A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes.

Thomas Koeck; Anders H Olsson; Marloes Dekker Nitert; Vladimir Sharoyko; Claes Ladenvall; Olga Kotova; Erwin Reiling; Tina Rönn; Hemang Parikh; Jalal Taneera; Johan Eriksson; Metodi D Metodiev; Nils-Göran Larsson; Alexander Balhuizen; Holger Luthman; Alena Stančáková; Johanna Kuusisto; Markku Laakso; Pernille Poulsen; Allan Vaag; Leif Groop; Valeriya Lyssenko; Hindrik Mulder; Charlotte Ling

doi:10.1016/j.cmet.2010.12.007

A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes.

Thomas Koeck, Anders H Olsson, Marloes Dekker Nitert, Vladimir Sharoyko, Claes Ladenvall, Olga Kotova, Erwin Reiling, Tina Rönn, Hemang Parikh, Jalal Taneera, Johan Eriksson, Metodi D Metodiev, Nils-Göran Larsson, Alexander Balhuizen, Holger Luthman, Alena Stančáková, Johanna Kuusisto, Markku Laakso, Pernille Poulsen, Allan VaagLeif Groop, Valeriya Lyssenko, Hindrik Mulder, Charlotte Ling

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Sammanfattning

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.

Originalspråk	engelska
Sidor (från-till)	80-91
Tidskrift	Cell Metabolism
Volym	13
Nummer	1
DOI	https://doi.org/10.1016/j.cmet.2010.12.007
Status	Published - 2011

Bibliografisk information

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Medical Genetics Unit (013241550), Islet cell physiology (013212142), Neuronano Research Center (NRC) (013210020), Molecular Metabolism (013212001), Department of Clinical Sciences, Malmö (013240000), Diabetes and Endocrinology (013241530)

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Cell- och molekylärbiologi

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10.1016/j.cmet.2010.12.007

http://www.ncbi.nlm.nih.gov/pubmed/21195351?dopt=Abstract

1 Doktorsavhandling (sammanläggning)

Genetic and epigenetic influence on oxidative phosphorylation, islet function and type 2 diabetes in humans
Olsson, A. H., 2012, Department of Clinical Sciences, Lund University. 66 s.
Forskningsoutput: Avhandling › Doktorsavhandling (sammanläggning)

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Koeck, T., Olsson, A. H., Dekker Nitert, M., Sharoyko, V., Ladenvall, C., Kotova, O., Reiling, E., Rönn, T., Parikh, H., Taneera, J., Eriksson, J., Metodiev, M. D., Larsson, N.-G., Balhuizen, A., Luthman, H., Stančáková, A., Kuusisto, J., Laakso, M., Poulsen, P., ... Ling, C. (2011). A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes. Cell Metabolism, 13(1), 80-91. https://doi.org/10.1016/j.cmet.2010.12.007

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title = "A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes.",

abstract = "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.",

author = "Thomas Koeck and Olsson, {Anders H} and {Dekker Nitert}, Marloes and Vladimir Sharoyko and Claes Ladenvall and Olga Kotova and Erwin Reiling and Tina R{\"o}nn and Hemang Parikh and Jalal Taneera and Johan Eriksson and Metodiev, {Metodi D} and Nils-G{\"o}ran Larsson and Alexander Balhuizen and Holger Luthman and Alena Stan{\v c}{\'a}kov{\'a} and Johanna Kuusisto and Markku Laakso and Pernille Poulsen and Allan Vaag and Leif Groop and Valeriya Lyssenko and Hindrik Mulder and Charlotte Ling",

note = "The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Medical Genetics Unit (013241550), Islet cell physiology (013212142), Neuronano Research Center (NRC) (013210020), Molecular Metabolism (013212001), Department of Clinical Sciences, Malm{\"o} (013240000), Diabetes and Endocrinology (013241530)",

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doi = "10.1016/j.cmet.2010.12.007",

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Koeck, T, Olsson, AH, Dekker Nitert, M, Sharoyko, V, Ladenvall, C, Kotova, O, Reiling, E, Rönn, T, Parikh, H, Taneera, J, Eriksson, J, Metodiev, MD, 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 2011, 'A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes.', Cell Metabolism, vol. 13, nr. 1, s. 80-91. https://doi.org/10.1016/j.cmet.2010.12.007

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T1 - A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes.

AU - Koeck, Thomas

AU - Olsson, Anders H

AU - Dekker Nitert, Marloes

AU - Sharoyko, Vladimir

AU - Ladenvall, Claes

AU - Kotova, Olga

AU - Reiling, Erwin

AU - Rönn, Tina

AU - Parikh, Hemang

AU - Taneera, Jalal

AU - Eriksson, Johan

AU - Metodiev, Metodi D

AU - Larsson, Nils-Göran

AU - Balhuizen, Alexander

AU - Luthman, Holger

AU - Stančáková, Alena

AU - Kuusisto, Johanna

AU - Laakso, Markku

AU - Poulsen, Pernille

AU - Vaag, Allan

AU - Groop, Leif

AU - Lyssenko, Valeriya

AU - Mulder, Hindrik

AU - Ling, Charlotte

N1 - The information about affiliations in this record was updated in December 2015. The record was previously connected to the following departments: Medical Genetics Unit (013241550), Islet cell physiology (013212142), Neuronano Research Center (NRC) (013210020), Molecular Metabolism (013212001), Department of Clinical Sciences, Malmö (013240000), Diabetes and Endocrinology (013241530)

PY - 2011

Y1 - 2011

N2 - 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.

AB - 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.

U2 - 10.1016/j.cmet.2010.12.007

DO - 10.1016/j.cmet.2010.12.007

M3 - Article

C2 - 21195351

SN - 1550-4131

VL - 13

SP - 80

EP - 91

JO - Cell Metabolism

JF - Cell Metabolism

IS - 1

ER -

A common variant in TFB1M is associated with reduced insulin secretion and increased future risk of type 2 diabetes.

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FN:s Globala mål

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Genetic and epigenetic influence on oxidative phosphorylation, islet function and type 2 diabetes in humans

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