Diabetes mellitus characteristics in an international trial cohort with wolfram syndrome

Joanne McCabe; Gema Esteban-Bueno; Renuka Dias; Benjamin Wright; Christophe Orssaud; Wojciech Mlynarski; Agathe Roubertie; Martin Wilson; Patrick Yu-Wai-Man; Tracy Lynch; Amandip Malhi; Darren Barton; Victoria Homer; Timothy Barrett

doi:10.1530/endoabs.111.P91

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Endocrine Abstracts (2025) 111 P91 | DOI: 10.1530/endoabs.111.P91

BSPED2025 Poster Presentations Diabetes 4 (10 abstracts)

Diabetes mellitus characteristics in an international trial cohort with wolfram syndrome

Joanne McCabe ^1,2,3 , Gema Esteban-Bueno ⁴ , Renuka Dias ^5,6 , Benjamin Wright ⁷ , Christophe Orssaud ⁸ , Wojciech Mlynarski ⁹ , Agathe Roubertie ¹⁰ , Martin Wilson ¹¹ , Patrick Yu-Wai-Man ^12,13 , Tracy Lynch ¹⁴ , Amandip Malhi ¹⁵ , Darren Barton ¹⁵ , Victoria Homer ¹⁵ & Timothy Barrett ^1,6

Author affiliations

¹Department of Cancer and Genomic Sciences, University of Birmingham, Birmingham, United Kingdom; ²Warwick Medical School, University of Warwick, Coventry, United Kingdom; ³University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; ⁴Unidad de Gestión Clinica Almeria Periferia, Distrito Sanitario Almeria, Sistema Sanitario Publico Andaluz (SSPA), Consejeria de Salud y Consumo (Junta de Andalucia), Seville, Spain; ⁵Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom; ⁶Department of Paediatric Endocrinology, Birmingham Women’s and Children’s Hospital, Birmingham, United Kingdom; ⁷Department of Neurology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, United Kingdom; ⁸Functional Unit of Ophthalmology; Ophthalmological Rare Diseases Reference Center, Paris, France; ⁹Department of Paediatrics, Oncology and Haematology, Medical University of Lodz, Lodz, Poland; ¹⁰Département de Neurologie Pédiatrique, CIC pédiatrique, CHU Gui de Chauliac, INM, INSERM U 1298, Montpellier, France; ¹¹Centre for Human Brain Health, School of Psychology, University of Birmingham, Birmingham, United Kingdom; ¹²John van Geest Centre for Brain Repair and MRC Mitochondrial Biology Unit, Department of Clinical Neurosciences, University of Cambridge, Cambridge, United Kingdom; ¹³Addenbrooke’s Hospital NHS Foundation Trust, Cambridge, United Kingdom; ¹⁴Wolfram Syndrome UK, Worthing, United Kingdom; ¹⁵Cancer Research UK Clinical Trials Unit, University of Birmingham College of Medical and Dental Sciences, Birmingham, United Kingdom

This study reports baseline diabetes mellitus (DM) characteristics and predictors of DM progression in 63 participants with genetically confirmed Wolfram syndrome enrolled in the TREATWOLFRAM international clinical trial (ClinGov NCT03717909). Wolfram syndrome is a rare, monogenic, neurodegenerative and DM disorder typically diagnosed in childhood or adolescence. Participants were recruited from the UK, France, Poland, and Spain between 2019 and 2021. Beta cell function at baseline was assessed by haemoglobin and insulin dose-adjusted A1c (HbA1c and IDAA1c), fasting C-peptide, and fasting C-peptide corrected for fasting blood glucose. These were then compared according to age, sex, time since DM diagnosis, and WFS1 mutation type. At baseline, 97% had DM, with a median duration of 10.6 years (range 1 day to 51.0 years). Median HbA1c was 7.5% (range 5% to 12.4%); median IDAA1c was 10.8 (range 5.0 to 16.7); median fasting C-peptide was 86 pmol/l (range 31.5 pmol/l to 472.5 pmol/l); and median glucose-adjusted fasting C-peptide was 7.8 (range 2.9 to 52.5). Fasting C-peptide levels were inversely correlated with time since DM diagnosis (P = 0.03, n = 14), declining most rapidly in the first 9.75 years according to piece-wise regression. Fasting C-peptide levels were typically below 80 pmol/l (indicating absolute insulin requirement) after 9.30 years. Glucose-adjusted fasting C-peptide showed a similar negative correlation with time since DM diagnosis (P = 0.01, n = 14). Results suggested higher C-peptide levels in males (median 207.5 pmol/l, range 65.5 to 472.5 pmol/l, n = 6) than females (median 61.75 pmol/l, range 31.5 to 98 pmol/l, n = 8). No associations were found between beta-cell function markers (C-peptide, IDAA1c, HbA1c) and age, sex, or type of WFS1 mutation. There was a significantly younger age of DM onset for individuals with higher frequencies of nonsense/frameshift mutations (P = 0.002). The study concludes that C-peptide levels decline over time in individuals with Wolfram syndrome, falling to <80pmol/l after 9.30 years. Results showed some difference in C-peptide between males and females. There is little influence from age or genetic mutation class. These findings are important for clinical management and for evaluating new treatments targeting diabetes progression in Wolfram syndrome.