The DOI matches its Crossref record; 21 of the 21 references it cites were found in a registry or an index.
Impaired insulin secretion and β-cell loss in tissue-specific knockout mice with mitochondrial diabetes
Abstract
Mitochondrial dysfunction is an important contributor to human pathology and it is estimated that mutations of mitochondrial DNA (mtDNA) cause approximately 0.5-1% of all types of diabetes mellitus. We have generated a mouse model for mitochondrial diabetes by tissue-specific disruption of the nuclear gene encoding mitochondrial transcription factor A (Tfam, previously mtTFA; ref. 7) in pancreatic beta-cells. This transcriptional activator is imported to mitochondria, where it is essential for mtDNA expression and maintenance. The Tfam-mutant mice developed diabetes from the age of approximately 5 weeks and displayed severe mtDNA depletion, deficient oxidative phosphorylation and abnormal appearing mitochondria in islets at the ages of 7-9 weeks. We performed physiological studies of beta-cell stimulus-secretion coupling in islets isolated from 7-9-week-old mutant mice and found reduced hyperpolarization of the mitochondrial membrane potential, impaired Ca(2+)-signalling and lowered insulin release in response to glucose stimulation. We observed reduced beta-cell mass in older mutants. Our findings identify two phases in the pathogenesis of mitochondrial diabetes; mutant beta-cells initially display reduced stimulus-secretion coupling, later followed by beta-cell loss. This animal model reproduces the beta-cell pathology of human mitochondrial diabetes and provides genetic evidence for a critical role of the respiratory chain in insulin secretion.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“TFAM deletion in pancreatic β-cells leads to diabetic mice (Silva et al., 2000).”
From Role of the mitochondrial DNA replication machinery in mitochondrial DNA mutagenesis, aging and age-related diseases (2017) · cites this paper as Silva et al., 2000
In the citing paper
“We have studied a variety of mouse models with decreased mtDNA expression (10, 12–18) and such mice have increased cell death with little or no increase of oxidative stress (18, 30).”
From Progressive parkinsonism in mice with respiratory-chain-deficient dopamine neurons (2007) · cites this paper as [15]
In the citing paper
“Consistent with this possibility, -cell specific deletion of Tfam reduces insulin secretory capacity and -cell mass, yielding so-called mitochondrial DM (241).”
From The role of mitochondria in the pathogenesis of type 2 diabetes (2010) · cites this paper as [241]
Citations
Cites
Mitochondrial diseases in man and mouse
Wallace, D. C. (1999) · Science · doi:10.1126/science.283.5407.1482 · Cited by 3,060
Method for the Isolation of Intact Islets of Langerhans from the Rat Pancreas
Lacy, P. E., & Kostianovsky, M. (1967) · Diabetes · doi:10.2337/diab.16.1.35 · Cited by 2,741
Mitochondrial transcription factor A is necessary for mtDNA maintance and embryogenesis in mice
Larsson, N.-G., Wang, J., Wilhelmsson, H., Oldfors, A., Rustin, P., Lewandoski, M., Barsh, G. S., & Clayton, D. A. (1998) · Nature Genetics · doi:10.1038/ng0398-231 · Cited by 1,594
Postic, C., Shiota, M., Niswender, K. D., Jetton, T. L., Chen, Y., Moates, J. M., Shelton, K. D., Lindner, J., Cherrington, A. D., & Magnuson, M. A. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.1.305 · Cited by 1,302
Kulkarni, R., Brüning, J. C., Winnay, J. N., Postic, C., Magnuson, M. A., & Kahn, C. R. (1999) · Cell · doi:10.1016/s0092-8674(00)80546-2 · Cited by 1,148
A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA.
Kadowaki, T., Kadowaki, H., Mori, Y., Tobe, K., Sakuta, R., Suzuki, Y., Tanabe, Y., Sakura, H., Awata, T., Goto, Y.-I., et al. (1994) · New England Journal of Medicine · doi:10.1056/nejm199404073301403 · Cited by 551
Similarity of Human Mitochondrial Transcription Factor 1 to High Mobility Group Proteins
Parisi, M. A., & Clayton, D. A. (1991) · Science · doi:10.1126/science.2035027 · Cited by 548
MOLECULAR GENETIC ASPECTS OF HUMAN MITOCHONDRIAL DISORDERS
Larsson, N.-G., & Clayton, D. A. (1995) · Annual Review of Genetics · doi:10.1146/annurev.ge.29.120195.001055 · Cited by 493
Wang, J., Wilhelmsson, H., Graff, C., Li, H., Oldfors, A., Rustin, P., Brüning, J. C., Kahn, C. R., Clayton, D. A., Barsh, G. S., et al. (1999) · Nature Genetics · doi:10.1038/5089 · Cited by 435
Self-citationMajamaa, K., Moilanen, J. S., Uimonen, S., Remes, A. M., Salmela, P. I., Kärppä, M., Majamaa‐Voltti, K., Rusanen, H., Sorri, M., PEUHKURINEN, K. J., et al. (1998) · The American Journal of Human Genetics · doi:10.1086/301959 · Cited by 385
Flagged first, then by citations
Cited by
Sorted by citations
Items 401–433 of 433
Mechanism and Regulation of Mitochondrial Transcription in Animal Cells
Polosa, P. L., Roberti, M., & Cantatore, P. (2011) · Springer eBooks · doi:10.1007/978-3-642-22380-8_11
Mitochondrial form and function in pancreatic β-cells and brown adipocytes
Wikström, J. D. (2010) · KTH Publication Database DiVA (KTH Royal Institute of Technology)
Monogenic Disorders of the β‐Cell
Pearson, E. R., & Hattersley, A. T. (2003) · Wiley eBooks · doi:10.1002/0470862092.d0406
Chapter 6 Pathophysiology of Mitochondrial Disease as Illuminated by Animal Models
Wallace, D. (2002) · Blue books of practical neurology · doi:10.1016/s1877-3419(09)70065-0
Lipid metabolism in the pancreatic beta-cell. Implications for insulin secretion.
Fex, M. (2006) · Lund University Publications (Lund University)
From the pancreatic beta cell to the endothelium:Pathophysiological aspects of Type 2 Diabetes
Nitert, M. D. (2007) · Lund University Publications (Lund University)
Marmolino, D., & Pandolfo, M. (2011) · Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles)
Signaling in Diabetes and Metabolic Syndrome
Marín-García, J. (2011) · Springer eBooks · doi:10.1007/978-1-4419-9461-5_16
Romano, C. (2007) · Università degli Studi di Napoli Federico II · doi:10.6092/unina/fedoa/1443
Generació d'un model de malaltia mitocondrial humana en "Drosophila melanogaster"
Guitart, T. (2010) · LA Referencia (Red Federada de Repositorios Institucionales de Publicaciones Científicas)
Metabolic Syndrome, Diabetes and Cardiometabolic Risks in Aging
Marı́n-Garcı́a, J., Goldenthal, M. J., & Moe, G. W. P. L. (2007) · Springer eBooks · doi:10.1007/978-0-387-74072-0_9
Age-Related Mitochondrial DNA Depletion and the Impact on Pancreatic Beta Cell
Nile, D. L., Brown, A. E., Kumaheri, M. A., Blair, H., Miwa, S., Cree, L. M., Payne, B. A. I., Chinnery, P. F., Brown, L., Gunn, D. A., et al. (2014)
Cardiac and skeletal muscle adaptations in health and disease
Andersson, D. C. (2009)
The Nutrient Paradox Oxidative Stress in Pancreatic β-Cells
Fridlyand, L. E., & Philipson, L. H. (2005) · doi:10.1201/9781420038798-20
Parker, E., Phillips, D. I. W., Cockington, R. A., Cull, C. A., & Poulton, J. (2016)
Malaisse, W. J., & Sener, A. (2008)
進, 鈴. (2004) · 糖尿病 · doi:10.11213/tonyobyo1958.47.500
The Role of SIRT1 in Pancreatic Beta Cells
Luu, L. (2013) · TSpace (University of Toronto)
MITOCHONDRIAL OXIDATIVE STRESS AND BIOGENESIS DURING ACETAMINOPHEN HEPATOTOXICITY
Du, K. (2017) · KU ScholarWorks (The University of Kansas)
Medini, H., Cohen, T., & Mishmar, D. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.07.21.213801
Matsuo, M., Iwasaki, N., & Saito, K. (2018) · Institutional Repositories DataBase (IRDB) · doi:10.24488/twmuj.2018003
Model Cells and Organisms in Mitochondrial Diseases
Stefanatos, R. K. A., Sanz, A., & Fernández‐Ayala, D. J. M. (2021) · Springer eBooks · doi:10.1007/978-3-030-70147-5_10
Role of Mitochondria in β-Cell Function and Dysfunction
Maechler, P., Li, N., Casimir, M., Vetterli, L., Frigerio, F., & Brun, T. (2014) · Springer eBooks · doi:10.1007/978-94-007-6884-0_7-2
Role of Mitochondria in β-Cell Function and Dysfunction
Maechler, P., Li, N., Casimir, M., Vetterli, L., Frigerio, F., & Brun, T. (2013) · Springer eBooks · doi:10.1007/978-94-007-6884-0_7-1
Guillausseau, P.-J., Laloi-Michelin, M., Meas, T., Virally, M., Bitu, J., Massin, P., Bellanné‐Chantelot, C., & Timsit, J. (2012) · EMC - Endocrinologie - Nutrition · doi:10.1016/s1155-1941(12)70012-4
Guillausseau, P.-J., Laloi-Michelin, M., Virally, M., Massin, P., Bellanné‐Chantelot, C., & Timsit, J. (2005) · EMC - Endocrinologie · doi:10.1016/j.emcend.2005.06.002
Jiang, S., Yuan, T., Kremer, L. S., Rosenberger, F. A., Hansen, F. M., Borg, M. L., Rubalcava-Gracia, D., Mennuni, M., Filograna, R., Alsina, D., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.09.22.558955
Developmental Origins of Disease: The Role of Oxidative Stress
Simmons, R. A. (2014) · Oxidative stress in applied basic research and clinical practice · doi:10.1007/978-1-4939-1405-0_6
Glucotoxicity in insulin-producing β-cells.
Nyblom, H. K. (2007) · KTH Publication Database DiVA (KTH Royal Institute of Technology)
Shah, J., Mahajan, A., & Muley, A. (2026) · Precision Nutrition · doi:10.1097/pn9.0000000000000136
Doctorate Program in Molecular Oncology and Endocrinology
Hoyos, J. M. (2006)
DNA Polymerase Gamma Mutations in Male Infertility and Ageing
Rovio, A. T. (2006) · Tampere University Institutional Repository (Tampere University)
Metadata
- Authors
- Silva, J. P., Köhler, M., Graff, C., Oldfors, A., Magnuson, M. A., Berggren, P.-O., & Larsson, N.-G.
- Affiliations
- Karolinska University Hospital (SE)
- Sahlgrenska University Hospital (SE)
- Vanderbilt University (US)
- Corresponding author
- Larsson, Nils-Göran
- ORCID
- Venue
- Nature Genetics
- Published
- 2000-11
- Volume
- 26
- Issue
- 3
- Pages
- 336-340
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1579112009
- Cited by
- 433
- References
- 21
- Citations by year
- 2026: 8 · 2025: 5 · 2024: 11 · 2023: 12 · 2022: 20 · 2021: 12 · 2020: 15 · 2019: 9 · 2018: 10 · 2017: 11 · 2016: 14 · 2015: 13 · 2014: 17 · 2013: 16 · 2012: 19
- FWCI
- 19.08
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Keywords
- mitochondrial diabetes, mitochondrial dysfunction, TFAM, beta cell destruction, insulin secretion, stimulus-secretion coupling, mtDNA depletion, oxidative phosphorylation, mitochondrial membrane potential, calcium signaling, beta-cell mass, electron transport chain, pancreatic islets, mouse model
- MeSH terms
- Insulin Secretion, Adenosine Triphosphate, Age Factors, Animals, Calcium, Electron Transport Complex IV, Diabetes Mellitus, Disease Models, Animal, DNA-Binding Proteins, DNA, Mitochondrial, Exocytosis, Glucose, High Mobility Group Proteins, Humans, Insulin, Islets of Langerhans, Mice, Transgenic, Nuclear Proteins, Organ Specificity, Oxidative Phosphorylation, Recombinant Fusion Proteins, Secretory Rate, Succinate Dehydrogenase, Transcription Factors, Transcription, Genetic, Viral Proteins, Potassium Channels, Trans-Activators, Ion Transport, Gene Targeting, Disease Progression, Transgenes, Integrases, Calcium Channels, L-Type, Mitochondrial Proteins, Xenopus Proteins, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
