Journal of Clinical Endocrinology & Metabolism最新文献

Context: Hereditary medullary thyroid carcinoma (MTC) is an inherited syndrome accounting for 25% of MTC cases. It is caused by germline RET mutations, which can be inherited or occur de novo.

Objective: This study aimed to define the prevalence and genetics of de novo MEN2 syndromes, which are not yet fully understood, and to characterize the parental origin of the RET de novo mutation.

Methods: We selected 152 of 215 families with hereditary MTC. In de novo cases, we sequenced the wild-type and mutated alleles of the index cases and compared their single nucleotide polymorphism profiles with those of their parents. Digital droplet PCR was performed to determine the presence of mosaicism in both the index case and the parents.

Results: In 24 of 152 (15.78%) families, the index case had a de novo mutation. Single nucleotide polymorphism analysis demonstrated that in all cases, the mutation occurred on the paternal allele. The absence of mosaicism supported the hypothesis that the mutation occurred during spermatogenesis. The mean age of fathers at the time of conception was, in some cases but not all, relatively advanced.

Conclusion: The prevalence of de novo hereditary MEN2 syndromes was approximately 16%, including MEN2B, and around 9% for other phenotypes. All de novo cases were of paternal origin and likely resulted from an acquired alteration in sperm DNA. The possible role of advanced paternal age in promoting de novo mutations could not be ruled out.

Context: Patients with familial partial lipodystrophy (FPLD) have increased risk of hepatic steatosis and its complications, for which there is no approved therapy.

Objective: This work aimed to investigate the efficacy and safety of obeticholic acid (OCA), a farnesoid X receptor agonist, for reducing hepatic steatosis in patients with FPLD.

Methods: A randomized, double-blind, placebo-controlled, crossover trial was conducted at an academic referral center. Ten women (age 19-60 years) with the Dunnigan variety of FPLD (FPLD2), harboring pathogenic heterozygous variants in the lamin A/C gene and hepatic steatosis (liver fat >5.6% by proton-density fat fraction mapping by magnetic resonance imaging), were included. Intervention included OCA 25 mg daily vs matched placebo for 4 months each with a 4-month washout period in between. The primary end point variable was liver fat. Secondary end point variables were serum triglycerides (TGs) and transaminase levels.

Results: All patients completed the trial. OCA therapy caused significant (39.6%) reduction in liver fat as compared to placebo (median liver fat [minimum-maximum]; 6.4% [2.4%-18.0%] vs 10.6% [3.4%-29.3%], respectively; P value for treatment × month interaction = .03). There were no significant differences in serum TGs or transaminase levels during OCA and placebo therapy. Overall, OCA was well tolerated except for itching in 4 patients compared to 2 on placebo. OCA, as compared to placebo, caused 24% increase in serum low-density lipoprotein cholesterol (mean 129 mg/dL vs 104 mg/dL, respectively; P = .0016).

Conclusion: OCA is safe and effective in lowering hepatic TG levels in patients with FPLD2.

Background: Risk alleles in lysine-specific demethylase 1 (LSD1) and striatin (STRN) are independently associated with greater salt-sensitive blood pressure (SSBP) and increased aldosterone and/or mineralocorticoid receptor (MR) activity. We tested the hypothesis that Black, but not White, risk allele carriers in both genes would have a more severe degree of SSBP than those carrying a single risk allele from either gene alone.

Methods: Individuals from the HyperPATH cohort were assessed for blood pressure and hormone levels after controlled low- and liberal-sodium diets. Black and White individuals with genotype data for LSD1 (rs587168) and STRN diplotype (rs888083 and rs6744560) were included.

Results: A total of 127 Black individuals were categorized: (1) higher risk: individuals who carried 1 or 2 risk alleles from both LSD1 and STRN and (2) lower risk: individuals who did not meet these criteria. In multivariable analysis, SSBP was higher among the higher risk vs the lower risk groups (18.9 ± 1.8 mm Hg vs 10.8 ± 1.6 mm Hg, P < .0001). Among hypertensive individuals, SSBP was 22.9 ± 2.5 mm Hg vs 12.9 ± 2.1 mm Hg for the higher risk vs lower risk groups, respectively (P < .0001). These results were confirmed in a second cohort of 37 Black individuals (P = .029). In 396 White individuals, no differences were observed.

Conclusion: Black, but not White, individuals with risk alleles from both LSD1 and STRN (44% of subjects) exhibited a higher degree of SSBP. In light of the MR-related drivers of SSBP in this population, MR blockade may be particularly effective.

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.

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.

Objective: To investigate the impact of sodium-glucose cotransporter 2 (SGLT2) inhibitors on the incidence, complications, and therapeutic demands of anemia in patients with diabetes utilizing real-world data, compared to treatment with dipeptidyl peptidase 4 (DPP4) inhibitors.

Methods: In this retrospective cohort study, the dataset was sourced from the data repositories of Clalit Health Services. From January 1, 2016, through December 31, 2021, we identified patients with type 2 diabetes who received treatment with SGLT2 inhibitors and compared them with a matched control group treated with DPP4 inhibitors using propensity score. The primary endpoint was the prevalence of anemia.

Results: A total of 22 896 patients were included in this study, with 11 448 individuals administered SGLT2 inhibitors, and an equal number treated with DPP4 inhibitors. We found a significant lower hazard of anemia among patients treated with SGLT2 inhibitors (HR = 0.6, 95% CI 0.58-0.63) compared to those treated with DPP4 inhibitors. Moreover, the risk of hospitalizations attributed to anemia was significantly lower with SGLT2 inhibitors (HR 0.67, 95% CI 0.58-0.77). SGLT2 inhibitors were associated with a lower necessity for anemia treatment (HR 0.84, 95% CI 0.78-0.92, P < .001).

Conclusion: SGLT2 inhibitors demonstrated a lower prevalence of anemia and a lower risk of hospitalizations attributed to anemia when compared to treatment with DPP4 inhibitors in patients with diabetes.

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: 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: 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.