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 V. Sharoyko, Claes Ladenvall, Olga Kotova, Erwin Reiling, Tina Rönn, Hemang Parikh, Jalal Taneera, Johan G. 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*

*Corresponding author af dette arbejde
82 Citationer (Scopus)

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.

OriginalsprogEngelsk
TidsskriftCell Metabolism
Vol/bind13
Udgave nummer1
Sider (fra-til)80-91
Antal sider12
ISSN1550-4131
DOI
StatusUdgivet - 5 jan. 2011
Udgivet eksterntJa

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