Loss of TFB1M results in mitochondrial dysfunction that leads to impaired insulin secretion and diabetes.

@article{Sharoyko2014LossOT,
  title={Loss of TFB1M results in mitochondrial dysfunction that leads to impaired insulin secretion and diabetes.},
  author={Vladimir V. Sharoyko and Mia Abels and Jiangming Sun and Lisa M. Nicholas and In{\^e}s Guerra Mollet and Jelena A. Stamenkovic and Isabel G{\"o}hring and Siri Malmgren and Petter Storm and Jo{\~a}o Fadista and Peter Sp{\'e}gel and Metodi D Metodiev and Nils-G{\"o}ran Larsson and Lena Eliasson and Nils Wierup and Hindrik Mulder},
  journal={Human molecular genetics},
  year={2014},
  volume={23 21},
  pages={
          5733-49
        }
}
We have previously identified transcription factor B1 mitochondrial (TFB1M) as a type 2 diabetes (T2D) risk gene, using human and mouse genetics. To further understand the function of TFB1M and how it is associated with T2D, we created a β-cell-specific knockout of Tfb1m, which gradually developed diabetes. Prior to the onset of diabetes, β-Tfb1m(-/-) mice exhibited retarded glucose clearance owing to impaired insulin secretion. β-Tfb1m(-/-) islets released less insulin in response to fuels… 

Figures from this paper

DIMT1, a regulator of ribosomal biogenesis, controls β-cell protein synthesis, mitochondrial function and insulin secretion
TLDR
A role of DIMT1 in ribosomal biogenesis that perturbs protein synthesis, resulting in mitochondrial dysfunction and disrupted insulin secretion is highlighted, both being potential pathogenetic factors in T2D.
Mitochondrial transcription factor B2 is essential for mitochondrial and cellular function in pancreatic β-cells
Transcribing β-cell mitochondria in health and disease
  • H. Mulder
  • Medicine, Biology
    Molecular metabolism
  • 2017
Perturbed Mitochondrial Metabolism in Islets from Donors with Type-2 Diabetes
TLDR
By linking the metabolome to the transcriptome, it is showed that perturbed mitochondrial metabolism is a feature of ß-cell dysfunction in T2D.
Mitochondrial dysfunction and pancreatic islet β-cell failure (Review)
TLDR
The present review examined the potential factors underlying mitochondrial dysfunction and their association with islet β-cell failure, which may offer novel insights regarding future strategies for the preservation of mitochondrial function and enhancement of antioxidant activity for individuals with diabetes mellitus.
Disruption of CR6-interacting factor-1 (CRIF1) in mouse islet beta cells leads to mitochondrial diabetes with progressive beta cell failure
TLDR
The results indicate that mitochondrial OxPhos dysfunction triggers progressive beta cell failure that is not halted by treatment with a GLP-1 agonist, and the Crif1beta−/− mouse is a useful model for the study ofBeta cell failure caused by mitochondrial Ox Phos dysfunction.
Mitoribosome insufficiency in β cells is associated with type 2 diabetes-like islet failure.
TLDR
D deregulation of most mitoribosomal genes in islets from individuals with type 2 diabetes, including partial downregulation of CRIF1 is found, which predisposes rodents to glucose intolerance, which resembles the early stages of type 1 diabetes in humans.
The pathogenetic role of β-cell mitochondria in type 2 diabetes.
TLDR
It is argued that alterations in mitochondria may be a culprit in the pathogenetic processes culminating in type 2 diabetes.
Mitochondrial regulation of β-cell function: maintaining the momentum for insulin release
...
...

References

SHOWING 1-10 OF 52 REFERENCES
A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes.
Impaired insulin secretion and β-cell loss in tissue-specific knockout mice with mitochondrial diabetes
TLDR
This animal model reproduces the β-cell pathology of human mitochondrial diabetes and provides genetic evidence for a critical role of the respiratory chain in insulin secretion.
Functional and morphological alterations of mitochondria in pancreatic beta cells from type 2 diabetic patients
TLDR
In pancreatic beta cells from type 2 diabetic subjects, the impaired secretory response to glucose is associated with a marked alteration of mitochondrial function and morphology, which leads to lower ATP, decreased ATP/ADP ratio, with consequent reduction of insulin release.
Diabetes associated cell stress and dysfunction: role of mitochondrial and non‐mitochondrial ROS production and activity
TLDR
NADPH oxidase associated ROS may be a useful target for intervention strategies based on reversing the negative impact of glucolipotoxicity in diabetes and may alter parameters of signal transduction, insulin secretion, insulin action and cell proliferation or cell death.
High glucose inhibits glucose‐6‐phosphate dehydrogenase, leading to increased oxidative stress and β‐cell apoptosis
  • Zhaoyun ZhangC. Liew R. Stanton
  • Biology
    FASEB journal : official publication of the Federation of American Societies for Experimental Biology
  • 2010
TLDR
High‐glucose‐mediated decrease in G6PD activity may provide a mechanistic explanation for the gradual loss of β cells in patients with diabetes.
Mitochondrial transcription factors B1 and B2 activate transcription of human mtDNA
TLDR
The presence of two proteins that interact with mammalian POLRMT may allow flexible regulation of mtDNA gene expression in response to the complex physiological demands of mammalian metabolism.
Tight Coupling between Glucose and Mitochondrial Metabolism in Clonal β-Cells Is Required for Robust Insulin Secretion*
TLDR
Tight metabolic regulation enhancing mitochondrial metabolism and restricting glycolysis in 832/13 cells is required for clonal β-cells to secrete insulin robustly in response to glucose, suggesting that a similar prioritization of mitochondrial metabolism is required in healthy humanβ-cells.
Functional and molecular defects of pancreatic islets in human type 2 diabetes.
TLDR
24-h exposure to glutathione significantly improved glucose-stimulated insulin release and decreased nitrotyrosine concentration, with partial recovery of insulin mRNA expression, providing direct evidence that the defects of insulin secretion in type 2 diabetic islets are associated with multiple islet cell alterations.
Role of mitochondria in beta-cell function and dysfunction.
TLDR
The mitochondrion-dependent pathways of regulated insulin secretion are described and Mitochondrial defects, such as mutations and reactive oxygen species production, are discussed in the context of beta-cell failure that may participate to the etiology of diabetes.
Chronic High Glucose and Pyruvate Levels Differentially Affect Mitochondrial Bioenergetics and Fuel-stimulated Insulin Secretion from Clonal INS-1 832/13 Cells
TLDR
The present study supports the idea that glucose-induced disturbances of stimulus-secretion coupling by extramitochondrial metabolism upstream of pyruvate, rather than exhaustion from metabolic overload, underlie glucotoxicity in insulin-producing cells.
...
...