 53.8 years, with roughly equal gender distributions. Twenty-eight percent of the events occurred in the absence of antihyperglycemic therapy. The incidence of hypoglycemia peaked between midnight and 6 AM. There were 36 instances of recurrent hypoglycemia associated with antihyperglycemic therapy, with 78% (n = 28) cases involving basal insulin. Patients on basal insulin who developed hypoglycemia did not have their dose changed prior to the time of the next administration in 75% of the cases. CONCLUSION: Hypoglycemia in hospitalized patients may occur with greater frequency overnight. Although cumbersome, routine nocturnal glycemic testing should be considered. Education regarding insulin management in the hospital and improved communication between night and day staff may aid in decreasing subsequent hypoglycemic events.

Thyroid hormone analogues for the treatment of metabolic disorders: new potential for unmet clinical needs?

OBJECTIVE: To provide a comprehensive review of the discovery and development of selective thyroid hormone receptor agonists and provide a discussion of their use in hyperlipidemia, obesity, and type 2 diabetes mellitus. METHODS: Preclinical and clinical English language literature from 1930 to present was reviewed and thematically summarized. RESULTS: Human trials have shown that thyroid hormone receptor ß (TRß) agonists effectively lower low-density lipoprotein, triglycerides, apolipoprotein B, and lipoprotein(a) levels. In preclinical studies, TRß agonists enhance reverse cholesterol transport and decrease atherosclerosis in selected models. While animal data suggest these drugs may have additional utility to modulate weight and improve glucose homeostasis, human studies have not shown similar results. CONCLUSION: TRß agonists are a novel therapeutic class for lipid management. Their mechanism of action for lipid lowering is distinct from statin drugs, suggesting a strong possibility for synergistic effects with combined therapy. The long-term effects of these drugs on cardiovascular outcomes, however, are unknown. Recently, the development of the most promising agent in this class, eprotirome, was halted over toxicology concerns following long-term canine studies. Consequently, the future of contemporary TRß agonists is unclear. The creation of a next generation of TRß agonists that provide additional tissue specific effects or bind TRß with even higher selectivity may lead to improved safety and efficacy and allow for their application to other metabolic disorders like obesity and type 2 diabetes mellitus.

Vitamin D3 supplementation improves insulin sensitivity in subjects with impaired fasting glucose.

Vitamin D has in vitro and in vivo effects on ß cells and insulin sensitivity. Vitamin D deficiency (VDD) has been associated with the onset and progression of type 2 diabetes mellitus (DM-2). However, studies involving supplementation of vitamin D in subjects with previously established diabetes have demonstrated inconsistent effects on insulin sensitivity. The aim of this open-label study was to assess the effects of high-dose vitamin D3 supplementation on insulin sensitivity in subjects with VDD and impaired fasting glucose. We studied 8 subjects with VDD and prediabetes with the modified, frequently sampled intravenous glucose tolerance (mFSIGT) test before and after vitamin D supplementation. Vitamin D3 was administered as 10,000 IU daily for 4 weeks. The mFSIGT was analyzed with MinMod Millennium (purchased from Dr. Richard Bergman, Keck School of Medicine of USC, Los Angeles, Calif) to obtain estimates of acute insulin response to glucose (AIRg), insulin sensitivity (SI), and disposition index (DI). We found that AIRg decreased (P = 0.011) and SI increased (P = 0.012) after a intervention with vitamin D. If these findings are repeated in a randomized, double-blind study, the results indicate that orally administered high-dose vitamin D3 supplementation improves insulin sensitivity in subjects with impaired fasting glucose and suggests that high-dose vitamin D3 supplementation might provide an inexpensive public health measure in preventing, or at least delaying, the progression from impaired fasting glucose to diabetes.

Overlapping roles of the glucose-responsive genes, S14 and S14R, in hepatic lipogenesis.

The Spot 14 (S14; Thrsp) gene has been implicated in supporting regulated lipogenesis in mammals. S14 gene expression in liver is controlled by a wide variety of hormones and dietary factors in parallel with the major lipogenic enzyme genes. In addition, mice deleted for the S14 gene display reduced de novo lipogenesis in the lactating mammary gland. However, no decrease in hepatic lipogenesis was observed in the S14 null mouse. It was postulated that this difference could be due to the expression of a paralogous gene called S14R (S14 related; Mig12) in the liver but not mammary tissue. To test this hypothesis, we used small interfering RNA to simultaneously reduce levels of S14 and S14R in cultured primary hepatocytes. We found that rates of lipogenesis were decreased by approximately 65% in cells treated with insulin and high glucose. This reduction was associated with a decrease in total liver triacylglycerols and an altered morphology of lipid droplets. Expression of either S14 or S14R gene products was sufficient to fully restore normal lipogenesis. No change in the hepatic expression of other major lipogenic enzyme genes occurred during manipulation of S14 and/or S14R levels. These data support the hypothesis that both S14 and S14R are directly involved in supporting hepatic lipogenesis and that the two proteins play overlapping roles in this process.

The Thrsp null mouse (Thrsp(tm1cnm)) and diet-induced obesity.

We created a Thrsp (Spot 14 or S14) null mouse (Thrsp(tm1cnm)) to study the role of Thrsp in de novo lipid synthesis. The Thrsp null mouse exhibits marked deficiencies in de novo lipogenesis in the lactating mammary gland. We now report the Thrsp gene deletion affects body weight and glucose tolerance associated with increased insulin sensitivity. By post-natal day 150 the rate of first generation C57BL/6J backcross Thrsp null mouse weight gain slowed compared to wild type animals. This was due to changes in body fat mass. We studied mice backcrossed for 5 and 11 generations. The weight difference between the null and wild type adult mice diminished with progressive backcross generations. In conclusion the Thrsp gene is involved in the regulation of diet-induced obesity and deletion of Thrsp leads to an improvement in age associated glucose tolerance.

Effect of epoprostenol on the thyroid gland: enlargement and secretion of thyroid hormone.

OBJECTIVE: To demonstrate the direct stimulation of thyroid tissue in the absence of thyroid-stimulating immunoglobulin after exposure to epoprostenol. METHODS: Seronegative thyrotoxicosis, diffuse goiter, and homogeneous uptake on thyroid scintigraphy were noted in a patient with pulmonary arterial hypertension (PAH) being treated with intravenously administered epoprostenol (prostaglandin I2 or PGI2). More cases with similar characteristics were identified on review of the thyroid function in patients with PAH who were treated with this medication. Fifty-four adult patients with PAH were studied. The study subjects were divided into 2 groups based on whether they were treated with PGI2 or not. Thyroid functions were reviewed, and the prevalence of thyroid disease was assessed. We then compared the prevalence of hyperthyroidism in our study subjects with the prevalence of hyperthyroidism in the general female population using data from published studies. RESULTS: We noted a high prevalence (3 of 45 or 6.7%) of thyroid-stimulating immunoglobulin-negative thyrotoxicosis in adults with preexisting PAH being treated with epoprostenol (PGI2) in the absence of other mechanisms or drugs to explain the hyperthyroidism. The prevalence of hyperthyroidism in our study population was significantly greater (P<.01 by X2 analysis) than that in the general female population in other published reports. CONCLUSION: The data suggest that epoprostenol is a medication associated with stimulation of thyroid tissue, goiter formation, and hyperthyroidism. Patients receiving this drug need to undergo close follow-up for the development of thyrotoxicosis and goiter.

Optimal free thyroxine levels for thyroid hormone replacement in hypothyroidism.

OBJECTIVE: To determine whether a difference exists in the free thyroxine level required to achieve a normal thyrotropin (thyroid-stimulating hormone or TSH) level between patients with primary hypothyroidism and euthyroid control subjects and compare the free thyroxine levels in patients with primary and secondary hypothyroidism receiving thyroid hormone replacement. METHODS: We retrospectively assessed TSH and free thyroxine values in 58 patients with primary hypothyroidism and 78 euthyroid control subjects for whom screening thyroid function tests had been performed. From the medical records, we also obtained free thyroxine values for 23 patients with central hypothyroidism receiving stable levothyroxine replacement therapy. RESULTS: The mean free thyroxine level was significantly higher in patients with primary hypothyroidism than in euthyroid control subjects (1.36 +/- 0.201 ng/dL versus 1.10 +/- 0.155 ng/dL, respectively; P

Hepatic expression of the SPOT 14 (S14) paralog S14-related (Mid1 interacting protein) is regulated by dietary carbohydrate.

The Spot 14 (S14) gene is rapidly up-regulated by signals that induce lipogenesis such as enhanced glucose metabolism and thyroid hormone administration. Previous studies in S14 null mice show that S14 is required for normal lipogenesis in the lactating mammary gland, but not the liver. We speculated that the lack of a hepatic phenotype was due to the expression of a compensatory gene. We recently reported that this gene is likely an S14 paralog that we named S14-Related (S14-R). S14-R is expressed in the liver, but not in the mammary gland. If S14-R compensates for the absence of S14 in the liver, we hypothesized that, like S14, S14-R expression should be glucose responsive. Here, we report that hepatic S14-R mRNA levels increase with high-carbohydrate feeding in mice or within 2 h of treating cultured hepatocytes with elevated glucose. A potential carbohydrate response element (ChoRE) was identified at position -458 of the S14-R promoter. Deletion of or point mutations within the putative S14-R ChoRE led to 50-95% inhibition of the glucose response. Gel-shift analysis revealed that the glucose-activated transcription complex carbohydrate responsive element-binding protein/Max-like protein X (Mlx) binds to the S14-R ChoRE. Finally, S14-R glucose induction is completely blocked when a dominant-negative form of Mlx is overexpressed in primary hepatocytes. In conclusion, our results indicate that the S14-R gene is a glucose-responsive target of carbohydrate responsive element-binding protein/Mlx and suggest that the S14-R protein is a compensatory factor, at least partially responsible for the normal liver lipogenesis observed in the S14 null mouse.

Triiodo-L-thyronine rapidly stimulates alveolar fluid clearance in normal and hyperoxia-injured lungs.

RATIONALE: Edema fluid resorption is critical for gas exchange and requires active epithelial ion transport by Na, K-ATPase and other ion transport proteins. OBJECTIVES: In this study, we sought to determine if alveolar fluid clearance (AFC) is stimulated by 3,3',5 triiodo-L-thyronine (T(3)). METHODS: AFC was measured in in situ ventilated lungs and ex vivo isolated lungs by instilling isosmolar 5% bovine serum albumin solution with fluorescein-labeled albumin tracer and measuring the change in fluorescein isothiocyanate-albumin concentration over time. MEASUREMENTS AND MAIN RESULTS: Systemic treatment with intraperitoneal injections of T(3) for 3 consecutive days increased AFC by 52.7% compared with phosphate-buffered saline-injected control rats. Membranes prepared from alveolar epithelial cells from T(3)-treated rats had higher Na, K-ATPase hydrolytic activity. T(3) (10(-6) M), but not reverse T(3) (3,3',5' triiodo-L-thyronine), applied to the alveolar space increased AFC by 31.8% within 1.5 hours. A 61.5% increase in AFC also occurred by airspace instillation of T(3) in ex vivo isolated lungs, suggesting a direct effect of T(3) on the alveolar epithelium. Exposure of rats to an oxygen concentration of greater than 95% for 60 hours increased wet-to-dry lung weights and decreased AFC, whereas the expression of thyroid receptor was not markedly changed. Airspace T(3) rapidly restored the AFC in rat lungs with hyperoxia-induced lung injury. CONCLUSIONS: Airspace T(3) rapidly stimulates AFC by direct effects on the alveolar epithelium in rat lungs with and without lung injury.

T3 increases Na-K-ATPase activity via a MAPK/ERK1/2-dependent pathway in rat adult alveolar epithelial cells.

Thyroid hormone (T3) increases Na-K-ATPase activity in rat adult alveolar type II cells via a PI3K-dependent pathway. In these cells, dopamine and beta-adrenergic agonists can stimulate Na-K-ATPase activity through either PI3K or MAPK pathways. We assessed the role of the MAPK pathway in the stimulation of Na-K-ATPase by T3. In the adult rat alveolar type II-like cell line MP48, T3 enhanced MAPK/ERK1/2 activity in a dose-dependent manner. Increased ERK1/2 phosphorylation was observed within 5 min, peaked at 20 min, and then decreased. Two MEK1/2 inhibitors, U0126 and PD-98059, each abolished the T3-induced increase in the quantity of Na-K-ATPase alpha(1)-subunit plasma membrane protein and Na-K-ATPase activity. T3 also increased the phosphorylation of MAPK/p38; however, SB-203580, a specific inhibitor of MAPK/p38 activity, did not prevent the T3-induced Na-K-ATPase activity. SP-600125, a specific inhibitor of the MAPK/JNK pathway, also did not block the T3-induced Na-K-ATPase activity. Phorbol 12-myristate 13-acetate (PMA) significantly increased ERK1/2 phosphorylation and Na-K-ATPase activity. The PMA-induced Na-K-ATPase activity was inhibited by U0126. These data indicate that activation of MAPK-ERK1/2 was required for the T3-induced increase in Na-K-ATPase activity in addition to the requirement for the PI3K pathway.

Thyroid hormone rapidly stimulates alveolar Na,K-ATPase by activation of phosphatidylinositol 3-kinase.

PURPOSE OF REVIEW: Nongenomic actions of 3,3',5-triiodo-L-thyronine (T3) occur quite rapidly usually via activation of signaling cascades. In this review, we focus on recent advances made in the understanding of activation of the phosphatidylinositol 3-kinase pathway by T3 in alveolar epithelial cells, resulting in upregulation of Na,K-ATPase hydrolytic activity and potential physiological significance of this finding. RECENT FINDINGS: T3 stimulates the Src family of kinases. Activation of Src-kinase and phosphatidylinositol 3-kinase/protein kinase B is required for the T3-induced stimulation of alveolar epithelial Na,K-ATPase activity in rat alveolar epithelial cells. The stimulation does not require transcription. This T3-sensitive Na,K-ATPase stimulation in rat alveolar epithelial cells is switched on late in gestation. In skin fibroblasts phosphatidylinositol 3-kinase is also involved in the nongenomic T3 stimulation of ZAK1-4alpha protein expression, an endogenous calcineurin inhibitor. SUMMARY: T3 plays an important role in cell survival and differentiation. Nongenomic regulation of phosphatidylinositol 3-kinase and downstream molecules by T3 is being recognized in different tissues. Upregulation of alveolar Na,K-ATPase is one such molecule, which plays an important role in removal of edema fluid from the alveolar space. These effects are rapid and do not require direct nuclear gene transcription.

Developmental acquisition of T3-sensitive Na-K-ATPase stimulation by rat alveolar epithelial cells.

Late in gestation, the developing air space epithelium switches from chloride and fluid secretion to sodium and fluid absorption. Absorption requires Na-K-ATPase acting in combination with apical sodium entry mechanisms. Hypothyroidism inhibits perinatal fluid resorption, and thyroid hormone [triiodothyronine (T3)] stimulates adult alveolar epithelial cell (AEC) Na-K-ATPase. This study explored the developmental regulation of Na-K-ATPase by T3 in fetal rat distal lung epithelial (FDLE) cells. T3 increased Na-K-ATPase activity in primary FDLE cells from gestational day 19 [both primary FDLE cells at embryonic day 19 (E19) and the cell line FD19 derived from FDLE cells at E19]. However, T3 did not increase the Na-K-ATPase activity in less mature FDLE cells, including primary E17 and E18 FDLE cells and the cell line FD18 (derived from FDLE cells at E18). Subsequent experiments assessed the T3 signal pathway to define whether it was similar in the late FDLE and adult AEC and to determine the site of the switch in responsiveness to T3. As in adult AEC, in the FD19 cell line, the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin blocked the T3-induced increase in Na-K-ATPase activity and plasma membrane quantity. T3 caused a parallel increase in phosphorylation of Akt at Ser473 in FDLE cells from E19, but not from E17 or E18. In the FD18 cell line, transient expression of a constitutively active mutant of the PI3K catalytic p110 subunit significantly augmented the Na-K-ATPase activity and the cell surface expression of Na-K-ATPase alpha(1) protein. In conclusion, FDLE cells from E17 and E18 lacked T3-sensitive Na-K-ATPase activity but acquired this response at E19. The developmental stimulation of Na-K-ATPase by T3 in rat FDLE cells requires activation of PI3K, and the acquisition of T3 responsiveness may be at PI3K or upstream in the signaling pathway.