Journal of Clinical Endocrinology & Metabolism最新文献

Context: Hypertriglyceridemia is a risk factor for developing type 2 diabetes (T2D) and might contribute to its pathogenesis either directly or through elevation of nonesterified fatty acids (NEFAs).

Objective: This study aimed at comparing the glucometabolic effects of acute hypertriglyceridemia alone or combined with NEFA elevation in subjects without diabetes.

Methods: Twenty-two healthy lean volunteers underwent 5-hour intravenous infusions of either saline or Intralipid, without (n = 12) or with heparin (I + H; n = 10) to activate the release of NEFAs. Oral glucose tolerance tests (OGTTs) were performed during the last 3 hours of infusion. Insulin sensitivity, insulin secretion rate (ISR), model-derived β-cell function, and insulin clearance were measured after 2 hours of lipid infusion and during the OGTTs.

Results: In fasting conditions, both lipid infusions increased plasma insulin and ISR and reduced insulin clearance without affecting plasma glucose and insulin sensitivity. These effects on insulin and ISR were more pronounced for I + H than Intralipid alone. During the OGTT, the lipid infusions markedly impaired glucose tolerance, increased plasma insulin and ISR, and decreased insulin sensitivity and clearance, without significant group differences. Intralipid alone inhibited glucose-stimulated insulin secretion (ie, β-cell glucose sensitivity) and increased β-cell potentiation, whereas I + H had neutral effects on these β-cell functions.

Conclusion: In healthy nonobese subjects, mild acute hypertriglyceridemia directly reduces glucose tolerance and insulin sensitivity and clearance, and has selective and opposite effects on β-cell function that are neutralized by NEFAs. These findings provide new insight into plausible biological signals that generate and sustain insulin resistance and chronic hyperinsulinemia in the development of T2D.

Context: Steroidogenic factor 1 (NR5A1/SF-1) is a nuclear receptor that regulates sex development, steroidogenesis, and reproduction. Genetic variants in NR5A1/SF-1 are common among differences of sex development (DSD) and associate with a wide range of phenotypes, but their pathogenic mechanisms remain unclear.

Objective: Novel, likely disease-causing NR5A1/SF-1 variants from the SF1next cohort of individuals with DSD were characterized to elucidate their pathogenic effect.

Methods: Different in silico tools were used to predict the impact of novel NR5A1/SF-1 variants on protein function. An extensive literature review was conducted to compare and select the best functional studies for testing the pathogenic effect of the variants in a classic cell culture model. The missense NR5A1/SF-1 variants were tested on the promoter luciferase reporter vector -152CYP11A1_pGL3 in HEK293T cells and assessed for their cytoplasmic/nuclear localization by Western blot.

Results: Thirty-five novel NR5A1/SF-1 variants were identified in the SF1next cohort. Seventeen missense NR5A1/SF-1 variants were functionally tested. Transactivation assays showed reduced activity for 40% of the variants located in the DNA binding domain and variable activity for variants located elsewhere. Translocation assessment revealed 3 variants (3/17) with affected nuclear translocation. No clear genotype-phenotype, structure-function correlation was found.

Conclusion: Genetic analyses and functional assays do not explain the observed wide phenotype of individuals with these novel NR5A1/SF-1 variants. In 9 individuals, additional likely disease-causing variants in other genes were found, strengthening the hypothesis that the broad phenotype of DSD associated with NR5A1/SF-1 variants may be caused by an oligogenic mechanism.

Purpose: This study aims to evaluate the efficacy and safety of intravenous (IV) tocilizumab (TCZ) in the treatment of Graves' ophthalmopathy (GO).

Methods: A comprehensive search was conducted across the Web of Science, PubMed, Embase, Cochrane Library, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov databases from inception to April 2024. Randomized controlled trials and cohort studies that used IV TCZ for treating GO were included.

Results: Twelve studies encompassing 219 patients with active, steroid-resistant GO were analyzed. The meta-analysis demonstrated significant improvements in Clinical Activity Score (CAS) response (effect size [ES] = 0.98; 95% confidence interval [CI], 0.93-1.00), proptosis response (ES = 0.50; 95% CI, 0.27-0.73), and diplopia response (ES = 0.48; 95% CI, 0.24-0.74). The ES for adverse events was 0.27 (95% CI, 0.22-0.33), with only 3 severe cases necessitating treatment discontinuation, and a low reactivation rate (ES = 0.01; 95% CI, 0.00-0.04). TCZ treatment led to a mean CAS reduction of 4.60 points (95% CI, 3.88-5.32) across 10 studies, a mean proptosis reduction of 2.04 mm (95% CI, 1.42-2.65) across 7 studies, and a mean decrease in TSH receptor antibodies levels of 10.62 IU (95% CI, 4.67-10.62) across 5 studies.

Conclusion: This meta-analysis provides robust evidence supporting the efficacy and safety of IV TCZ in patients with GO who are resistant to glucocorticoid therapy. The results highlight TCZ's comparable efficacy to glucocorticoids and suggest that TCZ could significantly expand clinical management options for GO. In the future, more high-quality, large-scale randomized controlled trials are still needed to confirm these findings.

Context: The active surveillance (AS) program for papillary thyroid carcinoma (≤1 cm) at low risk (mPTC) showed a low percentage of progression.

Objective: The aim of this study was to find a molecular signature of cases that showed disease progression during AS, which would allow their early identification.

Methods: We performed next-generation sequencing of 95 fine-needle aspiration cytology specimens from cases prospectively enrolled in the AS program to analyze key somatic driver alterations or gene fusions implicated in PTC tumorigenesis. TERT promoter analysis was performed using Sanger sequencing or droplet digital polymerase chain reaction.

Results: BRAF p.V600E was found in 66.3% (63/95) of mPTC and was the most common somatic alteration, followed by RAS oncogene mutations detected in 3.2% of mPTC (3/95: 2 NRAS and 1 KRAS) and gene fusions detected in 3.2% of mPTC (3/95: 1 RET-PTC1, 1 TFG-NTRK1, 1 ALK imbalance). No TERT promoter mutations (C228T and C250T) were found in the analyzed mPTC (84/95). The comparison between the molecular profile and the clinical outcome of the mPTC (stable vs progressive disease) showed no correlation (P = .6) and did not identify a molecular signature able to identify progressive mPTC.

Conclusion: The molecular profile of mPTC is like that of bigger PTC with the exception that none of them showed a TERT promoter mutation. The identification of the most common driver mutations, such as BRAF, RAS, or gene fusions, is not helpful for the early identification of mPTC that will show disease progression during follow-up in the AS program.

Catecholamine-producing tumors of childhood include neuroblastic tumors, phaeochromocytoma, and paraganglioma (PPGL). PPGL and neuroblastic tumors can arise in similar anatomical locations and clinical presentations can overlap, resulting in diagnostic challenges. Distinguishing between these tumor types is critical as management and long-term surveillance strategies differ depending on the diagnosis. Herein we describe 2 clinical cases and illustrate key considerations in the diagnostic workup of a neuroblastoma vs PPGL for patients presenting with adrenal, pelvic, and retroperitoneal masses in childhood.

Context: Despite the growing evidence pointing to the detrimental effects of air pollution on diabetes mellitus (DM), the relationship remains poorly explored, especially in desert-adjacent areas characterized by high aridity and pollution.

Objective: We conducted a cross-sectional study with health examination data from more than 2.9 million adults in 2 regions situated in the southern part of the Taklamakan Desert, China.

Methods: We assessed 3-year average concentrations (2018-2020) of particulate matter (PM1, PM2.5, and PM10), carbon monoxide (CO), nitrogen dioxide (NO2), and sulfur dioxide (SO2) through a space-time extra-trees model. After adjusting for various covariates, we employed generalized linear mixed models to evaluate the association between exposure to air pollutants and DM.

Results: The odds ratios for DM associated with a 10 µg/m3 increase in PM1, PM2.5, PM10, CO, and NO2 were 1.898 (95% CI, 1.741-2.070), 1.07 (95% CI, 1.053-1.086), 1.013 (95% CI, 1.008-1.018), 1.009 (95% CI, 1.007-1.011), and 1.337 (95% CI, 1.234-1.449), respectively. Notably, men, individuals aged 50 years or older, those with lower educational attainment, nonsmokers, and those not engaging in physical exercise appeared to be more susceptible to the adverse effects of air pollution. Multiple sensitivity analyses confirmed the stability of these findings.

Conclusion: Our study provides robust evidence of a correlation between prolonged exposure to air pollution and the prevalence of DM among individuals living in desert-adjacent areas. This research contributes to the expanding knowledge on the relationship between air pollution exposure and DM prevalence in desert-adjacent areas.

Background: Hypoglycemic pharmacotherapy interventions for alleviating the risk of dementia remain controversial, particularly regarding dipeptidyl peptidase 4 (DPP4) inhibitors vs metformin. Our objective was to investigate whether the initiation of DPP4 inhibitors, as opposed to metformin, was linked to a reduced risk of dementia.

Methods: We included individuals with type 2 diabetes over 40 years old who were new users of DPP4 inhibitors or metformin in the Chinese Renal Disease Data System database between 2009 and 2020. The study employed Kaplan-Meier and Cox regression for survival analysis and the Fine and Gray model for the competing risk of death.

Results: Following a 1:1 propensity score matching, the analysis included 3626 DPP4 inhibitor new users and an equal number of metformin new users. After adjusting for potential confounders, the utilization of DPP4 inhibitors was associated with a decreased risk of all-cause dementia compared to metformin [hazard ratio (HR) 0.63, 95% confidence interval (CI) 0.45-0.89]. Subgroup analysis revealed that the utilization of DPP4 inhibitors was associated with a reduced incidence of dementia in individuals who initiated drug therapy at the age of 60 years or older (HR 0.69, 95% CI 0.48-0.98), those without baseline macrovascular complications (HR 0.62, 95% CI 0.41-0.96), and those without baseline microvascular complications (HR 0.67, 95% CI 0.47-0.98).

Conclusion: In this real-world study, we found that DPP4 inhibitors presented an association with a lower risk of dementia in individuals with type 2 diabetes than metformin, particularly in older people and those without diabetes-related comorbidities.