A Common Variant in TFB1M Is Associated with Reduced Insulin Secretion and Increased Future Risk of Type 2 Diabetes
Open accessAbstract
Type 2 diabetes (T2D) evolves when insulin secretion fails. Insulin release from the pancreatic β cell is controlled by mitochondrial metabolism, which translates fluctuations in blood glucose into metabolic coupling signals. We identified a common variant (rs950994) in the human transcription factor B1 mitochondrial (TFB1M) gene associated with reduced insulin secretion, elevated postprandial glucose levels, and future risk of T2D. Because islet TFB1M mRNA levels were lower in carriers of the risk allele and correlated with insulin secretion, we examined mice heterozygous for Tfb1m deficiency. These mice displayed lower expression of TFB1M in islets and impaired mitochondrial function and released less insulin in response to glucose in vivo and in vitro. Reducing TFB1M mRNA and protein in clonal β cells by RNA interference impaired complexes of the mitochondrial oxidative phosphorylation system. Consequently, nutrient-stimulated ATP generation was reduced, leading to perturbed insulin secretion. We conclude that a deficiency in TFB1M and impaired mitochondrial function contribute to the pathogenesis of T2D.
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A common mtDNA variant in TFB1M is associated with reduced insulin secretion.
“In addition, PGC1α silencing in healthy human islets resulted in reduced insulin secretion145, a phenomenon also found in patients with a common mtDNA variant in mitochondrial transcription factor B1 (TFB1M)146.”
From Mitochondrial and metabolic dysfunction in ageing and age-related diseases (2022) · cites this paper as [146]
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- Authors
- Koeck, T., Olsson, A. H., Nitert, M. D., Sharoyko, V. V., Ladenvall, C., Kotova, O., Reiling, E., Rönn, T., Parikh, H., Taneera, J., Eriksson, J. G., Metodiev, M. D., Larsson, N.-G., Balhuizen, A., Luthman, H., Stančáková, A., Kuusisto, J., Laakso, M., Poulsen, P., Vaag, A., Groop, L., Lyssenko, V., Mulder, H., & Ling, C.
- Affiliations
- Lund University (SE)
- Leiden University Medical Center (NL)
- University of Helsinki (FI)
- Max Planck Institute for Biology of Ageing (DE)
- University of Eastern Finland (FI)
- Novo Nordisk (Denmark) (DK)
- Corresponding author
- Ling, Charlotte
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 13
- Issue
- 1
- Pages
- 80-91
- ISSN
- 1550-4131 (ISSN-L)
- OpenAlex
- W2009372627
- Cited by
- 105
- References
- 41
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 8 · 2023: 6 · 2022: 12 · 2021: 5 · 2020: 7 · 2019: 3 · 2018: 3 · 2017: 7 · 2016: 3 · 2015: 10 · 2014: 6 · 2013: 6 · 2012: 10
- FWCI
- 8.18
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Leiden Repository (Leiden University) (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- Funders
- Vetenskapsrådet
- Novartis
- Region Skåne
- European Foundation for the Study of Diabetes (B31 5631/2006)
- Diabetestutkimussäätiö
- Academy of Finland
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- TFB1M, type 2 diabetes, insulin secretion, pancreatic beta cells, mitochondrial metabolism, oxidative phosphorylation, postprandial blood glucose, genetic susceptibility, islet gene expression, ATP production, glucose-stimulated insulin secretion
- MeSH terms
- Insulin Secretion, Animals, Blood Glucose, Cell Line, Diabetes Mellitus, Type 2, DNA-Binding Proteins, Female, Humans, Insulin, Islets of Langerhans, Male, Mice, Transgenic, Middle Aged, Mitochondria, RNA, Messenger, Transcription Factors, Genetic Variation, Gene Expression, Muscle, Skeletal, Gene Silencing, Mitochondrial Proteins, Quantitative Trait Loci, Insulin-Secreting Cells, Mice, Genetic Loci
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