Journal of Clinical Endocrinology & Metabolism最新文献

Context: The glucose management indicator (GMI) is an estimated glycated hemoglobin (A1C) derived from sensor glucose. Though it is being used to approximate A1C in clinical trials, there are no data on direction and magnitude of change in GMI vs A1C after an intervention.

Objective: To evaluate the magnitude and direction of changes in A1C compared to GMI across different baseline glycemic categories in type 1 diabetes (T1D) clinical trials.

Methods: Baseline and 3-month central laboratory-measured A1C and estimated GMI from sensor glucose were collected from T1D clinical trials (DCLP3, DCLP5, and WISDM), encompassing children, adolescents, adults, and older adults. Magnitude and direction of changes (baseline-3 months) in A1C vs GMI were compared overall across the studies and by stratified baseline A1C (<7%, 7%-9%, >9%).

Results: A modest correlation was found between changes in A1C and GMI (r = 0.34). Participants with baseline A1C > 9% had larger reductions in A1C compared to GMI (-1.2 [-2.1 to -0.6] vs -0.6 [-0.94 to 0], P < .01). Those with baseline A1C between 7% and 9% showed a greater decline in A1C than GMI (-0.4 [-0.9 to -0.1] vs -0.12 [-0.49 to 0.21], P < .01). No significant difference was observed for baseline A1C < 7%.

Conclusion: Change in GMI is influenced by the baseline A1C of the participants and it underestimates the true change in A1C. Use of GMI as an endpoint in clinical trials may not reliably capture efficacy of an intervention in T1D trials or real-world studies.

Context: Very-low-calorie ketogenic diet (VLCKD) is used for weight loss and management of obesity-related comorbidities.

Objective: We aimed at evaluating the effects of VLCKD on body composition and energy metabolism.

Methods: This prospective outpatient study included 17 women with obesity (mean age 41.6 years; body mass index 37.5 kg/m2) who followed a 1-month VLCKD (700-800 kcal/day, carbohydrate 11%, fat 46%, protein 43%) at the University Hospital of Pisa. Measurements of 24-hour energy expenditure (24hEE) and substrate oxidation were conducted in a metabolic chamber at day 1 (V1), day 8 (V2), and day 29 (V3). Body composition was assessed by Dual energy X-ray absorptiometry. Twenty-two women with obesity fed a balanced isocaloric diet served as controls.

Results: Compared with controls, carbohydrate oxidation (CarbOx) was lower, whereas fat oxidation (FatOx) and protein oxidation (ProtOx) were higher in the VLCKD group at V1. CarbOx decreased by 65%, while FatOx increased by 11% at V3. The rate of ProtOx was already higher than in controls at V1 and remained stable throughout the study. After 1 month, body weight decreased by 7%, reflecting an 8.8% reduction in fat mass and a 5.6% reduction in lean soft tissue (LST). A 10% decrease in 24hEE and 24-hour sleeping metabolic rate was observed at V3 compared with V1.

Conclusion: VLCKD promotes weight loss in women with obesity. Our findings highlight the shift in energy metabolism towards increased FatOx accompanied by a modest increase in protein oxidation, a decrease in LST and a reduction in EE.

Context: A preclinical state of Graves' ophthalmopathy (pre-GO) exists during the progression from Graves' hyperthyroidism (GH) to GO.

Objective: To distinguish the pre-GO state and identify key pathways of T-cell immunity.

Methods: Twenty-four GH (without ophthalmopathy within 6-month follow-up), 10 pre-GO (ophthalmopathy occurred within 6-month follow-up), and 21 GO patients were enrolled, and the transcription and DNA methylation profiles of peripheral blood mononuclear cells were generated. The differentially expressed genes (DEGs), differentially methylated CpG sites (DMCs), and differentially methylated genes (DMGs) were identified. Cluster analysis, functional analysis, and data integration analysis using latent components (DIABLO) were performed to distinguish pre-GO and identify key pathways. Flow cytometry was performed for in vitro verification.

Results: In total, 731, 1214, and 372 DEGs and 1583, 277, and 555 DMCs were detected via pairwise comparisons of GH vs GO, pre-GO vs GO, and GH vs pre-GO, respectively. DIABLO accurately discriminated the pre-GO state via 17 DMC and 11 DEG features ( receiver operating characteristic = 0.9975 and 0.9407, respectively). The functional analysis revealed that the DMGs and DEGs were enriched in T-cell differentiation pathways and related cytokine pathways, respectively. Further cluster analysis revealed a cluster of pre-GO-specific DEGs enriched in the hypoxia pathway. Flow cytometry confirmed that hypoxia promoted Th1, Th17, and antigen-specific CD4+ cytotoxic T-cell differentiation.

Conclusion: The pre-GO state was identified from GH and GO and characterized by upregulation of the hypoxia pathway that may promote effector CD4+ T-cells differentiation. These findings provide new insight into the pathogenesis and prevention of GO.

Context: Congenital hypogonadotropic hypogonadism (CHH) in infant boys is a rare disorder that can manifest as micropenis and/or cryptorchidism. Mini-puberty is considered a window of opportunity for CHH diagnosis and treatment. The lack of testosterone (T) elevation during this period is the gold standard for CHH diagnosis, but hormonal evaluation is not always available at this time.

Objectives: The aim was to compare inhibin B (INHB), anti-Müllerian hormone (AMH), T, LH, and FSH between infant boys (1 to 365 days) with micropenis and/or cryptorchidism due to isolated CHH (iCHH), CHH as part of combined pituitary hormone deficiency (CPHD), or of idiopathic origin (controls) and to determine discriminating cutoffs for CHH diagnosis based on sensitivity (Se) and specificity (Sp).

Methods: This multicenter study from 7 University Hospitals in France included 138 boys aged 0 to 12 months (58 with iCHH, including 28 with a positive molecular diagnosis, 32 with CPHD, and 48 controls). Four periods of interest were studied: between 1 to 4 days, 15 to 65 days (early mini-puberty, corresponding to the T peak), 66 to 179 days (late mini-puberty), and 180 to 365 days (post mini-puberty).

Results: Out of mini-puberty, the best-discriminating hormones were INHB between 1 to 4 days (Se/Sp 100%/75% at 150 pg/mL and 89%/100% at 85 pg/mL) and INHB and AMH after 180 days (INHB: Se/Sp 100%/100% at 100 pg/mL; AMH: Se/Sp 100%/92% at 600 pmol/L, and 75%/100% at 370 pmol/L). INHB and/or AMH discriminating performances were good (area under the receiver operating characteristic curve ≥ 0.95) across all 4 periods.

Conclusion: Inhibin B and/or AMH can be used to diagnose CHH in boys < 1 year of age.

Context: The relationship between initial changes in estimated glomerular filtration rate (eGFR) and urine albumin to creatinine ratio (UACR), and their independent association with clinical outcomes in type 2 diabetes (T2D) patients receiving sodium-glucose cotransporter 2 inhibitors (SGLT2is), remains unclear.

Objective: This study aimed to investigate the association between initial changes in eGFR and UACR with consequent cardiovascular and kidney outcomes in an Asian population with T2D following SGLT2i treatment in a real-world setting.

Methods: Using a large multicenter medical database in Taiwan, we analyzed 8222 T2D patients with baseline and 3-month follow-up eGFR and UACR measurements, receiving SGLT2is between June 1, 2016, and December 31, 2021. We assessed risks of major adverse renal events (MARE), major adverse cardiovascular events (MACE), hospitalization for heart failure (HHF), and all-cause mortality using a Cox proportional hazards model.

Results: After 3 months of SGLT2i treatment, patients were categorized based on early changes in eGFR (no decline, 0%-10% decline, > 10% decline) and UACR (no reduction, 0%-30% reduction, > 30% reduction). Among those with no initial eGFR decline (40.9%), 19.8% had no initial UACR reduction, 8.4% had 0% to 30% reduction, and 12.7% had greater than 30% reduction. For those with greater than 10% initial eGFR decline (21.5%), 6.5% had no UACR reduction, 4.3% had 0% to 30% reduction, and 10.7% had greater than 30% reduction. Patients with greater than 10% initial eGFR decline but no UACR reduction showed higher risks of MARE (adjusted HR [aHR]: 2.34; 95% CI, 1.32-4.15), MACE (aHR: 1.83; 95% CI, 1.01-3.29), and HHF/cardiovascular death (aHR: 1.93; 95% CI, 1.05-3.55) compared to those with modest early eGFR decline and UACR reduction.

Conclusion: T2D patients experiencing profound early eGFR decline without concordant UACR reduction while on SGLT2is represent a high-risk subgroup with worse clinical outcomes. These findings suggest the need for closer monitoring and potentially more aggressive therapeutic strategies for this patient population.

Context: 47,XXY/Klinefelter syndrome (XXY) is associated with impaired testicular function and differences in physical growth, metabolism, and neurodevelopment. Clinical features of XXY may be influenced by testosterone during the minipuberty period of infancy.

Objective: We tested the hypothesis that exogenous testosterone treatment positively affects short-term physical, hormonal, and neurodevelopmental outcomes in infants with XXY.

Design: Double-blind randomized controlled trial, 2017-2021.

Setting: US tertiary care pediatric hospital.

Patients: Infants 30 to 90 days of age with prenatally identified, nonmosaic 47,XXY (n = 71).

Intervention: Testosterone cypionate 25 mg IM injections every 4 weeks for 3 doses.

Main outcome measures: The a priori primary outcomes were change in percent fat mass z-scores and change in the total composite percentile on Alberta Infant Motor Scales assessment from baseline to 12 weeks.

Results: The between-group difference in change in percent fat mass z-scores was -0.57 (95% CI, -1.1 to -0.06; P = .03), secondary to greater increases in lean mass in the testosterone-treated group (1.5 ± 0.4 kg vs 1.2 ± 0.4; P = .001). Testosterone suppressed gonadotropins and inhibin B (P < .001 for all). In contrast, there were no significant group differences in short-term motor, cognitive, or language outcomes (P > .15 for all).

Conclusions: In this double-blind randomized controlled trial in infants with XXY, testosterone injections resulted in physical effects attributable to systemic androgen exposure; however, this dose suppressed the hypothalamic-pituitary-gonadal axis. Neurodevelopment outcomes were not impacted by treatment. These results do not support routine testosterone treatment in infants with XXY; however, long-term follow-up on physical health, neurodevelopment, and testicular function is needed.

Context: Increasing evidence supports the presence of oxytocin deficiency (OXT-D) in hypopituitarism and hypothalamic damage (HHD). Identifying an applicable and reliable test to diagnose OXT-D is an unmet need. Melatonin (MEL) might be a candidate for such a test as it regulates OXT release in animals.

Objective: This work aimed to examine the effects of melatonin on OXT release in HHD compared to healthy controls (HCs) and to describe the psychopathology, sexual function, and quality of life (QoL) and their associations with OXT.

Methods: This proof-of-concept study (NCT05319301) included 20 participants with HHD (11 women) and 20 HCs (11 women). Blood samples were collected over 120 minutes to assess plasma OXT. A linear mixed-effects regression model was used to evaluate the change in OXT in response to MEL in HHD compared to HCs.

Results: MEL significantly increased OXT at T90 vs T0 in HCs compared to the HHD group (difference 14.57 pg/mL 26% increase; 95% CI, 1.90-27.23; P = .02). The HHD group had more depression symptoms, alexithymia, impaired sexual function, and worse QoL compared to HCs. The mean percentage change in OXT from T0 to T90 was negatively associated with depressive and alexithymia symptoms in the HHD group and anxiety in both groups.

Conclusion: The reduced OXT response after MEL in HHD supports the existence of an impaired OXT response at least in a subset of patients with HHD. The associations between OXT changes and psychopathology suggest its role in mood and QoL. These findings support further investigation into MEL's role as a diagnostic tool to address OXT-D.

Context: The transformation of follicular granulosa cells into luteal cells of the corpus luteum remains poorly understood in the human ovary.

Objective: To investigate the luteinization process and steroidogenic differences between granulosa cells from small antral and preovulatory follicles in vitro.

Methods: At the University Hospital of Copenhagen, Denmark, and Wake Forest Institute for Regenerative Medicine, USA, granulosa-lutein cells were obtained from 12 women undergoing IVF treatment, while follicular granulosa cells from unstimulated small antral follicles and corpus luteum were collected from 18 women undergoing ovarian tissue cryopreservation. Cells were cultured for up to 96 hours or 12 days with or without androstenedione or testosterone supplementation and analyzed using RT-qPCR and steroid hormone assays.

Results: In follicular granulosa cells, luteinization markers (CYP11A1, P < .05; STAR, P < .001) increased within 24 to 48 hours, while granulosa markers (HSD17β1, P < .001; CYP19A1, P < .05) decreased within 6 to 12 hours. Luteinizing hormone/choriogonadotropin receptor remained unchanged. By 48 hours, gene expression resembled that of the corpus luteum. In contrast, granulosa-lutein cells exhibited highly luteinized profiles from day 0, with significantly higher progesterone/(17)estradiol ratios. Androgen supplementation and long-term follicle-stimulating hormone exposure did not alter luteinization.

Conclusion: This study uniquely demonstrates that unstimulated follicular granulosa cells undergo a gradual, intrinsic luteinization process, independent of external hormonal triggers. In contrast, granulosa-lutein cells are already highly luteinized upon aspiration. These findings challenge conventional views on luteinization and highlight intrinsic cellular programming as a key driver, offering new insights into ovarian physiology and potential therapeutic targets for reproductive disorders.

Context: Transitioning from pediatric to adult-centered diabetes care may be challenging, especially for young individuals at risk for and with youth-onset type 2 diabetes (Y-T2D) who have a high disease burden and rapidly progressive disease. However, the scope of transition readiness, range of psychosocial factors, and perceived barriers among Y-T2D are understudied.

Objective: In Y-T2D attending an adult diabetes transition clinic, our objectives were to (1) characterize attitudes toward transition readiness, (2) examine relationships among depressive and anxiety-related symptoms and transition readiness, and (3) identify perceived barriers and facilitators of diabetes self-care.

Methods: Transition readiness was assessed with the Endocrine Society "Self-assessment of Worries, Concerns, and Burdens Related to Diabetes and Preparation for Transitioning," and mood symptoms with the Patient Health Questionnaire (PHQ-9), and the Generalized Anxiety Disorder (GAD-7) questionnaire. Logistic regression analyses evaluated the response to transition readiness by mood symptoms. Qualitative analysis identified themes of diabetes self-care in a subset of Y-T2D.

Results: Survey response rate was 89%; n = 65; age: 19.6 ± 2.0 years (mean ± SD); 85% Y-T2D; 15% prediabetes; 57% female; 78% Black; body mass index: 38.0 ± 8.2; and hemoglobin A1c: 7.6 ± 2.7%. Perceived challenges were reported in 95% of participants, and 54% reported worrying about their future. Mild or greater depressive and anxiety-related symptoms were associated with higher odds of reporting social, emotional, and cognitive challenges. Stress, socioeconomic difficulties, and challenges with organizational cognitive functioning were reported barriers to diabetes self-care.

Conclusion: Mood symptoms and difficulties with organizational cognitive functioning were commonly reported in Y-T2D during the transitioning period. Interventions are needed to successfully address these psychosocial factors.