Journal of the Endocrine Society最新文献

Humans are chronically exposed to numerous environmental pollutants, many of which became widespread due to rapid industrialization and modernization over the past century. These pollutants, including persistent organic pollutants, heavy metals, and fine particulate matter, can function as endocrine disruptors and disrupt hormonal signaling and other cellular mechanisms, resulting in a wide spectrum of adverse health effects and contributing to the rising burden of chronic diseases. Despite mounting evidence of their public health effect, there are currently no widely implemented intervention strategies to mitigate these effects. Given the ubiquity of these pollutants and strong epidemiological and mechanistic evidence linking them to oxidative stress and reduced physiological levels of antioxidant vitamins (AVs), the use of AVs as a protective intervention is a promising and practical opportunity. AVs are generally safe, widely available, cost-effective, and easily integrated into dietary habits, further enhancing their appeal as potential preventive measures. This review critically examines the current literature on the modifying effects of vitamins, particularly their effect on the health risks associated with various classes of environmental pollutants. We also discuss methodological challenges in interpreting findings within the complex framework of human exposure, assessment of vitamin levels, and interindividual variability. Finally, we propose future research directions that could help realize the potential of vitamins as an accessible intervention to counteract the adverse health effects of widespread environmental pollution.

Aims: To examine prescription of guideline-recommended therapies and achievement of treatment targets across the span of older adulthood in type 1 diabetes (T1D) in the United States and Germany/Austria.

Materials and methods: Cross-sectional data of adults aged ≥60 years with T1D for ≥1 year seen in 2022 in the T1D Exchange Quality Improvement Collaborative (T1DX-QI) and the Diabetes Prospective Follow-up (DPV) registry. Descriptive statistics and within-registry comparisons across age groups using analysis of variance and chi-squared tests were used to analyze the data.

Results: Thirty-six hundred adults aged ≥60 years, median age 67.5 [interquartile range (IQR) 63.4, 72.8] in T1DX-QI (n = 1549) and 68.9 (IQR 63.6, 75.7) in DPV (n = 2051) were included. The prevalence of atherosclerotic cardiovascular disease (ASCVD) (34.6% vs 16.8%) and chronic kidney disease (28.5% vs 11.8%) was higher in the DPV than the T1DX-QI. Lipid-lowering therapy for secondary prevention (52.9% vs 38%) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker use (55.3% vs 44.8%) were higher in the DPV. Continuous glucose monitoring use was similar (50.3% vs 47.9%), insulin pump use was >2 × higher (40.7% vs 17%), and automated insulin delivery use was >3 × higher (20.4% vs 6.4%) in the T1DX-QI as compared to the DPV.

Conclusion: Despite a high prevalence of ASCVD and risks of hypoglycemia, guideline-recommended treatments including lipid-lowering therapy for secondary prevention and diabetes technologies were used in approximately half or fewer of older adults with T1D. Additional attention to prescribing and practices to support clinicians and older adults in the use of diabetes technologies is urgently needed.

Context: Little is known about the association between prepregnancy homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of β-cell function (HOMA-β) levels and risk of gestational diabetes mellitus (GDM).

Objective: To examine the association between prepregnancy levels of HOMA-IR and HOMA-β and risk of GDM and whether these associations vary by race and ethnicity.

Research design and methods: We conducted a nested case-control study among women who had a serum sample from 1984 to 1996 used to measure glucose and insulin and a subsequent pregnancy from 1984 to 2009. GDM cases (n = 254) were matched with 2 randomly selected control subjects (n = 497) on serum collection date, age at collection, number of intervening pregnancies, and age at delivery. We used conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for GDM by HOMA-IR and HOMA- β, overall and stratified by race and ethnicity.

Results: Increasing levels of HOMA-IR were associated with higher odds of GDM (adjusted OR for 1 SD increase: 1.31 [95% CI 1.12,1.54]) and tertile 3 compared to tertile 1 (3.04 [95% CI 1.81, 5.12]). Models stratified by race/ethnicity suggest this association was significant among Asian and non-Hispanic Black populations for tertile 3 (3.83 [95% CI 1.39, 10.57] and 2.18 [95% CI 1.03, 4.61], respectively). Among non-Hispanic Black individuals, a 1 SD increase in HOMA-IR also increased risk of GDM (OR: 1.59, 95% CI 1.17, 2.17). There was no significant association between HOMA-IR and GDM among non-Hispanic White or Hispanic individuals. There was no association between HOMA-β and GDM risk.

Conclusion: Higher HOMA-IR levels before pregnancy were associated with an elevated risk of GDM.

Context: Current guidelines recommend performing preoperative additional imaging in patients with medullary thyroid cancer (MTC) when calcitonin levels exceed 500 pg/mL to detect distant metastases (M1). However, this recommendation is based on limited evidence. Whether this is the optimal cutoff, including other diagnostic characteristics, has only been partially evaluated in research.

Objective: The aims of this study were to evaluate the current calcitonin-driven recommendation and to investigate whether other diagnostic characteristics can be added to improve prediction of M1 disease at diagnosis.

Methods: Adult MTC patients treated in a tertiary care hospital between 1984 and 2023 with a preoperative calcitonin measurement were retrospectively collected. M1 disease was detected by preoperative imaging or biopsy. Logistic regression was used to identify new predictors for M1 at diagnosis.

Results: In total, 81 patients with MTC were included for analysis. M1 disease at presentation was found in 27%. Sensitivity and specificity for the current calcitonin cutoff were 90.9% (95% CI, 72.2-97.5) and 47.5% (95% CI, 35.3-60.0), respectively. In multivariable analysis, presence of suspicious lymph nodes on preoperative ultrasound was the strongest predictor (odds ratio [OR] 6.7; 95% CI, 1.3-34.2; P = .022) followed by calcitonin (OR 1.9; 95% CI, 1.2-2.8; P = .005) for M1 disease.

Conclusion: To our knowledge, this is the first study investigating the optimal combination of predictors for M1 disease in MTC at diagnosis. Suspicious lymph nodes on ultrasound is the strongest predictor for M1 disease, well exceeding calcitonin levels. Incorporating suspicious lymph nodes and calcitonin into a novel clinical decision tool may optimize M1 detection while reducing unnecessary imaging.

Post-bariatric hypoglycemia (PBH) is a late complication of metabolic and bariatric surgery that typically manifests over 1 year after the procedure. The clinical manifestation spans from mild hypoglycemia responsive to dietary modifications to severe hypoglycemia with neuroglycopenic symptoms. Despite its clinical significance and the growing body of evidence, the management of PBH remains heterogeneous, primarily due to its complex, multifactorial pathophysiology, the lack of standardized diagnostic criteria and Food and Drug Administration (FDA)-approved pharmacological treatments, and discrepancies in diagnostic and therapeutic approaches across available clinical guidelines. This consensus aims to establish a unified, evidence-based, and patient-centered management protocol for PBH. A panel of 16 experts, encompassing representatives from all Gulf Cooperation Council (GCC) countries and Europe, conducted an extensive review of the current literature to assemble the most recent evidence on PBH management. The panel then collaboratively developed a set of statements to standardize the diagnosis and treatment of PBH. Consensus was reached on all the statements using the Delphi method. Consensus was attained on 45 statements encompassing the entire PBH management continuum, including diagnosis, dietary management, patient education, and pharmacological treatment, with special considerations during pregnancy, long-term monitoring, and practical aspects of clinical management. Implementing these consensus statements into clinical practice will contribute to the standardization of PBH management. Furthermore, the statements highlight significant gaps in PBH management, including the lack of PBH-specific therapies and the scarcity of robust trials, which urgently require attention in future research and clinical development.

Context: Regardless of age, metabolic dysfunction-associated steatotic liver disease (MASLD) occurs in 70% of adults with type 2 diabetes (T2D) and increases the risk of metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, and cirrhosis. However, many studies focus on older adults.

Objective: To determine the frequency of screening for MASLD in young adults with T2D attending outpatient clinics.

Methods: A retrospective cohort study on young adults (aged 18-44 years) with T2D who accessed care at a tertiary care center from January 1, 2018, to December 31, 2022. At-risk MASH was diagnosed with vibration-controlled transient elastography, magnetic resonance elastography, or liver biopsy.

Results: Of 6891 participants included, 16% (n = 1100) had a diagnosis of MASLD. Those with MASLD were more likely to have cardiometabolic risk factors (83% vs 72%, P < .001) and cardiovascular disease (22% vs 16%, P < .001). Only 12% of those with MASLD underwent further investigation (1.9% of the total cohort), which was associated with dyslipidemia (odds ratio [OR], 2.4; 95% CI, 1.5-3.8), ALT >40 U/L (OR, 2.1; 95% CI, 1.4-3.0), or the use of 3 or more diabetes medications (OR, 2.1; 95% CI, 1.5-3.1). In those with further workup, 38% had at-risk MASH. The fibrosis-4 index was elevated in 16% of those with MASLD and only 28% of those with confirmed at-risk MASH or worse.

Conclusion: Screening for MASLD in young adults with T2D is frequently missed. There is a lack of accurate noninvasive tools in this population. Increased awareness of screening young adults with T2D for at-risk MASH is urgently needed to prevent progression to cirrhosis.

Objective: Obesity impairs endometrial receptivity; however, the mechanism remains unclear. Obesity is associated with elevated leptin levels, and leptin receptor (Ob-Rb) has been demonstrated to be expressed in the human endometrium, but the mechanistic pathway of leptin and endometrial dysfunction has not yet been explored.

Methods: In a human study, serum leptin levels and expressions of Ob-Rb, signal transducers and activators of transcription (STAT-3), and endometrial receptivity factors [leukemia inhibitory factor (LIF) and vascular endothelial growth factor (VEGF)] were compared in midsecretory phase endometrium among normal-weight, overweight, and obese women. In an animal study of a diet-induced obesity (DIO) mouse model, a leptin resensitization mouse model and Ob-Rb inhibitor mouse model were established.

Results: Serum leptin levels were higher in women with overweight/obesity and female DIO mice compared with those with normal weight. The expressions of Ob-Rb, pSTAT-3, and the endometrial receptivity factors of LIF and VEGF were decreased in obese women and DIO mice. Pregnancy rates and the average blastocyst numbers were lower in DIO mice than those in normal-weight mice. After leptin resensitization in DIO mice, the expression of Ob-Rb, pSTAT-3, and endometrial receptivity were increased, whereas these were all decreased in the Ob-Rb inhibitor mouse model compared with normal-weight mice.

Conclusion: Obesity-induced Ob-Rb/STAT-3 signaling dysfunction is a central mechanism impairing endometrial receptivity. Leptin resensitization via weight loss partially reverses these effects, suggesting potential therapies for targeting leptin resistance or Ob-Rb/STAT-3 signaling in obesity-related infertility.

Context: The outcomes of pemafibrate administration on hypertriglyceridemia and metabolic dysfunction-associated steatotic liver disease associated with adult growth hormone deficiency (AGHD) are unknown.

Objective: To evaluate the effects of pemafibrate on hypertriglyceridemia and liver parameters in AGHD in a real-world setting.

Design: A prospective observational study (December 2019-August 2023).

Setting: Two referral hospitals in Japan.

Patients: Thirty-four consecutive Japanese patients with AGHD complicated with hypertriglyceridemia. Hypertriglyceridemia was defined using a fasting serum triglyceride (TG) concentration of ≥1.7 mmol/L or treated with lipid-lowering medication.

Treatment: Patients were prescribed pemafibrate or continued conventional therapy for 24 weeks.

Main outcome measure: The percentage reduction in fasting serum TG level between baseline and 24 weeks was evaluated. Hepatic parameters, including hepatic steatosis index (HSI) derived from aspartate aminotransferase, alanine aminotransferase, and body mass index, were also evaluated, along with other metabolic parameters. The Mann-Whitney U-test and Fisher's exact test were used to compare the change between groups. A multiple regression was performed to identify predictors of TG change.

Results: The change in serum TG level was significantly larger in the pemafibrate group than that in the conventional group (median: -51.0% [interquartile range (IQR): -69.0% to -21.0%] vs -13.0% [IQR: -34.0% to 9.0%], P = .0138). HSI decreased after 24 weeks of pemafibrate. Relative TG change correlated with baseline body mass index [regression coefficient (β) .0463, P < .0001] and HSI (β .0645, P = .0107).

Conclusion: Pemafibrate had beneficial effects on hypertriglyceridemia as well as liver metabolism of patients with AGHD. However, its efficacy was attenuated by obesity.

Traumatic spinal cord injury (SCI) is a major insult that causes motor and sensory neurological deficits and multisystem dysfunction. The skeletal system is severely affected after SCI, with disuse bone loss being one of the most common and challenging complications. Changes in bone mass and structure after SCI are progressive and involve both trabecular and cortical components of the long bones below the lesion. The weight-bearing trabecular regions of the distal femur and proximal tibia are the most compromised sites with the highest incidence of fracture. Furthermore, SCI-associated bone loss is resistant to currently available pharmacologic and rehabilitative treatment, especially during the chronic phase after injury. Therefore, there is a need to highlight the scale of this clinical problem in the SCI patient population and address the challenges. Protection against bone loss during the early phases and restoration of bone structure in the later or chronic phases of SCI are necessary to reduce the risk of fracture and avoid the associated morbidities and mortalities and allow safe use of walking aids and exoskeletal ReWalk devices. Identifying the potential mechanisms underlying SCI-induced bone loss is critical so that new and more effective therapeutic strategies can be developed. The goal of this review is to provide an up-to-date overview of SCI bone loss and discuss challenges, potential mechanisms, and progress in pharmacological treatment.

Context: Once-weekly long-acting growth hormone (GH) analogue (LA-GHA) treatments offer an alternative to once-daily GH injections for the treatment of children and adults with GH deficiency (GHD). With these new LA-GHA options, it is important to understand patients' and caregivers' treatment preferences.

Objective: This work aimed to understand the injection/device attributes important to patients with GHD and caregivers when choosing LA-GHA treatment options.

Methods: In this cross-sectional study, a targeted literature review and qualitative interviews informed the development of an online survey. The survey included a discrete choice experiment, comprising a series of choice tasks. Respondents selected between hypothetical, experimentally designed, once-weekly LA-GHA device features corresponding to currently available devices. Study participants were patients/caregivers in the United States, self-reporting a GHD diagnosis and current short-acting GH injection use: adults (aged ≥18 years), caregivers of children (aged 3-11 years), and dyads of adolescents (aged 12-17 years) and their caregivers.

Results: In total, 100 participants completed the survey: 50 adults, 25 caregivers, and 25 adolescent/caregiver dyads. Overall, the most important LA-GHA attributes identified were postinjection pain (27%), the number of injections needed for 1 full dose (23%), and the time needed to prepare the device before each injection (16%). The profile similar to somapacitan-beco had the highest predicted choice probability (82%) compared with the profiles similar to lonapegsomatropin-tcgd (16%) and somatrogon-ghla (2%).

Conclusion: Understanding patient and caregiver preferences for LA-GHA devices with less injection pain and greater ease of use highlights the value of shared decision-making, potentially leading to better treatment adherence and subsequent clinical outcomes.