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

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.

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Journal
EBioMedicine
Published
2026-09-01
DOI
https://doi.org/10.1016/j.ebiom.2026.106458
Primary Topic
Mitochondrial Function and Pathology
Type
article
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0.00

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article

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

Christian Schlein, Marcus Deschauer, Vincenzo Montano, Lucia Ruggiero et al.
EBioMedicine
Mitochondrial Function and Pathology
article

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

Christian Schlein, Marcus Deschauer, Vincenzo Montano, Lucia Ruggiero, Elena Procopio, Piervito Lopriore, Annemarie Thaele, Serenella Servidei, Thomas Klopstock, Cornelia Kornblum, Massimiliano Filosto, Alexander Mensch, Jochen Schäfer, Luisa Semmler, Tiziana Mongini, Daniela Karall, Caterina Garone, Guido Primiano, Olimpia Musumeci, Chiara La Morgia, Markus Schuelke, Holger Prokisch, Michelangelo Mancuso, Maria Lucia Valentino, Peter Freisinger, Rita Rinaldi, Giulia Cecchi, Maja Hempel, René Santer, David Strube, Li Zeng, Valeria Nicoletta, Ludger Schöls, Almut T. Bischoff, Saskia Wortmann, Boriana Büchner, Nikolas Boy, Costanza Lamperti, Rania Kotzaeridou, Valerio Carelli, Enrico Bertini, Kristl Claeys, Heinrich Sasse, Claudio Bruno, Chirstian Kmop, Felix Distelmaier, Jürgen-Christoph von Kleist
article en

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.

EBioMedicineVol. 131
University of Pisa (IT), Paracelsus Medical University (AT), University Hospital Bonn (DE), German Center for Neurodegenerative Diseases (DE), Agostino Gemelli University Polyclinic (IT), Helmholtz Zentrum München (DE), Humboldt-Universität zu Berlin (DE), Munich Cluster for Systems Neurology (DE), Institute of Human Genetics (PL), München Klinik (DE), Istituto delle Scienze Neurologiche di Bologna (IT), Kreiskliniken Reutlingen (DE), German Centre for Cardiovascular Research (DE), Friedrich Baur Stiftung (DE), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), BG University Hospital Bergmannsheil Bochum (DE), University Hospital in Halle (DE), Fondazione IRCCS Istituto Neurologico Carlo Besta (IT), Ludwig-Maximilians-Universität München (DE), University of Bologna (IT)
Bundesministerium für Bildung und Forschung, Ministero della Salute
Openalex Percentile: Top 18%
Mitochondrial Function and Pathology
DOIOpen Access PDFOpenAlex
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