Journal of Clinical Endocrinology & Metabolism最新文献

Context: Epidemiological evidence regarding prenatal per- and polyfluoroalkyl substance (PFAS) exposure and long-term maternal metabolic health outcomes is lacking.

Objective: Quantify associations between prenatal PFAS concentrations and maternal metabolic biomarkers of glucose homeostasis 7 to 9 years later.

Methods: We measured second trimester plasma concentrations of 9 PFAS in participants enrolled in the Maternal-Infant Research on Environmental Chemicals (MIREC) study. We measured individual biomarkers of glucose homeostasis (fasting intact proinsulin, C-peptide, insulin, glucose, and hemoglobin A1C levels) in samples collected 7 to 9 years after the MIREC pregnancy (n = 258) and derived indicators of pancreatic beta cell function (proinsulin to insulin [PI:INS], proinsulin to C-peptide [PI:CP] ratios) and insulin resistance (homeostatic model assessment for insulin resistance [HOMA-IR], triglyceride-glucose index). Using multivariable linear regression models, we quantified the percent change in each outcome per doubling of individual PFAS concentrations. We used quantile g-computation and weighted quantile sum regression to evaluate the mixture of PFAS.

Results: Prenatal perfluorononanoic acid and perfluorodecanoic acid concentrations were associated with 13.9% (95% CI: 0.8, 28.8) and 10.5% (95% CI: -1.0, 23.4) higher HOMA-IR values as well as 11.9% (95% CI: 0.1, 25.1) and 8.9% (95% CI: -1.5, 20.3) higher fasting insulin concentrations, respectively. A doubling of perfluorooctanoic acid concentrations was associated with increases in intact proinsulin concentrations (12.8% [95% CI: -3.5, 31.8]) and beta cell function ratios (PI:INS: 11.5% [95% CI: -4.4, 30.1]; PI:CP: 13.5% [95% CI: -2.4, 32.0]).

Conclusion: Prenatal exposure to PFAS may impact long-term maternal insulin resistance and beta cell function, key risk factors for type 2 diabetes. These associations differ by specific PFAS.

Context: Patients with type 1 diabetes (T1D) have increased risk of post-fracture complications, such as impaired healing and surgical complications compared to patients without diabetes. However, it is not known if this translates to higher healthcare costs.

Objective: We aimed to compare the direct healthcare costs within the first year of hip, humerus, forearm, foot, and ankle fractures between patients with T1D and matched controls.

Methods: Patients with hip, humerus, forearm, foot, and ankle fractures in the period 2011-2019 were identified from the Danish National Patient Register. Patients with T1D were matched 1:4 with patients without diabetes. Costs for hospitalizations, primary care physicians, physiotherapy, and medication within the first year after a fracture were calculated.

Results: We identified 973 hip, 622 humerus, 1144 forearm, 945 foot, and 472 ankle fractures in patients with T1D. The direct healthcare cost within 1 year after fracture was significantly higher among patients with T1D compared to patients without diabetes for humerus (€726 vs €562), forearm (€441 vs €269), foot (€225 vs €123), and ankle fractures (€551 vs €367). By contrast, the direct healthcare cost of hip fractures was similar in patients with T1D and controls (€9463 vs €9429).

Conclusion: While hip fractures were the most costly site, there were no differences in the 1-year post-fracture direct healthcare costs. However, the costs were significantly higher at all other fracture sites among patients with T1D. Increased uptake of fracture prevention strategies among T1D may help reduce fracture risk and subsequently costs.

Context: An analysis based on a large number of detailed patient data was performed to accurately assess the impact of radioiodine therapy (RAIT) for Graves' disease (GD) on thyroid cancer.

Objective: The purpose was to investigate whether the occurrence of newly diagnosed thyroid cancer is increased after RAIT for GD, and whether thyroid cancer following RAIT has poor prognosis.

Methods: A total of 13 874 eligible patients diagnosed with untreated GD were retrospectively analyzed. The incidence rates of newly developed thyroid cancer by each treatment method for GD was evaluated using the person-year method. Among the 23 179 patients who underwent RAIT for GD, including those with recurrent GD or a history of prior treatment for GD, those who developed thyroid cancer after RAIT were analyzed. Logistic regression analysis was performed to investigate the risk factors for thyroid cancer.

Results: A total of 2273 cases underwent RAIT, 287 underwent surgical treatment, and 11 314 were treated with medication only, and new-onset thyroid cancer was identified in 8 patients in the RAIT group and 39 in the medication-only group. A total of 107 218 person-years were observed, but no significant difference was observed in the incidence rate of thyroid cancer with treatment for GD. Of the 23 179 cases that underwent RAIT, 17 developed thyroid cancer. Sixteen were diagnosed with papillary thyroid carcinoma (PTC), of which 15 were microcarcinomas. Logistic regression analysis did not identify any significant risk factors for thyroid cancer development.

Conclusion: In this study, the incidence of new thyroid cancer cases did not increase following RAIT for GD. Most thyroid cancers that developed after RAIT were micro-PTCs, with no evidence suggesting a poor prognosis.

Context: Metabolic syndrome (MetS) risk factors emerge in childhood. The precursors may include familial association through genetic inheritance or cohabitation.

Objective: To examine cross-sectional associations of MetS components between spouses and between parents and their 5- to 19-year-old offspring.

Methods: Data were obtained from 1255 mother-father-offspring triads enrolled in a longitudinal study in an Indigenous community in Arizona (1965-2007). Parent-offspring measures of waist circumference, triglycerides, high-density lipoprotein cholesterol (HDL-C), systolic blood pressure (SBP), diastolic blood pressure, and fasting glucose were used for MetS diagnosis. Parental MetS and its components were defined according to the modified criteria of Adult Treatment Panel III. Additional offspring measures included glycated hemoglobin, fasting insulin, Homeostatic Model Assessment for Insulin Resistance (HOMA-IR), and type 2 diabetes (T2D).

Results: Parental MetS components associated significantly with higher risk of diabetes and with higher central adiposity, triglycerides, SBP, fasting glucose and insulin, and HOMA-IR and lower HDL-C in the offspring. These associations were stronger during adolescence and more pronounced between maternal-offspring dyads. For instance, offspring of mothers with hyperglycemia had 10.3 mg/dL higher fasting glucose at ages 12 to 19 years (vs 2.61 mg/dL higher fasting glucose at ages 5-11 years) than the offspring of mothers with normal glucose levels. Parental diabetes partially explained some of these associations. We also found significant spousal concordance in metabolic risk attributes.

Conclusion: Parental MetS characteristics were significantly associated with T2D and cardiometabolic risk factors in offspring. Associations were stronger during adolescence and between maternal-offspring pairs. These findings strongly support the need for family-based interventions directed at modifying health behaviors in high-risk population groups.

Context: The biochemical diagnosis of carcinoid syndrome (CS) is established through the measurement of 24-hour urine 5-hydroxyindoleacetic acid (5-HIAA), but these measurements are prone to sampling error and may be troublesome for patients. Serum 5-HIAA measurements might constitute a more reliable and convenient alternative to diagnose CS.

Objective: To assess the diagnostic value of serum 5-HIAA measurements in patients with CS.

Design: Retrospective cohort study.

Setting: Tertiary care hospital.

Patients: 379 patients with a neuroendocrine tumor (NET), of whom 136 (35.9%) had CS; 153 control samples were included.

Intervention: Paired serum and 24-hour urine 5-HIAA measurements.

Main outcome measure(s): Performance of serum and 24-hour urine 5-HIAA for the diagnosis of CS, measured by area under the receiver operating characteristic curve (AUROC).

Results: Serum 5-HIAA performance was similar to that of 24-hour urine 5-HIAA for the diagnosis of CS in the total NET cohort (n = 379, AUROC 0.824 vs 0.843, P = .50) and in a subgroup of somatostatin analog (SSA)-naïve patients (n = 141, AUROC 0.915 vs 0.938, P = .66). Optimal cutoff value of serum 5-HIAA for the diagnosis of CS was 139.4 nmol/L (sensitivity 96.3%, specificity 87.6%) as determined in a subgroup analysis of SSA-naive patients with CS and controls. Serum 5-HIAA correlated well with 24-hour urine 5-HIAA (r = 0.892, P < .001) and the presence of flushing, diarrhea, and carcinoid heart disease (odds ratio 1.047-1.073 for every 100 nmol/L increase, P < .001).

Conclusion: Serum 5-HIAA measurements are equivalent to 24-hour urine 5-HIAA measurements for the diagnosis of CS in patients with NET and form an accessible alternative.

Context: The use of corticosteroids (CS) has been associated with higher body mass index (BMI) and waist circumference (WC) in cross-sectional studies. However, longitudinal data are scarce, particularly for locally administered forms.

Design: We analyzed weight and waist circumference changes in 81 361 Lifelines Cohort Study participants (mean age 46.3 years, mean BMI 26.0 kg/m2, 41% male, mean follow-up 3.9 years) via linear regression. Sensitivity analyses included stratification by sex and BMI. Short-term weight changes post-start were assessed in a subset using linear mixed-effect models.

Results: We found 23.8% CS users during the study period. Individuals reporting any new use of CS gained significantly more weight compared to nonusers at follow-up (β .034 kg/year, P = .021), particularly among those initiating local CS use (β .037 kg/year, P = .017). Use of new systemic CS was associated with increased WC (β .200 cm/year, P < .001). Discontinuation of CS led to decreased WC (β -.078 cm/year, P = .028). These effects were particularly observed in female participants and individuals with BMI ≥25 kg/m2, but not in male participants and those with BMI < 25 kg/m2. Short-term weight-inducing effects of CS were not observed in the weeks after initiation of CS use.

Conclusion: This study demonstrates that CS use, including locally administered forms, is associated with long-term increases in weight and WC, notably in female individuals and those with overweight or obesity. Discontinuing CS was linked to reductions in WC. These findings underscore the need to carefully assess chronic systemic and local CS use, as discontinuation could benefit obesity-related outcomes in certain patients.

Context: Immune checkpoint inhibitor (ICI)-related hypothyroidism is mostly irreversible and prompt thyroid hormone replacement therapy is crucial, especially for patients undergoing neoadjuvant immunotherapy.

Objective: This study aimed to propose a novel titration strategy for ICI-related hypothyroidism, evaluate levothyroxine (LT4) dose differences between hypothyroidism patterns, and develop a predictive equation for the optimal LT4 dose.

Design: Retrospective study.

Setting: Tertiary academic hospital.

Patients: A total of 109 patients with ICI-related hypothyroidism.

Interventions: Rapid vs conventional titration strategy.

Main outcome measures: The time to achieve normal free thyroxine and TSH levels.

Results: Patients with transient thyrotoxicosis followed by overt hypothyroidism required higher LT4 doses to achieve a euthyroid state compared to isolated overt hypothyroidism, with a mean difference of 0.23 μg/kg/day (95% CI, 0.08-0.38). In patients with ICI-related overt hypothyroidism and no cardiac disease, who had elevated TSH levels within 4 weeks of the last documented low or normal TSH, a rapid titration strategy was implemented. This strategy significantly improved the cumulative incidence of achieving normal free thyroxine and TSH levels compared to conventional titration strategy (hazard ratio, 4.44; 95% CI, 2.24-8.82; and hazard ratio, 4.11; 95% CI, 2.18-7.73, respectively), with a comparable safety profile. Predicted LT4 dose at euthyroid state (µg/kg/day) = (-0.016 × body weight) + (0.109 × baseline TSH level) + 2.661 for patients with thyrotoxicosis followed by overt hypothyroidism.

Conclusion: LT4 requirements vary depending on the subtype of ICI-related hypothyroidism. The rapid titration strategy reduced the time to achieve a euthyroid state without a significant increase in adverse effects compared to conventional LT4 replacement therapy.

Objective: Type 2 diabetes risk prediction models lack the option to predict risk conditional on initiating different preventive interventions. Our objective was to develop and validate a diabetes risk prediction model with individualized preventive intervention effects among racially diverse populations.

Methods: The derivation cohort included participants in the Diabetes Prevention Program (DPP) trial randomized to placebo, metformin, or intensive lifestyle intervention (n = 2640). A risk prediction model for incident diabetes was developed using Cox proportional hazards regression using clinically available predictors: sex, glycated hemoglobin, fasting plasma glucose (FPG), body mass index (BMI), triglycerides, and intervention. To create individualized intervention effects, pairwise interactions between intervention and age, FPG, and BMI were included. The discrimination, calibration, and net benefit of the model's 3-year predictions for incident diabetes were internally validated within the DPP and externally validated among participants with prediabetes in the Multi-Ethnic Study of Atherosclerosis (MESA; n = 2104).

Results: In DPP and MESA, mean (SD) age was 51 years (11) and 64 (10), and 67% and 50% of participants were women, respectively. The mean C-statistic was 0.71 [95% confidence interval (CI): 0.68, 0.74] in DPP and 0.86 (95% CI: 0.83, 0.88) in MESA. The optimal preventive intervention (lowest 3-year risk) was lifestyle for 86% and 97% of DPP and MESA participants, respectively, and metformin for the remaining. Model performance was similar across race/ethnicity groups.

Conclusion: This is the first study to develop and validate a diabetes risk prediction model with individualized preventive intervention effects that may improve clinical decision-making and diabetes prevention.

Context: Epidemiological data suggest that participants with lower vs higher body mass index (BMI) resist exposure to the obesogenic environment.

Objective: To test this, we analyzed the relationship between overfeeding-induced weight and fat mass gains with baseline BMI and body fat percentage.

Methods: In this controlled intervention study, 34 men (age 26 ± 5 years; BMI 25.5 ± 2.4 kg/m2; body fat [by dual-energy x-ray absorptiometry] 19.3 ± 5.1%) consumed for 8 weeks 40% more energy than needed at weight maintenance. The energy costs of weight and fat mass gain were calculated as the 8-week excess energy consumed divided by weight or fat mass gain. Energy expenditure (baseline and after overfeeding) was determined using a metabolic chamber and doubly labeled water. Transcriptomic analysis was conducted from abdominal subcutaneous adipose tissue samples.

Results: Body weight increased 7.2 ± 2.1 kg and fat mass 4.0 ± 1.4 kg. There was no statistical association between baseline BMI and weight and fat mass gains. However, baseline body fat percentage was significantly associated with weight (r = 0.57) and fat mass (r = 0.59) gains. Body fat percentage was also statistically associated with energy cost of weight (r = -0.38) and fat mass (r = -0.40) gains. Metabolic adaptation in energy expenditure (adaptive thermogenesis) was unrelated to the energy cost of weight and fat mass gains. Transcriptomics analysis showed that high energy cost of weight gain was associated with upregulation of inflammation-related pathways.

Conclusion: Body fat percentage at baseline was inversely associated with overfeeding-induced weight and fat gain resistance. The underlying compensatory response appears unrelated to changes in energy expenditure.