Mitochondrial diabetes mellitus: real world insights from the GENOMIT registry–a multinational, longitudinal cohort study
Year: 2026
Type: article
Study design: Observational Study
Abstract: BACKGROUND: Diabetes mellitus is a common but incompletely characterised manifestation of mitochondrial diseases (MD). Data on risk factors, clinical course, and treatment recommendations are lacking. METHODS: In this multinational cohort study, we analysed longitudinal data of patients with a genetically confirmed MD from the GENOMIT registry included at German, Austrian, and Italian sites between 07/2009-01/2025. Our objectives were to (1) expand the genetic spectrum of mitochondrial diabetes mellitus (mDM), (2) identify risk factors, (3) delineate the clinical course, and (4) characterise real-world use of antidiabetic therapies. FINDINGS: Of 2399 patients, 1225 (51%) were female, and 281 (12%; 172 female) had mDM. Diabetes occurred across 31 genotypes and exhibited marked genotype dependence, with the highest prevalence in m.3243A>G carriers (177/360 [49%]). Only the m.3243A>G variant was associated with a significantly increased risk of mDM (HR = 10.3; 95% CI 5.2-20.4, p < 0.0001), whereas single mtDNA deletions, multiple mtDNA deletions, and primary LHON variants, as well as sex, BMI, ethnicity, smoking, hypertension and dyslipidaemia did not show a significant association. Median diabetes onset in patients with the m.3243A>G variant was at 47.7 years (SD 45.2-52.0). Among patients with mDM, 140/281 (50%) used insulin, and 111/281 (40%) received non-insulin antidiabetic drugs, most commonly metformin, which was discontinued in 8/50 users. Literature review revealed neurological events temporally linked to metformin application in m.3243A>G carriers, though long-term use without adverse events was likewise reported. INTERPRETATION: mDM is frequent in patients with MD, and the individual risk is strongly genotype dependent. While caution is warranted, our data do not justify universal avoidance of metformin; prospective, genotype-informed studies are needed to guide management. FUNDING: German Ministry of Research, Technology and Space; Italian Ministry of Health; European Union.
Source: EBioMedicine
Authors: Luisa Semmler, Boriana Büchner, Cornelia Kornblum, Marcus Deschauer, Saskia Wortmann, Chiara La Morgia, Serenella Servidei, Peter Freisinger, Alexander Mensch, Markus Schuelke, Holger Prokisch, Michelangelo Mancuso, Costanza Lamperti, Thomas Klopstock, Enrico Bertini, Almut T. Bischoff, Nikolas Boy, Claudio Bruno, Valerio Carelli, Giulia Cecchi, Kristl Claeys, Felix Distelmaier, Massimiliano Filosto, Caterina Garone, Maja Hempel, Daniela Karall, Chirstian Kmop, Rania Kotzaeridou, Piervito Lopriore, Tiziana Mongini, Vincenzo Montano, Olimpia Musumeci, Valeria Nicoletta, Guido Primiano, Elena Procopio, Rita Rinaldi, Lucia Ruggiero, René Santer, Heinrich Sasse, Jochen Schäfer, Christian Schlein, Ludger Schöls, David Strube, Annemarie Thaele, Maria Lucia Valentino, Jürgen-Christoph von Kleist, Leopold Zeng
Institutions: TUM Klinikum, Helmholtz Munich, Institut für Humangenetik, LMU Klinikum, Ludwig-Maximilians-Universität München, University Hospital Bonn, Technical University of Munich, Paracelsus Medical University, Istituto delle Scienze Neurologiche di Bologna, University of Bologna, Agostino Gemelli University Polyclinic, Kreiskliniken Reutlingen, BG University Hospital Bergmannsheil Bochum, Humboldt-Universität zu Berlin, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Charité - Universitätsmedizin Berlin, University of Pisa, Fondazione IRCCS Istituto Neurologico Carlo Besta, German Center for Neurodegenerative Diseases, Munich Cluster for Systems Neurology
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,780
Awards: G2872175397, G4785174427
OpenAlex ID: W7204880169