Mitochondrial diabetes mellitus: real world insights from the GENOMIT registry-a multinational, longitudinal cohort study

September 01, 2026

Luisa Semmler 1, Boriana Büchner 2, Cornelia Kornblum 3, Marcus Deschauer 4, Saskia Wortmann 5, Chiara La Morgia 6, Serenella Servidei 7, Peter Freisinger 8, Alexander Mensch 9, Markus Schuelke 10, Holger Prokisch 11, Michelangelo Mancuso 12, Costanza Lamperti 13, Thomas Klopstock 14; GENOMIT study group

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.

Keywords: Diabetes mellitus; Metformin; Mitochondrial diabetes; Mitochondrial disease; m.3243A>G.

Collaborators

GENOMIT study group: 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

Affiliations

  1. Department of Neurology, TUM-University Hospital, Munich, Germany; Institute of Human Genetics, TUM-University Hospital, Munich, Germany; Institute of Neurogenomics, Computational Health Centre, Helmholtz Munich, Neuherberg, Germany.
  2. Friedrich-Baur-Institute at the Department of Neurology, LMU University Hospital, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany.
  3. Department of Neuromuscular Diseases, Centre for Neurology, University Hospital Bonn, Bonn, Germany.
  4. Department of Neurology, TUM-University Hospital, Munich, Germany.
  5. University Children’s Hospital, Paracelsus Medical University, Salzburg, Austria.
  6. IRCCS Istituto delle Scienze Neurologiche di Bologna, Programma di Neurogenetica, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy.
  7. Dipartimento di Neuroscienze, Organi di Senso e Torace, Fondazione Policlinico Universitario Agostino Gemelli Irccs, Roma, Italy.
  8. Klinikum am Steinenberg, Children’s Hospital Reutlingen, Reutlingen 72764, Germany.
  9. Department of Neurology, University Medicine Halle, Halle (Saale), Germany; BG University Hospital Bergmannsheil, Heimer Institute for Muscle Research, Bochum, Germany.
  10. Department of Neuropediatrics, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität Berlin, and Berlin Institute of Health, Berlin, Germany.
  11. Institute of Human Genetics, TUM-University Hospital, Munich, Germany; Institute of Neurogenomics, Computational Health Centre, Helmholtz Munich, Neuherberg, Germany; German Centre for Child and Adolescent Health (DZKJ), partner site Munich, Munich, Germany.
  12. Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, Pisa, Italy.
  13. UO di Genetica Medica e Neurogenetica, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.
  14. Friedrich-Baur-Institute at the Department of Neurology, LMU University Hospital, LMU Medizin, Ludwig-Maximilians-Universität München, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany; German Centre for Neurodegenerative Diseases (DZNE), Munich, Germany. Electronic address: Thomas.Klopstock@med.LMU.de.