Journal of Clinical Endocrinology & Metabolism最新文献

Context: Recent studies suggest that light-intensity physical activity may enhance cardiometabolic health and reduce mortality risk in adults. However, more information is required to understand the patterns of light-intensity physical activity and postprandial cardiometabolic health.

Objective: This study examined the effects of different light-intensity walking patterns on postprandial cardiometabolic responses in young obese adults.

Design: A randomized crossover trial was conducted.

Setting: The study was conducted in the laboratory.

Participants: The study analyzed baseline (fasting) and 6-hour postprandial concentrations of glucose, insulin, triglycerides, and blood pressure (BP) in 16 young obese adults.

Interventions: Participants underwent four 7-hour experimental conditions with a 7-20-day washout period: uninterrupted sitting (SIT), 30-minute light-intensity walking (EX+SIT), 3-minute light-intensity walking every 30 minutes (BR), and 30-minute light-intensity walking with 3-minute light-intensity walking every 30 minutes (EX+BR).

Main outcome measures: Incremental areas under the curve (iAUC) for each outcome and average BP were compared between SIT and walking conditions.

Results: Compared with SIT, all walking conditions reduced iAUCs for glucose and average diastolic BP (all p<0.05). Only EX+SIT and EX+BR reduced iAUCs for insulin (p<0.05). No significant differences were found for triglycerides iAUC and systolic BP between the four conditions (all p>0.05).

Conclusions: All patterns of light-intensity walking reduced postprandial glucose concentrations and diastolic BP in young obese adults, suggesting benefits for glycemic control. Continuous 30-minute light-intensity walking alone, or combined with brief 3-min bouts also attenuated postprandial insulin concentrations, highlighting light-intensity walking as a promising strategy for improving cardiometabolic health in young obese adults.

Objectives: Left ventricular thrombus (LVT) is associated with an increased risk of adverse cardiovascular events, and thyroid hormones are known to affect the cardiovascular system in various ways. However, subclinical thyroid dysfunction still deserves to be emphasized, and its impact on the prognosis of patients with LVT is rare but needs to be investigated.

Methods: We used retrospective data from patients diagnosed with LVT at Fuwai Hospital over the past 10 years to assess the relationship between thyroid functional status and prognosis of LVT using multivariate Cox proportional hazards models, and validated the improved predictive effect of including thyroid function in the prognostic assessment of LVT using receiver operating characteristic (ROC) curves.

Results: Subclinical hypothyroidism was significantly associated with a higher incidence of major adverse cardiovascular and cerebrovascular events (MACCEs) (HR 1.774, 95% CI: 1.053-2.989; p = 0.031) and cardiovascular death (HR 1.986, 95%CI: 1.110-3.553; p = 0.021) in LVT patients, whereas no significant correlation was observed in the subclinical hyperthyroidism group. In addition, including thyroid function in the prognostic consideration of LVT patients would contribute to the predictive effect of MACCEs (AUC for 1 year: 0.715; AUC for 2 years: 0.745; AUC for 3 years: 0.684).

Conclusion: Subclinical hypothyroidism can be used as an independent predictor of MACCEs in patients with LVT, and there is a clinical value in using subclinical hypothyroidism as an important factor suggesting a poor prognosis in patients with LVT.

Context: Osteogenesis imperfecta (OI) is a rare genetic bone disorder characterized by recurrent fractures. In adults, the value of bone mineral density (BMD) in fracture risk is unknown.

Objective: We prospectively investigated changes in BMD over time and analysed the determinants of fracture in OI.

Methods: Among 106 individuals with grade 1 and 4 OI in the Reference Centre of Rare Bone Diseases in Paris, we included those with BMD measurements at one or more skeletal sites (hip, lumbar spine, radius) from 2000 to 2022.

Results: For 71 individuals with reliable measurements (44 women, 8 postmenopausal; mean age 41.4 ± 13.7 years), baseline BMD was low at the lumbar spine only (mean Z-score -2.3±1.5), affecting mainly men (mean Z-score -3±1.6). Longitudinal changes were assessed for a median follow-up of 5.1 years (interquartile range 3.2-8.8). On adjustment for age, sex and body mass index, BMD did not significantly change at any site. Logistic regression analysis revealed a high probability of fracture with baseline BMD Z-score <-2 SD versus ≥-2 SD (odds ratio 4.38, 95% CI 1.10-21.75, p=0.048) and harbouring splicing, stop codon and frameshift variants of COL1 gene (odds ratio 29.8, 95% CI 2.56-1503, p=0.024).

Conclusion: our OI cohort showed low BMD at the lumbar spine but no significant change at any site after a median of 5.0 years of follow-up. The probability of fracture was associated with baseline BMD Z-score <-2 SD versus ≥-2 SD and harbouring COL1 splicing, stop codon and frameshift variants.

Context: Fracture risk is higher in type 2 diabetes (T2D) for a given bone mineral density (BMD) level. Increased oxidative stress in T2D induces diabetic complications and may affect T2D bone fragility.

Objective: To investigate whether the levels of plasma F2-isoprostanes, a reliable oxidative stress marker, are associated with incident clinical fracture risk in older adults with diabetes.

Design and setting: An observational cohort study was conducted in a well-characterized cohort from Health, Aging, and Body Composition study.

Participants: Older black and white ambulatory adults with baseline plasma F2-isoprostanes measurements (baseline age 70-79 years, T2D: N=132; non-diabetes: N=571) were selected from the study cohort of 3075 individuals.

Main outcome measures: Incident clinical fractures.

Results: In the Cox proportional hazard model with multivariate adjustments (including BMD, medications, and other risk factors), a 93% increase in incident clinical fracture risk was significantly associated with each SD increase in log plasma F2-isoprostanes in the T2D group (HR: 1.93, 95% CI 1.26-2.95, p=0.002), but there was no evidence of an association in the non-diabetes group (HR: 0.98, 95% CI 0.81-1.18, p=0.79, p for interaction < 0.001). Log plasma F2-isoprostanes were moderately correlated with a decline in baseline total hip BMD (r=-0.25, p=0.003), and with a 4-year decrease in total hip BMD (r=-0.28, p=0.008) in T2D. There was no evidence of correlation between log plasma F2-isoprostanes and circulating glycoxidation markers or bone turnover markers in either group.

Conclusions: Plasma F2-isoprostanes levels in individuals with diabetes are associated with increased incident clinical fracture risk independently of baseline BMD.

Context: Up to 20% of patients with X-linked hypophosphatemic rickets (XLH) have no causative variant identified on routine molecular diagnostic testing.

Objective: To identify intronic variants causing PHEX mis-splicing in patients with XLH.

Setting: The metabolic bone clinic of a paediatric orthopedic hospital.

Participants: Four patients (age 6 to 12 years; 3 girls) with clinically diagnosed XLH and no PHEX variant on routine testing.

Main outcome measures: RNA and DNA sequence analysis of PHEX.

Methods: Urine-derived cells were cultured, and mRNA was extracted and transcribed to cDNA. PHEX cDNA was amplified by PCR, followed by sequencing of PCR products. Sequencing of PHEX intronic DNA regions was performed to identify variants causing mis-splicing observed on RNA analysis.

Results: PHEX mis-splicing was identified in 3 of the 4 participants, and an intronic variant was identified in all 3 cases. In a 12-year-old boy, transcript analysis showed skipping of PHEX exon 13, while sequencing of PHEX intronic regions revealed a de novo 18 bp deletion in intron 13. In a 7-year-old girl, a pseudoexon in PHEX intron 17 was found, associated with a de novo deep intronic variant (c.1768+173A>G) that activated a cryptic splice donor site. Finally, an 84 bp pseudoexon in PHEX intron 21 caused by a recurrent de novo deep intronic variant (c.2147+1197A>G) was identified in an 11-year-old girl.

Conclusions: Analysis of RNA from urine-derived cells combined with sequencing of PHEX introns can identify deep intronic variants in individuals with XLH without a detectable PHEX variant in routine exon-centric molecular diagnosis.

Background and objective: Accumulating evidence had implicated pathological involvement of interleukins (ILs) in progression and complications in patients with type 2 diabetes mellitus (T2DM). Dipeptidyl peptidase-4 inhibitors (DPP-4i) produced favorable effects on glucose homeostasis in T2DM. This study aimed to evaluate the impact of DPP-4i on interleukins (ILs) concentrations in T2DM.

Data sources: PubMed, Embase and the Cochrane library were systematically searched for relevant articles from inception to May 31, 2024. Related searching items were used including DPP-4i, T2DM and randomized controlled trials (RCTs).

Study selection and data extraction: Placebo- or active agents-controlled human studies were screened. All the RCTs were identified if they provided detailed information on changes of ILs during DPP-4i treatment.

Data synthesis: A total of 14 RCTs involving 850 participants were identified. Pooled estimates revealed that DPP-4i significantly lower IL-6 concentrations (-0.54 pg/mL, 95% CI, -0.82 to -0.25, I2 = 10%, P = 0.0003) compared to placebo. Similar effects were demonstrated for IL-1β (-16.33 pg/mL, 95% CI, -19.56 to -13.11, I2 = 0%, P<0.00001), whereas the effect on IL-18 was not statistically significant (-13.55 pg/mL, 95% CI, -76.95 to 49.85, I2 = 0%, P = 0.68). Subgroup analysis on IL-6 demonstrated that marked effects were found in groups of basal IL-6 concentrations (< 5 pg/mL), BMI (≥ 28 kg/m2) and type of DPP-4i (linagliptin).

Conclusion: DPP-4i favorably decreased concentrations of IL-6 in patients with T2DM. The impact of DPP-4i on IL-1β and IL-18 needed to be explored with more studies. Further trials should be performed to elucidate this anti-inflammatory effect of DPP-4i during treatment of T2DM.

Homozygous familial hypercholesterolemia (HoFH) is a rare disease characterized by the presence of two pathogenic variants in the LDLR, APOB, PCSK9 or LDLRAP1 genes, which cause very high levels of LDL cholesterol and premature atherosclerotic cardiovascular disease (ASCVD).The objective of this study is to analyze the current situation regarding diagnosis, cardiovascular disease, lipid-lowering treatment and degree of control of lipids in patients with HoFH in the National Dyslipidemia Registry of the Spanish Atherosclerosis Society.

Methods: Subjects with HoFH, confirmed by the presence of two pathogenic variants in the genes mentioned above, included in the registry from 2013 to June 2023 with an updated review were analyzed.

Results: 71 HoFH subjects were included. 40.8% were women, aged 52 [24-62] years, 57 adults and 13 children. The median follow-up was 7 [4-13] years. Age of diagnosis was 14 [2-26] years, with 10% of ASCVD at diagnosis and 27% of current ASCVD at 40.6 (13.4) years of age. 38% were on PCSK9i, 9 patients on lomitapide, 9 on LDL apheresis and 1 patient on evinacumab. Subjects with more than 4 therapies achieved >80% reduction in LDLc. In the last visit, the median LDLc was 139.3 [89.4-204.2] mg/dL. ASCVD was strongly associated with male sex and family history of ASCVD, relative risk 5.26 (1.53-18.10) and 2.53 (1.03-6.26), p<0.05, respectively. Only 18% and 10% meet the recommended LDLc goal in primary and secondary prevention respectively.

Conclusions: The current situation of HoFH in Spain is better than expected, with marked reductions in LDLc levels with new treatments. In this population, recommended LDLc goals are difficult to achieve despite maximum lipid-lowering therapy. ASCVD has been reduced and delayed by two decades.