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PubMed2026

Molecular Signature of Prediabetes With High-Risk of Diabetes Revealed by Deep Plasma Proteome.

AIMS: Prediabetes is biologically heterogeneous, but molecular subtypes linked to diabetes progression remain poorly defined. We aimed to identify plasma proteome-based subtypes of impaired fasting glucose (IFG), characterise their molecular features and assess their association with future diabetes risk. MATERIALS AND METHODS: We quantified 2584 plasma proteins using liquid chromatography-mass spectrometry in 538 IFG participants from a prospective discovery cohort (Nutrition and Health of Aging Population in China, NHAPC). Proteomic subtypes were defined by consensus clustering, linked to longitudinal changes in insulin sensitivity and incident type 2 diabetes mellitus (T2DM), which were further validated in an independent Shanghai Brain Aging Study (SBAS) cohort. RESULTS: Two reproducible IFG molecular subtypes based on plasma proteomics were identified. The high-risk subtype showed higher incident diabetes and a greater 6-year decline in insulin sensitivity and was characterised by enrichment of glycolysis/gluconeogenesis, insulin signalling and neutrophil degranulation, together with a dyslipidemic lipidomic profile indicating co-dysregulation of glucose and lipid homeostasis. The low-risk subtype demonstrated a higher complement cascade and high-density lipoprotein particle remodelling signature. In the high-risk subtype, key proteins and lipids showed stronger associations with longitudinal declines in insulin sensitivity, including PPBP, PGK1 and ALDOA, as well as PE-P 18:0/20:3 and PE-P 18:1/20:3. CONCLUSIONS: Proteome-based molecular subtyping stratifies IFG individuals with similar fasting glucose levels but distinct biology and future diabetes risk, supporting earlier and more targeted prevention.

Humans↗

PubMed2025

AAV gene therapy for autosomal recessive deafness 9: a single-arm trial.

Gene therapy for congenital deafness has shown promising results in children but lacks data in older populations. We conducted a single-arm trial of adeno-associated virus (AAV)-OTOF gene therapy using the Anc80L65 capsid in ten participants with autosomal recessive deafness 9 aged 1.5 to 23.9 years at five sites in China. The primary endpoints were safety and tolerability within 5 years, and secondary endpoints assessed auditory function. Initial findings from the ten patients with 6-12 months of follow-up, including one patient who received two injections, revealed that the therapy was well tolerated, with 162 grade I/II adverse events. Decreased neutrophil percentage was the most common event (16 of 162). All ten participants had at least 6 months of follow-up and improved their pure-tone-average hearing level from baseline 106 ± 9 (mean ± s.d.) to 52 ± 30 decibels (dB). Other secondary endpoints showed similar improvements, including the average click auditory brainstem response (ABR) threshold, the tone-burst ABR threshold and the auditory steady-state response (101 ± 1 to 48 ± 26 dB, 91 ± 4 to 57 ± 19 dB and 80 ± 14 to 64 ± 21 dB, respectively). Post hoc analyses were conducted to evaluate the timecourse and factors contributing to the hearing improvement. Therapeutic effect was rapid, taking 1 month to achieve most of the overall hearing improvement. On an individual level, click and tone-burst ABR thresholds, but not the auditory steady-state response, reliably predicted the behavioral pure-tone-average thresholds after 4 months (R2 = 0.68, 0.73 and 0.17, respectively). An age-dependent therapeutic effect was observed, with optimal outcomes in 5- to 8-year-olds. These preliminary results show that AAV-OTOF was safe and well tolerated in patients ranging from toddlerhood to adulthood. The trial remains ongoing and requires extended follow-up to confirm the long-term safety and efficacy. ClinicalTrials.gov registration: NCT05901480 .

Humans↗