Journal of Clinical Endocrinology & Metabolism最新文献

Introduction: The entero-insular axis, mediated by the incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), is fundamental to maintaining glucose homeostasis. Dysregulation of these hormones' biology contributes to the pathogenesis of type 2 diabetes (T2D), but the existence of a dysfunctional secretory pattern of incretins toward deterioration of glucose tolerance is still debated. In this study, we evaluate possible impairments in the overall incretin secretion from normal glucose tolerance to overt diabetes, as well as their association with impaired insulin secretion.

Methods: Sixty subjects with an unknown history of T2D who were not on antidiabetic treatments were divided into 3 groups according to oral glucose tolerance test-derived glucose tolerance: normal glucose tolerance (NGT) (n = 23), impaired glucose tolerance (IGT) (n = 16), and diabetes mellitus (DM) (n = 21). All subjects underwent deep metabolic evaluation with a mixed meal test (MMT) and euglycemic hyperinsulinemic clamp. During the MMT, we calculated the GIP/GLP-1 secretion ratio (SR) and the GIP/GLP-1 SR areas under the curve. Parameters of β cell function were obtained by mathematical modeling.

Results: Linear mixed model analysis revealed similar GIP and GLP-1 responses to MMT among the 3 groups, while GIP/GLP-1 SR was reduced in DM subjects compared to NGT and IGT. Further, multiple regression analysis showed a predictive role of GIP/GLP-1 SR on rate sensitivity and standardized insulin secretion at 5 mmol/L.

Conclusion: Our findings demonstrate that, despite similar GIP and GLP-1 secretion, the GIP/GLP-1 SR declines as glucose tolerance deteriorates, reflecting an imbalance in incretin dynamics rather than absolute hormone secretion. This imbalance may indicate early β cell dysfunction and chronic incretin resistance.

Context: Women with polycystic ovary syndrome (PCOS) are more prone to glucose metabolism abnormalities, likely due to increased visceral adiposity.

Objective: This study aimed to investigate the association of pancreatic and hepatic fat content with glucose metabolism in PCOS.

Methods: This study included 160 women with PCOS. All participants underwent an oral glucose tolerance test. Magnetic resonance imaging-derived proton density fat fraction was used to measure fat content in different visceral organs.

Results: Pancreatic interlobular fat volume, pancreatic body fat, and hepatic fat were significantly higher in PCOS patients with diabetes than in those with normal glucose tolerance (P < .05). Elevated pancreatic body fat (OR 2.21 [95% CI 1.01-4.85], P = .047) and hepatic average fat (OR 2.92 [95% CI 1.13-7.51], P = .026) were independently associated with higher impaired glucose regulation (IGR) risks. Only patients with elevated levels of both pancreatic body fat and hepatic average fat exhibited increased risk of IGR after multiple confounding adjustments (OR 5.49 [95% CI 1.63-18.47], P = .006). The hepatic average fat to pancreatic body fat ratio lost its significant association with IGR risk after multivariable adjustment (P = .705). The combination of pancreatic body fat and hepatic average fat with traditional risk factors (age, body mass index, waist to hip circumference ratio, serum triglycerides, and free androgen index) demonstrated a trend toward improved predictive performance for IGR, with the highest area under the curve (0.789) observed.

Conclusion: Pancreatic body and hepatic fat content predict IGR and synergistically regulate glucose metabolism in PCOS.

Context: Children born to mothers with gestational thyroid dysfunction may have an increased risk of adverse neurodevelopmental outcomes, but the effects of maternal thyroid function on brain microstructure are unknown.

Objective: To establish whether adolescent white matter microstructure is affected by suboptimal gestational thyroid function (SGTF).

Methods: The Controlled Antenatal Thyroid Screening (CATS) study randomized mothers with SGTF to levothyroxine or no supplementation from 12 weeks' gestation. For the current study, CATS children underwent microstructural magnetic resonance imaging (MRI), including diffusion MRI, to explore white matter microstructure and quantitative magnetization transfer (qMT) imaging to investigate myelin. Seventy-five children aged 11-16 years had usable diffusion and/or qMT data: untreated SGTF (n = 19), normal GTF (n = 21), or treated SGTF (optimally treated [n = 18], overtreated [n = 17]). The primary outcome was to examine the effects of SGTF and its treatment on white matter microstructure. Secondary and exploratory outcomes were to investigate the association of (1) maternal thyrotropin and free thyroxine levels with white matter microstructure, and (2) white matter microstructure with attention deficit hyperactivity disorder symptom scores.

Results: Untreated SGTF was associated with higher mean diffusivity (indicating reduced axonal integrity) than normal GTF (P = .007) within the inferior longitudinal fasciculus, a major white matter tract connecting the occipital and temporal lobes and involved in several cognitive functions. Secondary and exploratory outcomes did not survive corrections for multiple comparisons.

Conclusion: Untreated SGTF is associated with altered tract-specific microstructural morphology in adolescence, which may be reversible with levothyroxine administration in pregnancy.

Objective: To investigate the effect of varying visit-to-visit glucose variability (GV) on brain morphometry and cognitive performance in patients with type 2 diabetes mellitus (T2DM).

Methods: This was a retrospective cohort study in which we recruited 426 participants (173 T2DM patients and 253 healthy controls) who underwent cognitive assessment and structural magnetic resonance imaging. In patients with T2DM, visit-to-visit GV was calculated using the SD of glycated hemoglobin (HbA1c) during the follow-up period. Multiple linear regression models were used to analyze the associations between different levels of GV and brain morphometry as well as cognitive function after adjusting for mean HbA1c levels and other traditional risk factors.

Results: Higher GV is associated with poorer global cognitive performance and executive function. After full multivariate adjustment, higher GV is linked to cortical thinning in the left superior parietal cortex, right postcentral gyrus, and insula, as well as a reduction in total gray matter volume. In contrast, no association was observed between GV and cortical volume or surface area.

Conclusion: Our findings indicate that higher visit-to-visit GV is associated with reduced cortical thickness, total gray matter volume atrophy, and poorer cognitive performance in patients with T2DM, and these associations are independent of mean HbA1c levels.

Background: 46,XY gonadal dysgenesis is classified as complete (CGD) or partial (PGD) subtypes. The phenotype of PGD and the long-term outcome is not clearly defined.

Objective: To evaluate clinical features and pubertal outcome of PGD in a large cohort, using CGD as a comparator for diagnostic clarity.

Methods: Patients with 46,XY GD were identified from the I-DSD Registry and data on phenotype, genetics, biochemistry, gonadal histology, and pubertal development were collated in 3 categories; CGD (n = 100), PGD assigned female (PGDf, n = 107), and male (PGDm, n = 103) at birth.

Results: Most individuals with PGD presented with atypical genitalia in infancy, though, 18% of PGDf presented with delayed puberty and 8% with virilization. A genetic etiology was identified in 42% of the cohort, with common gene defects in SRY and WT1 in CGD and NR5A1 in PGD. Gonadal pre-/malignancy was found in 33.8% in CGD, 19.7% in PGDf, and 8.8% in PGDm. Among the PGDm (>13 years) with at least 1 gonad, 80% had spontaneous pubertal onset and 59% achieved Tanner G5 without hormone treatment. Labioscrotal gonads at presentation and testosterone response to human chorionic gonadotropin predicted onset of spontaneous puberty. In PGDf with gonads, 42% developed spontaneous virilization at puberty. Sex was reassigned in 16.1% and 5.3% of individuals with PGDf and PGDm, respectively.

Conclusion: This study highlights the heterogeneous phenotype of PGD and the consequent diagnostic challenge. Many PGD patients with preserved gonads have the potential to develop puberty spontaneously, though further study is needed to determine the risk of developing gonadal tumors.

Context: Although there is an established improved postoperative outcome for pituitary adenomas (PA) surgically resected at high-volume facilities (HVFs), access to these centers may not be equitable.

Objective: To investigate the racial and socioeconomic differences that lead to unequal distribution of access for PAs at HVFs in the United States.

Design and patients: Retrospective analysis of data from the National Cancer Database from 2004 to 2019 on 57 807 patients with PA.

Main outcome measures: Baseline description of patients treated at HVFs, survival outcomes, and predictors of survival were evaluated in patients with PA.

Results: A total of 47.6% (n = 27 523) underwent surgery at a HVF. On multivariable analysis, African-American race [odds ratio (OR): 0.89, P < .001] and Hispanic ethnicity (OR: 0.80, P < .001) had significantly lower odds of having a surgical procedure at a HVF as compared to a reference Caucasian population. Patients from rural locations (OR: 0.79, P = .003; reference = urban); with Medicaid insurance (OR: 0.86, P < .001; reference = private), those with lower income [<$40 227 (OR: 0.93, P = .049); reference = ≥$63 333], and patients from zip codes with large percentages of adults who did not graduate high school [≥17.6% (OR: 0.95, P < .001); reference = <6.3%] were significantly less likely to have surgery at a HVF. An increasing trend in access to surgical care at HVFs for PA patients over time was demonstrated [eg, 2005 (OR = 1.10 [0.97-1.26], P = .173) vs 2019 (OR = 1.27 [1.13-1.43], P < .001)].

Conclusion: There are significant racial and socioeconomic disparities in access to HVFs for adult patients seeking surgical resection of pituitary adenomas.

Context: Recent research links bone marrow adiposity tissue (BMAT) to osteoporosis and fracture risk. Typically, BMAT is assessed via magnetic resonance imaging, a costly and less accessible method. A new method uses high-resolution peripheral quantitative computed tomography (HRpQCT) to quantify BMAT.

Objective: To investigate if BMAT, derived from HRpQCT images, is associated with fracture incidence and osteoporosis prevalence in older women.

Methods: A total of 2984 women aged 75 to 80 years from the SUPERB cohort were included between March 2013 and May 2016. Bone characteristics, including bone densitometry and HRpQCT of the ultradistal tibia, were assessed. Bone marrow fat fraction (BMFF) was measured using HRpQCT. Incident fractures were tracked until March 2023. Linear regression was used to analyze associations between BMFF, anthropometrics, and bone mineral density (BMD). Cox and Poisson regression examined BMFF's association with incident fractures.

Results: BMFF was inversely associated with body mass index (r = -0.21, P < .001) and hip BMD (r = -0.50, P < .001). Over a median follow-up of 7.3 years, 797 major osteoporotic fractures (MOFs), 1069 any fractures, and 235 hip fractures occurred. Higher BMFF (per SD) increased the risk of MOF (HR 1.24, 95% CI 1.15-1.34), any fracture (HR 1.20, 95% CI 1.12-1.28), hip fracture (HR 1.22, 95% CI 1.06-1.40), and vertebral fracture (HR 1.24, 95% CI 1.12-1.38) in multivariable Cox models adjusted for age, body mass index, and clinical risk factors. Mediation analysis indicated that a significant proportion of these associations were mediated by femoral neck BMD.

Conclusion: Higher BMFF is associated with lower BMD and higher fracture risk in older women.

Context: Natural history and optimal therapeutic strategies of patients with head-and-neck paragangliomas (HNPGL) associated with germline mutations in succinate dehydrogenase genes (SDHx) are barely known. This study aims to describe the outcome of these patients depending on selected strategies.

Methods: We retrospectively analyzed the outcome of 65 SDHx-mutated patients presenting 108 HNPGL mostly located in the carotid (57%) and jugulotympanic (JT) (21.5%) areas. One hundred five HNPGLs (97%) were nonsecreting and nonmetastatic, with multiple tumors observed in 40 patients (62%). HNPGLs were initially managed by surgery for 56 (52%), monitoring for 31 (29%), and radiotherapy for 21 (19%). Unsuccessful tumor control (UTC) was defined as a tumor volume increase or a need to change therapeutic strategy. During a 7-year median follow-up period, 18 UTCs (17%) were observed in 17 patients. Among operated HNPGLs, 13 (23%) had an UTC, compared with 1 (5%) among the irradiated HNPGL and 4 (13%) among monitored HNPGLs. The incidence of UTC was significantly increased in HNPGL treated by incomplete surgical resection compared to HNPGL treated by complete surgery (50% vs 0%, P < .001). UTC was more frequent in the JT than in other locations (39% vs 11%, P < .002).

Results: Posttherapeutic complications were observed in 34 patients (55%), mainly neurological (73%) or vascular (15%), with a higher incidence after surgery than after irradiation (66% vs 14%, P < .001).

Conclusions: Most SDHx patients with monitored HNPGLs had a stable disease confirming the interest of initial time for observation before deciding to treat or not, particularly in asymptomatic patients.

Context: Altered myocardial mechano-energetic efficiency (MEE) is a substantial predictor of cardiovascular events and heart failure. Among the potential pathophysiological factors underlying MEE impairment, insulin-like growth factor 1 (IGF-1) may be a plausible candidate due to its role in the cardiovascular system.

Objective: This study aimed to analyze the relationship between plasma IGF-1 concentrations and myocardial MEE in a cohort of individuals older than 65 years, participating in the CATAnzaro MEtabolic RIsk factors (CATAMERI) study.

Methods: Myocardial MEE per gram of left ventricular mass (MEEi) was measured in 490 older participants with a broad spectrum of glucose tolerance using echocardiography.

Results: IGF-1 levels were positively associated with myocardial MEEi (r = 0.200; P < .001). Individuals in the highest tertile (tertile 3) of IGF-1 showed significantly lower heart rate and myocardial oxygen consumption, alongside a significant increase in myocardial MEEi compared to those in the lowest tertile. In multivariate linear regression analysis, IGF-1 levels were identified as the major determinant of MEEi, independently of well-established cardiometabolic risk factors.

Conclusion: These findings suggest that low circulating IGF-1 levels are associated with depressed myocardial MEEi in older individuals. This highlights the potential importance of monitoring IGF-1 in clinical evaluations to assess cardiovascular health.