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Semmler, L. ; Büchner, B.* ; Kornblum, C.* ; Deschauer, M.* ; Wortmann, S.* ; Morgia, C.L.* ; Servidei, S.* ; Freisinger, P.* ; Mensch, A.* ; Schuelke, M.* ; Prokisch, H. ; Mancuso, M.* ; Lamperti, C.* ; Klopstock, T.* ; Bertini, E.* ; Bischoff, A.T.* ; Boy, N.* ; Bruno, C.* ; Carelli, V.* ; Cecchi, G.* ; Claeys, K.* ; Distelmaier, F.* ; Filosto, M.* ; Garone, C.* ; Hempel, M.* ; Karall, D.* ; Kmop, C.* ; Kotzaeridou, R.* ; Lopriore, P.* ; Mongini, T.* ; Montano, V.* ; Musumeci, O.* ; Nicoletta, V.* ; Primiano, G.* ; Procopio, E.* ; Rinaldi, R.* ; Ruggiero, L.* ; Santer, R.* ; Sasse, H.* ; Schäfer, J.* ; Schlein, C.* ; Schöls, L.* ; Strube, D.* ; Thaele, A.* ; Valentino, M.L.* ; Kleist, J.v.* ; Zeng, L.*

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

EBioMedicine 131:106458 (2026)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Diabetes Mellitus ; Cohort Study ; Medline ; Cohort ; Mitochondrial Disease ; Disease
ISSN (print) / ISBN 2352-3964
e-ISSN 2352-3964
Journal EBioMedicine
Quellenangaben Volume: 131, Issue: , Pages: , Article Number: 106458 Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam [u.a.]
Reviewing status Peer reviewed
Institute(s) Institiute of Neurogenomics (ING)