Journal of Clinical Endocrinology & Metabolism最新文献

Context: Accurate assessment of the inflammatory status in thyroid eye disease (TED) is crucial for diagnosis and treatment; however, this assessment remains challenging.

Objectives: To study whether thyrotrophin receptor antibody (TRAb) can be utilized as a quantitative and objective indicator of the inflammatory status in patients with TED.

Methods: We gathered and analyzed TRAb and clinical characteristics from 226 consecutive TED patients. Additionally, we examined 27 inflammatory cytokines in the orbital adipose tissue of 41 patients and assessed the alterations in TRAb following IV methylprednisolone (IVMP) therapy in 40 patients.

Results: The 226 TED patients included 116 females and 110 males, with a mean age of 46.4 ± 12.2 years. The correlation between TRAb and clinical activity score (CAS) was the most pronounced (r = 0.427; P < .001). TRAb was identified as the most influential factor for CAS. Subsequent investigation into the relationship between TRAb and pathological inflammation revealed that TRAb exhibited a significant positive correlation with 7 proinflammatory cytokines [Interleukin (IL)-8, chemokine (C-C motif) ligand 3 (CCL-3), serpin E1, platelet-derived growth factor (PDGF)-AB, IL-12p70, IL-21, and PDGF-BB] and a significant negative correlation with 1 anti-inflammatory cytokine [bone morphogenetic protein 7 (BMP-7)]. IL-8, CCL-3, serpin E1, PDGF-AB, and IL-1β were significantly upregulated in the orbital adipose tissue of TRAb-positive patients compared to TRAb-negative patients. In contrast, BMP-7 demonstrated an opposite trend. Additionally, TRAb and CAS significantly decreased following IVMP therapy, with a significant correlation between the extent of reduction in TRAb and CAS.

Conclusion: TRAb significantly correlated with both CAS (clinical inflammation indicator) and inflammatory cytokines (pathological inflammation marker). Consequently, we propose, for the first time, that TRAb may serve as an objective and quantitative biomarker for assessing inflammation in TED.

Context: Dyslipidemia adversely affects female fertility; however, its relation with recurrent pregnancy loss (RPL) and its underlying mechanisms remains unclear.

Objective: This study aims to analyze the impact of dyslipidemia on natural killer (NK) cell cytotoxicities and autoimmunity in women with RPL and to elucidate how lipids affect cellular immunity.

Design: A retrospective cross-sectional study with ex vivo experiments.

Setting: University clinic.

Patients: One hundred fifteen RPL women, including 70 nondyslipidemia and 45 dyslipidemia women.

Interventions: Dyslipidemia.

Main outcome measures: Cellular immune activity and autoimmune parameters were evaluated.

Results: Out of 115 women, 45 (39.1%) had dyslipidemia. The prevalence of anti-single-stranded and anti-thyroglobulin antibodies was significantly higher in dyslipidemia women. NK cell cytotoxicity, measured at effector to target cell ratio (E:T) of 25:1 and 12.5:1, was significantly higher in women with dyslipidemia (P < .05). NK cell cytotoxicities (E:Ts of 25:1 and 12.5:1) were positively correlated with serum total cholesterol and low-density lipoprotein cholesterol levels (all P < .05). However, there were no differences in the T helper 1 (Th1)/Th2 cytokine-producing cell ratios between the two groups. The ex vivo study revealed that pretreatment with oxidized low density lipoprotein (oxLDL) enhanced the conjugation of NK cells with target cells and increased perforin secretion. NK cell cytotoxicities were significantly increased after pretreatment with 5 and 50 μg/mL oxLDL (P < .05 each).

Conclusion: A significant proportion of women with RPL have dyslipidemia, and the risk of autoimmune and cellular immune abnormalities is increased in women with a history of RPL and dyslipidemia.

Context: Relationship between obesity and the sense of taste is complex, with many inconsistent and conflicting findings that are largely methodology dependent. The impact of glucagon-like peptide-1 analogues on taste remains largely unaddressed.

Methods: In this 16-week, single-blinded, placebo-controlled study, 30 women with polycystic ovary syndrome (PCOS), aged 33.7 ± 6.1 years with a body mass index of 36.4 ± 4.4 kg/m2 were randomized to semaglutide 1.0 mg once weekly or placebo. Change in taste recognition was assessed by 16 strips impregnated with 4 different concentrations of the 4 basic tastes. Tongue biopsies were performed for gene expression analysis. Brain responses to visual cues of sweet and savory foods and to sweet solution dripping on the tongue were evaluated by functional magnetic resonance imaging.

Results: Semaglutide improved overall taste recognition score from 11.9 ± 1.9 points to 14.4 ± 1.0 points, with an estimated treatment difference of 2.5 points (95% CI, 1.7-3.3). The genes EYA, PRMT8, CRLF1, and CYP1B1, which are associated with taste signaling transduction pathways, neural plasticity, and renewal of taste buds, showed differential RNA expression by a multi-tiered analytical pipeline. Semaglutide decreased activation of putamen in response to visual food cues and increased activity in the angular gyrus of the parietal cortex in response to sweet solution after meal intake (semaglutide vs placebo, P < .001).

Conclusion: In women with obesity and PCOS, semaglutide improved an overall taste recognition score, altered RNA expression in the tongue and modified brain activity in response to sweet and savory food cues and to tasting sweet solution.

Context: The conventional approach to diet therapy for gestational diabetes mellitus (GDM) is carbohydrate modification to mitigate glucose-mediated fetal macrosomia. Maternal triglyceride concentrations more strongly relate to infant adiposity than maternal glucose.

Objective: This work aimed to assess the feasibility of a low-intensity dietary intervention designed to attenuate the rise in triglycerides compared to standard GDM management.

Methods: Women with GDM were randomly assigned at approximately 30 weeks' gestation to a standard care group (ie, usual GDM management) or to an intervention group, at an allocation ratio of 1:1. The intervention group received standard care plus individual counseling on reducing intake of ultraprocessed foods, increasing fruits, vegetables, fish and nuts, and changes to healthier fats. The primary outcome is study feasibility; secondary and exploratory outcomes include maternal dietary intakes, plasma triglyceride and glucose levels, and birth weight.

Results: Over 10 months of active recruitment, 444 women were invited to participate. Of these, 59 were eligible (13.2%), 38 (8.6%) consented and were randomly assigned (n = 19 intervention, n = 19 standard care), and 34 women completed the study. The recruitment rate was 1 per week, the retention rate was 89.5%, and the feasibility of eligibility criteria was 70.4%. Nearly all women in the intervention group who responded to the questionnaire (n = 15/16) reduced their ultraprocessed food intake, and 11 women increased their intake of nuts. There was no end of study differences in nonfasting plasma triglycerides (mean [95% CI] in intervention, 2.84 [2.22-3.46] mmol/L vs standard care, 3.40 [2.78-4.02] mmol/L). Mean birthweight was higher in the standard care group vs intervention group (mean difference [95% CI], 479.5 [110.7-848.3] g).

Conclusion: There was a modest recruitment rate and a high retention rate, indicating a diet aimed at attenuating triglycerides is feasible and highly acceptable in women with GDM. The positive improvements observed in maternal diet and desirable birth weight warrant further investigation in a larger, definitive, randomized controlled trial.

Context: Insulin resistance (IR) contributes to the pathogenesis of type 2 diabetes mellitus and is a risk factor for cardiovascular and neurodegenerative diseases. Amino acid and lipid metabolomic biomarkers associate with future type 2 diabetes mellitus risk in several epidemiological cohorts. Whether these biomarkers can accurately monitor changes in IR status following treatment is unclear.

Objective: Herein we evaluated the performance of clinical and metabolomic biomarker models to forecast altered IR, following lifestyle-based interventions.

Design: We contrasted the performance of two distinct insulin assay types (high-sensitivity ELISA and immunoassay) and built IR diagnostic models using cross-sectional clinical and metabolomic data. These models were used to stratify IR status in preintervention fasting samples, from 3 independent cohorts (META-PREDICT (n = 179), STRRIDE-AT/RT (n = 116), and STRRIDE-PD (n = 149)). Linear and Bayesian projective prediction strategies were used to evaluate models for fasting insulin and homeostatic model assessment 2 for insulin resistance and change in fasting insulin with treatment.

Results: Both insulin assays accurately quantified international standard insulin (R2 > 0.99), yet agreement between fasting insulins was less congruent (R2 = 0.65). A mean treatment effect on fasting insulin was only detectable using the ELISA. Clinical-metabolomic models were statistically related to fasting insulin (R2 0.33-0.39) but with modest capacity to classify IR at a clinically relevant homeostatic model assessment 2 for insulin resistance threshold. Furthermore, no model predicted treatment responses in any cohort.

Conclusion: We demonstrate that the choice of insulin assay is critical when quantifying the influence of treatment on fasting insulin, whereas none of the clinical-metabolomic biomarkers, identified in cross-sectional studies, are suitable for monitoring longitudinally changes in IR status.

Context: Choline is metabolized in kidney tubules but the relationship between choline metabolism and kidney disease has not been systematically characterized.

Objective: To study whether urine metabolites in the choline oxidation pathway may predict the risk of chronic kidney disease (CKD) progression in individuals with type 2 diabetes.

Methods: Outpatients (n = 1894) with type 2 diabetes were recruited from a secondary hospital and a primary care facility. Urine choline, betaine, dimethylglycine, and sarcosine were measured by liquid chromatography-mass spectrometry. CKD progression was defined as a composite of incident end-stage kidney disease (sustained eGFR <15 mL/min/1.73m2, maintenance dialysis, renal death) and doubling of serum creatinine.

Results: CKD progression occurred in 263 participants during a median follow-up of 9.2 years. High levels of urine choline and dimethylglycine were associated with an increased risk of CKD progression after adjustment for clinical risk factors (adjusted HR [95% CI], 1.32 [1.16-1.51] and 1.30 [1.14-1.47], respectively, per 1 SD). Urine choline and dimethylglycine were positively correlated with tubulopathy biomarkers, especially dickkopf-related protein 3 (dkk3, Spearman rho 0.55 and 0.53). The association between dkk3 and CKD progression was diminished but the association between choline, dimethylglycine, and CKD progression remained significant after mutual adjustments. Choline and dimethylglycine were also independently associated with risk of all-cause death (adjusted HR 1.20 [1.06-1.37] and 1.17 [1.04-1.33], respectively).

Conclusion: Urine choline and dimethylglycine independently predict the risk of CKD progression in individuals with type 2 diabetes. Dysregulation of intrarenal choline metabolism may be involved in tubulopathy leading to progressive loss of kidney function.

Context: Familial partial lipodystrophy, type 2 (FPLD2) or the Dunnigan variety, is a rare, autosomal dominant disorder characterized by selective loss of subcutaneous fat from the extremities and is caused by over 50 heterozygous missense LMNA variants. However, some patients with FPLD2 do not harbor the known pathogenic LMNA variants and there are only limited genotype-phenotype segregation data for a few other variants.

Objective: To report the genotype-phenotype relationships in 4 families with ultrarare and novel LMNA variants causing FPLD2.

Methods: Clinical, anthropometric, and laboratory data of affected and unaffected subjects from 4 families with female probands presenting with FPLD2 phenotype were collected retrospectively. The main parameters were clinical phenotype, skinfold thickness, regional body fat by dual-energy X-ray absorptiometry (DXA), metabolic variables, and prevalence of diabetes mellitus and hypertriglyceridemia.

Results: We found 2 ultrarare (p.N466D, and p.K515E) and 2 novel (p.R582S, and p.L241P) LMNA heterozygous variants in 4 unrelated FPLD2 families. All adult affected females had thigh skinfold thickness below the 10th percentile of normal and lower extremity fat below the 1st percentile of normal suggesting "typical" FPLD2. None of our patients had any cardiomyopathy, muscular dystrophy, neuropathy, or any progeroid features.

Conclusion: Our data provide further supporting evidence for the pathogenicity of 2 previously reported ultrarare heterozygous LMNA variants, p.N466D and p.K515E. We also report 2 novel variants, p.R582S and p.L241P, in patients with FPLD2. Thus, our study broadens the spectrum of pathogenic/likely pathogenic LMNA variants in FPLD2.

Context: More data are needed on the long-term postpartum metabolic risk of women with hyperglycemia in pregnancy less than gestational diabetes mellitus (GDM) based on the 2013 World Health Organization criteria.

Objective: This work aimed to determine the association of different degrees of gestational glucose intolerance (GI) on the metabolic profile and risk for GI in women and offspring 3 to 7 years postpartum.

Methods: This multicentric prospective follow-up study of the Belgian Diabetes in Pregnancy study (BEDIP-N, which was a prospective observational study) included 334 women and 296 children. Groups were stratified according to antenatal glucose challenge test (GCT) and diagnosis of GDM based on the 2013 World Health Organization criteria: normal glucose tolerant women with normal GCT (normal GCT-NGT group), NGT with abnormal GCT (abnormal GCT-NGT group), and a GDM group. Logistic regression was performed to adjust for following confounders: time since participation in BEDIP-N, ethnicity, prepregnancy body mass index (BMI), age, and current BMI.

Results: The GCT cutoff with the highest Youden index to predict GI in mothers 5.7 years postpartum was greater than or equal to 8.3 mmol/L (≥150 mg/dL). NGT women with GCT greater than or equal to 8.3 mmol/L (abnormal GCT-NGT group, n = 39) had a similarly increased risk for GI as women with GDM (n = 82) with an adjusted odds ratio of 2.87 (1.47-5.60; P = .0020) compared to the normal GCT-NGT group (n = 213). β-Cell function decreased over the different gestational glucose tolerance groups, with similar β-cell dysfunction in the GDM and abnormal GCT-NGT groups. Offspring of women with hyperglycemia less than GDM did not have an increased risk for an adverse metabolic profile postpartum.

Conclusion: NGT women with GCT greater than or equal to 8.3 mmol/L (≥150 mg/dL) in pregnancy have a similarly high risk for GI 5.7 years postpartum as women with GDM. These women also need postpartum follow-up to prevent GI.