Endocrinology

Metabolomic profiling refines prediction of incident type 2 diabetes

In up to 23,634 initially diabetes-free adults, 235 of 469 circulating metabolites were associated with incident type 2 diabetes over 26 years. Sixty-seven associations were novel, involving bile acids, lipids, carnitines, urea cycle intermediates, and several amino acid pathways. Genetic analyses linked many metabolites to insulin resistance, glucose and insulin responses, ectopic fat, energy regulation, and liver function traits. Lifestyle factors, particularly physical activity, obesity, and diet, explained more variance in diabetes-associated than non-associated metabolites. A 44-metabolite signature improved diabetes risk prediction beyond conventional factors, supporting metabolomics-guided precision prevention strategies. 1

Tirzepatide improves cardiometabolic risk in obesity-related OSA

In the SURMOUNT-OSA phase 3 program, tirzepatide reduced multiple cardiometabolic risk factors versus placebo in adults with obesity and obstructive sleep apnea. Mediation analyses showed that improvements in apnea-hypopnea index and hypoxic burden independently contributed to reductions in hs-CRP, HOMA-IR, and triglycerides. Weight loss and OSA metrics together, and weight alone, significantly mediated systolic but not diastolic blood pressure improvements. These findings imply that addressing both obesity and sleep-disordered breathing is needed to maximize cardiometabolic benefit in moderate-to-severe OSA. 2

MASLD shows persistent nocturnal metabolic dysfunction despite liver fat reduction

In a human isotope-tracer study, patients with MASLD displayed pronounced nighttime hepatic and peripheral insulin resistance compared with overweight controls. Nocturnal hepatic de novo lipogenesis, systemic NEFA exposure, and whole-body metabolic dysfunction were all upregulated in MASLD at night. Nighttime plasma insulin was lower due to reduced secretion and increased clearance, compounding insulin resistance. These diurnal abnormalities persisted after weight loss and liver fat reduction, suggesting primary circadian metabolic dysregulation. The data support targeting evening energy intake, exercise, and medication timing to mitigate nocturnal metabolic stress in MASLD. 3

Real-world teplizumab in stage 2 type 1 diabetes reproduces early glycemic benefits

This prospective observational study compared 30 teplizumab-treated and 10 untreated individuals with stage 2 type 1 diabetes in routine practice. Between 2 and 6 months after treatment, teplizumab recipients showed improved 2-hour OGTT glucose and modest HbA1c reductions versus baseline. Two-thirds of treated participants had stable or reduced CGM time ≥7.8 mmol/L, indicating preserved preclinical glycemic control. CD4 preproinsulin-specific T-cell receptors declined after therapy and correlated with higher C-peptide AUC, while Epstein–Barr virus-related TCRs were unchanged. Teplizumab was safely administered, supporting feasibility of disease-modifying immunotherapy and suggesting candidate immune biomarkers for monitoring response. 4