Journal of Clinical Endocrinology & Metabolism最新文献

Context: Staging preclinical type 1 diabetes (T1D) and monitoring the response to disease-modifying treatments rely on the oral glucose tolerance test (OGTT). However, it is unknown whether OGTT-derived measures of beta-cell function can detect subtle changes in metabolic phenotype, thus limiting their usability as endpoints in prevention trials.

Methods: We characterized the metabolic phenotype of individuals with islet autoimmunity in the absence (Stage 1) or presence (Stage 2) of dysglycemia. Participants were screened at a TrialNet site and underwent a 5-point, 2-hour OGTT. Standard measures of insulin secretion (AUC C-peptide, HOMA2-B) and sensitivity (HOMA-IR, HOMA2-S, Matsuda Index) and oral minimal model derived insulin secretion (phi total), sensitivity (SI), and clearance were adopted to characterize the cohort.

Results: Thirty participants with Stage 1 and 27 with Stage 2 T1D were selected. Standard metrics of insulin secretion and sensitivity did not differ between Stage 1 and Stage 2 T1D, while the oral minimal model revealed lower insulin secretion (p<0.001) and sensitivity (p=0.034) in those with Stage 2 T1D, as well as increased insulin clearance (p=0.006). A higher baseline phi total was associated with reduced odds of disease progression, independent of Stage [OR 0.92 (0.86, 0.98), p=0.016].

Conclusion: The oral minimal model describes the differential metabolic phenotype of Stage 1 and Stage 2 T1D and identifies phi total as a progression predictor. This supports its use as a sensitive tool and endpoint for T1D prevention trials.

Context: Dual oxidases (DUOXs) are essential for thyroid hormone synthesis. Rare DUOX variations have been detected in patients with congenital hypothyroidism (CH); however, their mode of inheritance and genotype-phenotype correlations remain unclear. Additionally, no study has determined whether common DUOX variants confer a risk of CH.

Objective: To elucidate the molecular and clinical characteristics of CH caused by rare and common DUOX variants.

Methods: Targeted next-generation sequencing was performed on 203 trios (parents and their child with CH) to screen for rare DUOX variants. For common variants, eight tag single nucleotide polymorphisms (SNPs) were genotyped among 298 trios and 439 healthy controls. The association between these SNPs and CH risk was analyzed using a case-control study and a family-based transmission disequilibrium test.

Results: The genetic contribution of rare DUOX variants to CH was 16.3% (DUOX2 14.3% and DUOXA2 2.0%). Familial co-segregation analysis suggested that DUOX variants were transmitted by an autosomal recessive pattern. These patients exhibited dyshormonogenesis and were more likely to develop into transient CH with the lower requirement of levothyroxine dose. Regarding common variants, five SNPs distributed across DUOXs were significantly associated with CH in both the case-control and family-based study. DUOX1 rs16939752 C>T and DUOXA1 rs3784576 C>A protected against CH, whereas DUOX2 rs269868 A>G, rs2001616 A>G and DUOXA2 rs2252371 T>C were associated with increased susceptibility to CH.

Conclusion: Our research confirmed that DUOX variants are inherited in an autosomal recessive manner. We present a comprehensive spectrum of rare and common DUOX variants that provides more accurate insights into the pathogenesis of CH associated with DUOX.

Background: Tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) were recognized to cause endocrine adverse reactions (EARs). However, combination therapy-associated EARs are still unclear.

Methods: This was a retrospective study based on FDA Adverse Event Reporting System. We identified 938,464 cases of all adverse events related to three types of treatments. A total of 22,275 cases were EARs and divided into TKIs (n=9,181), ICIs (n=11,363) and TKIs+ICIs group (n=1,731).

Results: The incidence of EARs was the highest in TKIs+ICIs followed by ICIs and TKIs group. TKIs+ICIs group had a higher risk of hypothyroidism than in ICIs group (OR 1.47, 95% CI [1.28-1.69]), while a lower risk compared to TKIs group (OR 0.68, 95% CI [0.58-0.79]). TKIs+ICIs group presented a higher risk of type 1 diabetes mellitus compared to TKIs group (OR 26.61, 95% CI [18.60-38.07]), but a lower risk compared to ICIs group (OR 0.63, 95% CI [0.47-0.84]). The risk of hypoglycaemia was approximately 2.77 times greater in TKIs+ICIs group than in ICIs group (OR 2.77, 95% CI [1.95-3.95]) and was also higher in TKIs group compared to ICIs group (OR 3.44, 95% CI [2.93-4.03]). Compared to ICIs group, TKIs+ICIs group did not display a higher risk of pituitary dysfunction and primary adrenal insufficiency. The mortality risk of TKIs+ICIs group was comparable to ICIs groups, but significantly lower than TKIs group.

Conclusions: EARs were more common in TKIs+ICIs therapy. The distribution of EARs in different glands varied among combination therapy and monotherapy. Combination therapy-associated EARs did not increase the risk of mortality.

Context: Diabetic kidney disease (DKD) is associated with an increased risk of cardiovascular events, end-stage renal disease, and mortality. Advanced glycation end products (AGEs) are related to DKD. However, data on the associations between long-term changes in AGEs and DKD are lacking.

Objective: We aimed to ascertain whether a long-term shift in serum AGE levels is associated with DKD development and progression in patients with poorly controlled diabetes.

Methods: The serum levels of the AGE, methylglyoxal-hydroimidazolone (MG-H1) were measured twice in 160 patients with diabetes. We categorized patients whose serum MG-H1 levels were <2.5 µg/mL at both measurements as the consistently low MG-H1 group. The primary endpoints were new or worsening DKD, which was defined as the occurrence of either a 30% decline in estimated glomerular filtration rate (eGFR), doubling of serum creatinine, development of macroalbuminuria, need for renal replacement therapy, or death due to renal disease. Hazard ratios (HRs) for new or worsening DKD, with 95% confidence intervals (CIs), were calculated using Cox proportional hazard models to compare the outcomes between the consistently low MG-H1 group and the other group.

Results: Compared to the other group, the consistently low MG-H1 group had a significantly lower risk of new or worsening DKD, after adjusting for possible confounders (HR: 0.48; 95% CI, 0.29-0.81; P = 0.01). Furthermore, the same relationship was observed in patients without eGFR <30 mL/min/1.73 m2, advanced DKD, or cardiovascular events.

Conclusions: Consistently low serum MG-H1 levels are associated with a lower frequency of DKD.

Aim: Metabolic dysfunction-associated steatotic liver disease (MASLD) is an umbrella term for simple hepatic steatosis and the more severe metabolic dysfunction-associated steatohepatitis. The current reliance on liver biopsy for diagnosis and a lack of validated biomarkers are major factors contributing to the overall burden of MASLD. This study investigates the association between biomarkers and hepatic steatosis and stiffness measurements, measured by FibroScan®.

Methods: Data from the National Health and Nutritional Examination Survey (2017-2020) was collected for 15,560 patients. Propensity score matching balanced the data with a 1:1 case-to-control for age and sex allowing for preliminary trend assessment. Random Forest machine learning determined variable importance for the incorporation of key biomarkers (age, sex, race, BMI, HbA1C, PFG, insulin, total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, ALT, AST, ALP, albumin, GGT, LDH, iron, total bilirubin, total protein, uric acid, BUN, and hs-CRP) into logistic regression models predicting steatosis (MASLD indicated by a controlled attenuation parameter™ score of >238 dB/m) and stiffness (hepatic fibrosis indicated by a median liver stiffness >7 kPa). Sensitivity analysis using XGBoost and Recursive Feature Elimination was performed.

Results: The Random Forest models (the most accurate) predicted MASLD with 79.59% accuracy (p<0.001) and specificity of 84.65% and, hepatic fibrosis with 86.07% accuracy (p<0.001) and sensitivity of 98.01%. Both the steatosis and stiffness models identified statistically significant biomarkers, with age, BMI, and insulin appearing significant to both.

Conclusion: These findings indicate that assessing a variety of biomarkers, across demographic, metabolic, lipid, and standard biochemistry categories, may provide valuable initial insights for diagnosing patients for MASLD and hepatic fibrosis.

Context: Hip fractures incur high morbidity and mortality. Data on secular trends in mortality from hip fractures and risk predictive models are scarce.

Objective: We aim to describe secular trends in 30-day mortality post-hip fracture surgery from the 2011-2017 National Surgical Quality Improvement Program (NSQIP) database, identify preoperative and on-discharge predictors of 30-day mortality and develop risk calculators.

Methods: We calculated yearly proportions of deaths and examined survival using Kaplan Meier curves. We implemented logistic regressions models, using SPSS and created calculators using Excel.

Results: In 84,824 cases of hip fracture surgery, the overall 30-day mortality was 6.8%. It decreased from 8.1% to 6.5% between 2011 and 2017 (p<0.001). Significant preoperative predictors of 30-day mortality on admission were male gender, age, lower BMI, white race, poorer functional health status, higher creatinine, lower hematocrit, >10% weight loss in the past 6 months, congestive heart failure within 30 days before surgery, and chronic obstructive pulmonary disease. Predictors on discharge included preoperative predictors with the exception of white race, hematocrit and > 10% weight loss in the past 6 months, and the addition of unplanned intubation, cerebrovascular accident, myocardial infarction, and pneumonia. The parsimonious preoperative risk calculator for mortality had 10 variables, an area under the curve (AUC) of 0.739, and a model fit R2 of 0.9716. The on-discharge calculator had 11 variables, an AUC of 0.800, and an R2 of 0.9924.

Conclusion: 30-day mortality post-hip fracture surgery decreased significantly from 2011 to 2017. Readily available clinical risk factors predict mortality, preoperatively and on discharge. While most predictors are non-modifiable, the calculators may better inform clinical decision-making.

Context: Immunohistochemistry (IHC) of cell lineage-specific transcription factors (TFs) has been added to the histopathological classification of pituitary adenomas since 2017, resulting in new histopathological subtypes of TF+/hormone- non-functioning pituitary adenomas (NFPAs) and a reduction in the prevalence of null cell adenomas (NCAs).

Objective: To evaluate associations between expression of cell lineage-specific TFs by IHC and radiological invasion and prognosis of NFPAs.

Data sources: A literature search in Medline, Embase, and CENTRAL was performed from inception up to July 11th 2023.

Study selection: Eligible studies were cohort studies reporting on radiological invasion, recurrence and/or radiotherapy in patients with NFPAs who tested positive for one cell lineage-specific TF or negative for all three. Finally, 27 out of 1985 studies were included.

Data extraction: Two authors independently extracted data and critically appraised risk of bias using the QUIPS tool.

Data synthesis: Random-effects inverse variance models were used to pool effect sizes. Prevalence rate ratios (PRR) were calculated using the Mantel-Haenszel method. Cavernous sinus invasion was more prevalent in NCAs and TPIT+ NFPAs compared with SF1+ NFPAs (PRR 1.60, 95% confidence interval (CI) 1.22-2.08, I2 10%, 95% prediction interval (PrI) 1.23-2.06, p=0.0036, and PRR 1.43, 95% CI 1.21-1.70, I2 0%, 95% PrI 1.17-1.76, p=0.0017, respectively), and in NCAs compared with PIT1+ (PRR 1.44, 95% CI 1.01-2.06, I2 0%, 95% PrI 0.83-2.50, p=0.0454). Limited number of studies precluded data syntheses of recurrence and radiotherapy.

Conclusions: The use of cell lineage-specific TFs by IHC enables to detect histopathological subtypes of NFPAs with distinct clinical behaviour.

Background: Highly effective CFTR modulators, such as elexacaftor/tezacaftor/ivacaftor (ETI), herald a new era in therapeutic strategy of cystic fibrosis (CF). ETI impact on glucose tolerance remains controversial.

Methods: All the participants underwent a baseline oral glucose tolerance test (OGTT) before ETI initiation (M0) and 12 months (M12), and at 24 months if possible. The cohort was stratified in two subgroups based on the baseline OGTT: normal glucose tolerance (NGT) and abnormal glucose tolerance (AGT) defined by impaired fasting glucose or impaired glucose tolerance or diabetes not requiring insulin treatment.

Results: We included 106 adolescents with CF (age 14.1±1.5 years), 75 with NGT, 31 with AGT. The baseline characteristics of the two groups were similar except for a higher glucose level at 1 and 2-h OGTT in the AGT group. ETI induced an increase in BMIz-score and in Forced Expiratory Volume in 1 second (FEV1) (p<0.001). After 12 months, participants with NGT did not experience any change of 1-h and 2-h glucose. By contrast, those with AGT displayed a reduction of 2-h glucose at M12 (p=0.006). 15out of the 31 (48%) adolescents in the AGT group reversed to NGT but 9/75 (17%) in the NGT group progressed to AGT. 3 participants with CF related diabetes at baseline reversed to AGT. 1-hour glucose concentrations at or above 8.7 mmol/L (157mg/dL) during baseline OGTT had 80% sensitivity to identify those with AGT at 12 months (OR 1.51 [1.20, 1.92], p=0.001). 20 participants had a 24-month OGTT that confirmed preserved insulin secretion.

Conclusion: ETI may improve glucose tolerance in adolescents with CF by preserving insulin secretion. 1-hour glucose during the OGTT helps to detect risk for AGT after ETI treatment.