Journal of Clinical Endocrinology & Metabolism最新文献

Context: Establishing the genetic basis of early-onset primary ovarian insufficiency (EO-POI, <25 years) is important, but defining variant pathogenicity is challenging.

Objective: We aimed to elucidate the genetic architecture of EO-POI in a unique, large cohort. Young women with EO-POI (n = 149; n = 31 familial, n = 118 sporadic) attending a specialist reproductive unit were included. Exome sequencing was performed. After filtering, variants were retained that were: (1) rare/novel (minor allele frequency <0.01%); (2) predicted pathogenic/likely pathogenic; and (3) enriched in the cohort. Each variant was assigned to a category: Category 1, variants in Genomics England Primary Ovarian Insufficiency PanelApp genes (n = 69); Category 2, variants in other POI-associated genes (n = 355) or Category 1 variants following unexpected inheritance patterns; and Category 3, homozygous variants in novel candidate POI genes.

Results: A total of 127 Category 1 or 2 variants were identified in 74 different genes (heterozygous 30.9%; homozygous 9.4%; polygenic 21.8%). In familial EO-POI, 64.7% (11/17 kindred) had a Category 1 or 2 variant identified (homozygous: STAG3, MCM9, PSMC3IP, YTHDC2, ZSWIM7; heterozygous: POLR2C, NLRP11, IGSF10, PRKD1, PLEC; polygenic: PDE3A, POLR2H, MSH6, CLPP). In sporadic EO-POI, 63.6% (n = 75/118) women had a variant identified: 21.2% (n = 25) Category 1; 42.4% (n = 50) Category 2. Novel POI candidate genes (Category 3) included PCIF1, DND1, MEF2A, MMS22L, RXFP3, C4orf33, and ARRB1.

Conclusion: The genetic basis of EO-POI is complex and affected genes span ovarian developmental processes from fetal life to adulthood. Establishing the pathogenicity of individual heterozygous variants can be challenging. However, some women have clear monogenic causes, particularly in familial POI with autosomal recessive inheritance. Others have potential polygenic causes. We describe novel candidate POI genes warranting further exploration.

Introduction: Short-term caloric restriction is a common practice even in lean and underweight women. We studied the impact of dietary restriction on sleep and its interplay with reproductive hormones across the menstrual cycle in women without obesity.

Methods: Seventeen healthy women without obesity, aged 23.6 ± 2.3 years (mean ± SD) underwent a neutral (± 0%) and deficient energy availability diet (-55%) in the early follicular phase of 2 menstrual cycles. Actigraphic data and urinary LH, estrone-3-glucuronide (E1G), and pregnanediol-3-glucuronide (PDG) were collected daily. Blood orexin and leptin were collected on the fifth day of each diet. Sleep was analyzed in relation to menstrual cycle phase, diet, and hormones.

Results: Decreased energy availability and menstrual cycle phase independently affected wake after sleep onset (WASO; P = .004, P = .007 for diet and cycle phase, respectively) and number of awakenings (NOA; P = .03, P = .0006, respectively) with the greatest sleep disruption in the late luteal phase. Sleep efficiency (SE) was lower and duration of awakenings was longer in association with dietary restriction. Orexin was positively associated with WASO (P = .02), the sleep fragmentation index (P = .001), and NOA (P = .009) and inversely related to SE (P = .02). Increasing PDG was associated with WASO (P < .05) and duration of awakenings (P < .05) and inversely associated with SE (P < .01). Increasing E1G was positively associated with WASO (P < .05) and NOA (P < .01).

Conclusion: Short-term modest caloric restriction independently disrupts sleep and exacerbates changes in sleep that occur across the menstrual cycle in healthy, young women without obesity.

Context: The telomere plays a critical role in maintaining genomic stability, and its length serves as a marker of cellular aging. Emerging evidence projects telomere length as a clinical risk factor for metabolic diseases.

Objective: Our present study examines the associations between telomere length and demographic factors including metabolic health in a multiethnic cohort to provide insight into the effect of ethnicity on the potential use of telomere length as a biomarker for assessing diabetes risk.

Methods: This cross-sectional study cohort comprised 2083 individuals of Arab, South Asian, or Southeast Asian descent living in Kuwait. Telomere lengths were measured from peripheral venous blood DNA using quantitative polymerase chain reaction-based techniques. Associations between telomere length and metabolic indicators (including body mass index [BMI], being diabetic, glycated hemoglobin A1c [HbA1c], fasting blood glucose [FBG], and homeostatic model assessment of insulin resistance [HOMA-IR]) were analyzed using Spearman correlation and quantile regression, adjusting for covariates.

Results: South Asian and Southeast Asian participants had significantly higher median telomere lengths than Arabs. Median telomere lengths varied significantly across sex, age tertiles, ethnicity, being diabetic, BMI, and HOMA-IR scores. Telomere length was negatively associated with being male (β = -.49; 95% CI, [-0.85 to -0.13]), diabetic (β = -.77; 95% CI, [-1.25 to -0.29]), age (β = -.06; 95% CI, [-0.08 to -0.04]), HOMA-IR (β = -1.01; 95% CI, [-1.43 to -0.575]), BMI (β = -.11; 95% CI, [-0.14 to -0.083]), and HbA1c (β = -.213; 95% CI, [-0.33 to -0.096]). Negative correlations between telomere lengths and triglycerides, HbA1c, FBG, insulin, and HOMA-IR levels were more highly significant in South Asians than in Arabs and Southeast Asians.

Conclusion: Our study underlines the significant influence of ethnicity on the interplay between telomere length and metabolic health, and emphasizes the need to incorporate ethnic background when relating telomere biology to metabolic disorders. It further highlights the potential to incorporate telomere length into clinical risk factors for diabetes.

Context: Patients affected by the classic form of congenital adrenal hyperplasia (CAH) need lifelong glucocorticoid (GC) therapy. GC represents one of the primary causes of secondary osteoporosis; however, the effect of steroid therapy on bone mineral density (BMD) in patients with CAH is still controversial.

Objective: To evaluate and compare the BMD of a group of prepubertal patients and a subgroup of young adult patients with CAH receiving chronic GC therapy, with healthy controls.

Design: Retrospective observational study.

Setting: A referral center for pediatric endocrinology.

Patients and healthy controls: Fifty-six prepubertal children with CAH treated with GC from diagnosis and 60 prepubertal healthy children of comparable age. A subgroup of 36 young patients was studied after the completion of puberty, and their BMD was compared to that of 51 young adult healthy volunteers.

Methods: BMD was measured in the lumbar spine and in the whole body by dual-energy x-ray absorptiometry. Multivariate models were used for the comparison of BMD measurements between patients and control subjects.

Results: Whole-body BMD measurements of patients were significantly lower compared with healthy controls, both in boys and in girls. No differences were found in lumbar spine measurements. BMD expressed as Z-score decreased markedly in CAH patients from prepuberty to adulthood, particularly in young adult males. Men with CAH showed lumbar spine BMD values significantly lower than control subjects.

Conclusion: Boys and young adult men with classic form of CAH have lower BMD values compared with healthy controls. This may put them at risk of developing osteoporosis early in life.

Context: Postoperative outcomes of patients with normotensive pheochromocytomas are poorly documented.

Objective: We aimed to evaluate the impact of preoperative hypertension on postoperative outcomes following adrenalectomy for pheochromocytoma.

Methods: An international retrospective study of patients undergoing adrenalectomy for pheochromocytoma in 46 centers between 2012 and 2022 was performed. Hypertensive and normotensive pheochromocytoma were defined respectively by the presence or absence of hypertension history before or at the time of pheochromocytoma diagnosis. To evaluate differences in postoperative outcomes between hypertensive and normotensive patients, propensity score matched (PSM) analysis was performed.

Results: Among 2016 patients with pheochromocytoma, 1034 (51.2%) had preoperative hypertension and 982 (49.8%) were normotensive. Hypertensive patients were 4.5 years older (P < .001), had a higher prevalence of type 2 diabetes (P < .001), had a higher median Charlson Comorbidity Index (2.0 vs 1.0; P < .001), and had an American Society of Anesthesiologists score of III to IV more frequently (41% vs 19.9%; P < .001) than normotensive patients. Nonadjusted analysis demonstrated that hypertensive patients had longer operative time (115.0 vs 103.5 minutes; P = .026), higher rate of vasopressors at skin closure (19.7% vs 15.4%; P = .013), more perioperative blood transfusions (7.7% vs 5.0%; P = .016), and an increased complication rate (21.6% vs 17.7%; P = .029). However, after 1:1 PSM, we found that readmission, complications, and serious complications were similar between cohorts.

Conclusion: Patients with hypertensive pheochromocytomas have a higher risk of postoperative complications than normotensive patients due to the association of hypertension with a higher burden of comorbidities and older age. However, hypertension is not an independent risk factor of postoperative complications after pheochromocytoma surgery.

Context: Optimal glucose management in individuals with type 2 diabetes (T2D) and end-stage kidney disease (ESKD) on hemodialysis is challenging.

Objective: We compared the detection of glycemic excursions with continuous glucose monitoring (CGM) and capillary blood glucose testing (CBG) in this population.

Methods: In this prospective observational study, insulin-treated adults with T2D on hemodialysis for 90 or more days wore a Dexcom G6-Pro CGM. Participants were instructed to perform CBG testing up to 4 times daily. We compared differences in glucose metrics and described CGM patterns in relation to dialysis sessions.

Results: Among 59 participants (age 57.7 ± 9 years, glycated hemoglobin A1c 7.09%), mean glucose measured by CBG and CGM was 165.7 ± 41.8 and 188.9 ± 45.0, with a time-in-range (TIR) of 68% ± 23 and 51% ± 26, respectively (P < .001). CGM detected that all participants had hyperglycemic episodes of 180 mg/dL, with time above range (TAR) of 180 mg/dL of 47.8% ± 27, and 90% had episodes greater than 250 mg/dL, with TAR greater than 250 mg/dL of 20.9% ± 21.7. CGM detected higher rates of hypoglycemia of less than 70 mg/dL, (47% vs 25%; P = .005) and less than 54 mg/dL, (25% vs 12%; P = .08) compared with CBG testing. Nocturnal and prolonged hypoglycemia less than 70 mg/dL were detected only by CGM (29% and 12%, respectively). CGM showed a pattern of improved glucose levels on predialysis days, lower glucose levels during hemodialysis, and a rapid rise during the postdialysis period.

Conclusion: In participants with T2D and ESKD on hemodialysis, CGM improved the detection of hyperglycemic and hypoglycemic events, particularly nocturnal and prolonged episodes. CGM revealed distinct glycemic patterns related to dialysis sessions, potentially enabling more personalized management.

Background: 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.

Objective: To describe the metabolic phenotype of people with Stage 1 and Stage 2 T1D using metabolic modelling of β cell function.

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 (area under the curve, C-peptide, Homeostatic Model Assessment [HOMA] 2-B) and sensitivity (HOMA Insulin Resistance, HOMA2-S, Matsuda Index) and oral minimal model-derived insulin secretion (φ total), sensitivity (sensitivity index), and clearance were adopted to characterize the cohort.

Results: Thirty participants with Stage 1 and 27 with Stage 2T1D 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 < .001) and sensitivity (P = .034) in those with Stage 2 T1D, as well as increased insulin clearance (P = .006). A higher baseline φ total was associated with reduced odds of disease progression, independent of stage (OR 0.92 [0.86, 0.98], P = .016).

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

Context: There is large variation in the individual risk of developing obesity-associated comorbidities. While obesity is highly prevalent in Mexico, data on the extent and heterogeneity of its associated comorbidities are lacking.

Objective: We estimated the prevalence of different obesity-associated comorbidities, and how they have changed over 15 years.

Methods: We gathered data from different editions of nationally representative health and nutrition surveys (ENSANUT) from 2006 to 2022. The prevalence of obesity and the coexistence with diabetes, dyslipidemia, hypertension, depression, and impaired mobility, which are outcomes used in the Edmonton Obesity Staging System (EOSS), which assesses 3 dimensions (medical, mental, and functional) across 5 incremental severity stages, by sex and age groups, were estimated across all included surveys. Metabolically healthy obesity (MHO) was defined as the absence of diabetes, dyslipidemia, and hypertension.

Results: A total of 20 758 participants were analyzed. Mean body mass index (BMI) increased progressively at all ages from 30.2 to 31.0 across survey rounds. Depression and impaired mobility were highly prevalent even among MHO individuals. While most people with obesity had at least one detectable abnormality, there was large heterogeneity in the presented comorbidities. The most prevalent EOSS categories were stage 2 for the medical dimension (90.1%), and stage 1 for the functional and mental dimensions (75.1% and 62.9%, respectively). The prevalence of obesity-related comorbidities increased with age but was similar across all surveys. In both sexes, MHO was less likely as age and BMI increased.

Conclusion: The prevalence of obesity comorbidities has been stable over time in Mexico but increases with age. The rising prevalence of obesity and the aging of the population will cause additional burdens to the population and the health system.

Context: Total fasting non-esterified fatty acid (NEFA) levels have been associated with mortality. The corresponding associations with NEFA levels following an oral glucose tolerance test (OGTT) and with individual fasting NEFA species are unclear.

Objective: We evaluated the associations of post-load NEFA, fasting subclasses and individual NEFA with mortality.

Methods: The Cardiovascular Health Study is a population-based cohort study of community-dwelling adults over 64 years of age from 4 US communities that began in 1989-1990. Participants had total NEFA measured enzymatically before and 2 hours after an OGTT from archived serum samples collected in 1996-1997. Fasting individual NEFA were also measured using gas chromatography. Cox proportional hazard models were used to evaluate adjusted hazard ratios (aHR) for mortality associated with fasting and post-load total NEFA, and fasting individual and fatty acid subclasses (saturated, monounsaturated, n-3 and n-6 polyunsaturated, and trans).

Results: The final population included 1996 participants (mean age 78 years; 60.5% female). Over a median 11-year follow-up period, 1678 participants died. Total fasting NEFA was associated with higher risk of all-cause mortality (aHR per SD: 1.17, 95% CI [1.10-1.23]). Total post-load NEFA was not associated with mortality. Among subclasses, only monounsaturated fatty acid (MUFA) was associated with total mortality (aHR 1.24, 95% CI [1.09-1.41]). For individual NEFAs, nervonic acid (aHR 1.06, 95% CI [1.01-1.12]), petroselaidic acid (aHR 1.21, 95% CI [1.03-1.42]), and eicosapentaenoic acid (aHR 0.90, 95% CI [0.82-0.99]) were associated with all-cause mortality.

Conclusion: Individual fasting NEFAs represent attractive candidates for medical and public health interventions aimed at improving survivorship in older adults and should be investigated further.