Daily Endocrinology Research Analysis

Gut microbiota contributes to prediabetes progression, however, whether microbiota features can guide targeted prevention and treatment for diabetes requires validation through large-scale clinical trials. Here, in a randomized, open-label trial, we randomly assigned 802 prediabetic subjects to a usual care control group (patient education and dietary recommendations, n = 393) or a dietary fiber intervention group (n = 409) for 6 months. The primary outcome was the percentage change in whole-blood HbA1c, and secondary outcomes were the changes in other glucose, insulin, lipid, liver and kidney function, and anthropometric parameters. There were no statistically significant differences in the primary and secondary outcomes between groups. In post-hoc analysis, we reclassified subjects into four clusters using a multivariate clustering model based on age, BMI, HbA1c, HOMA2-IR and HOMA2-B. These clusters differed in metabolic status, risks of diabetes and its complications, gut microbiome and serum metabolites. Notably, dietary fiber improved glycemic control in Clusters 3 and 4, but not in Clusters 1 and 2, consistent with observed gut microbiota alleviations. By using a LightGBM machine learning model, we calculated a microbiome-based clinical decision score to predict personalized fiber intervention responses and identified individuals who can get glycemic benefits. In conclusion, our study suggests that the gut microbiota response influences the effectiveness of dietary fiber intervention and provides a clinically applicable model to guide microbiome-targeted personalized medicine for prediabetes. Clinical Trial Registry: ChiCTR1900027663.

Intermittent fasting (IF) has gained attention as a potential intervention for cardiometabolic health, though its long-term effects remain unclear. In this randomized clinical trial, we assessed the impact of 6 months of IF on body composition, cardiovascular risk factors, and related molecular pathways in middle-aged (30-65 years) men and women with overweight (BMI 24.8-35 kg/m²). In this trial, 41 participants were randomized to either an intermittent fasting (IF) intervention or to maintain their habitual diet. The primary outcome (circulating CRP concentration) was previously reported; here, we present exploratory analyses focusing on metabolomic and transcriptomic responses. IF led to an 8% reduction in body weight, a 16% decrease in body fat, and significant improvements in lipid profile, including substantial reductions in plasma LDL-cholesterol, non-HDL-cholesterol, and triglycerides (p = 0.001). However, no significant changes were observed in other cardiometabolic risk factors. To investigate the underlying molecular mechanisms, we performed untargeted plasma metabolomics and transcriptomic analysis of colon mucosa biopsies. Significant multi-omic changes were identified, particularly in lipid metabolism, bile acid signaling, and enteroendocrine regulation. Notably, there was a downregulation of transcripts related to glucagon-like peptide 1 (GLP-1) and related enteroendocrine hormones. Correlation analysis highlighted key molecular pathways, with PPAR-α and B-cell-mediated immune processes significantly associated with changes in non-HDL cholesterol. Our findings extend the understanding of IF in humans beyond weight loss, providing key mechanistic insights to inform targeted therapies for improving cardiometabolic health. ClinicalTrials.gov NCT01964118.

BACKGROUND: Steroid hormone profiles in affective disorders suggest hypothalamic-pituitary-adrenal (HPA) axis dysregulation and may reveal novel therapeutic targets. However, most existing studies focus narrowly on glucocorticoids. This study aims to comprehensively characterize alterations in the steroid metabolome of adolescents with depressive symptoms. METHODS: This cross-sectional study analyzed the urinary excretion of 39 steroid metabolites (via gas chromatography-mass spectrometry) from 75 adolescent psychiatric patients with depressive symptoms (63 females, age 15.6 ± 1.3 years) and 75 healthy controls (64 females, age 15.3 ± 1.3 years), matched for age, sex, and pubertal status. RESULTS: Patients exhibited significantly elevated excretion rates (μg/24h) of corticosterone metabolites (median = 608.4, interquartile range (IQR): 342.4 - 1208.2 vs. controls: median = 321.0, IQR: 243.9 - 443.8), dehydroepiandrosterone (DHEA) metabolites (median = 1253.8, IQR: 569.8 - 2796.2 vs. median = 519.5, IQR: 254.0 - 1028.7), androgen metabolites (median = 6721.0, IQR: 4185.6 - 9395.8 vs. median = 3680.4, IQR: 2510.8 - 5419.0), and individual progesterone and glucocorticoid metabolites, while estradiol excretion was lower (median = 4.0, IQR: 2.9 - 5.8 vs. median = 5.8, IQR: 4.3 - 7.7). Analyses of enzyme activities via multivariate machine learning identified the tetrahydrated urinary metabolite ratio of 11-deoxycorticosterone (TH-DOC) to corticosterone metabolites as a biomarker to distinguish patients from controls (AUC = 0.800, 95%-CI [0.702 - 0.882]). CONCLUSIONS: Elevated excretion rates of ACTH-dependent hormones indicate chronic stress in adolescents with depressive symptoms. The TH-DOC-to-corticosterone metabolite ratio may help identify at-risk patients or guide personalized therapies.