Journal Article

DZNE-2026-00948

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Mitochondrial diabetes mellitus: real world insights from the GENOMIT registry-a multinational, longitudinal cohort study.

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

2026
Elsevier Amsterdam [u.a.]

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Please use a persistent id in citations: doi:10.1016/j.ebiom.2026.106458

Abstract: Diabetes mellitus is a common but incompletely characterised manifestation of mitochondrial diseases (MD). Data on risk factors, clinical course, and treatment recommendations are lacking.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.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.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.German Ministry of Research, Technology and Space; Italian Ministry of Health; European Union.

Keyword(s): Humans (MeSH) ; Female (MeSH) ; Registries (MeSH) ; Male (MeSH) ; Middle Aged (MeSH) ; Longitudinal Studies (MeSH) ; Diabetes Mellitus: epidemiology (MeSH) ; Diabetes Mellitus: drug therapy (MeSH) ; Diabetes Mellitus: etiology (MeSH) ; Diabetes Mellitus: genetics (MeSH) ; Diabetes Mellitus: diagnosis (MeSH) ; Risk Factors (MeSH) ; Mitochondrial Diseases: epidemiology (MeSH) ; Mitochondrial Diseases: genetics (MeSH) ; Mitochondrial Diseases: complications (MeSH) ; Adult (MeSH) ; DNA, Mitochondrial: genetics (MeSH) ; Genotype (MeSH) ; Aged (MeSH) ; Hypoglycemic Agents: therapeutic use (MeSH) ; Genetic Predisposition to Disease (MeSH) ; Prevalence (MeSH) ; Diabetes mellitus ; Metformin ; Mitochondrial diabetes ; Mitochondrial disease ; m.3243A>G ; DNA, Mitochondrial ; Hypoglycemic Agents

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Contributing Institute(s):

1. Clinical Research (Munich) (Clinical Research (Munich))

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2026

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Database coverage:
; ; ; ; Article Processing Charges ; Clarivate Analytics Master Journal List ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 10 ; JCR ; PubMed Central ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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