TY - JOUR
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 - Nitert, Marloes Dekker
AU - Sharoyko, Vladimir V.
AU - Ladenvall, Claes
AU - Kotova, Olga
AU - Reiling, Erwin
AU - Rönn, Tina
AU - Parikh, Hemang
AU - Taneera, Jalal
AU - Eriksson, Johan G.
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
PY - 2011/1/5
Y1 - 2011/1/5
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.
UR - http://www.scopus.com/inward/record.url?scp=78650924382&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2010.12.007
DO - 10.1016/j.cmet.2010.12.007
M3 - Journal article
C2 - 21195351
AN - SCOPUS:78650924382
SN - 1550-4131
VL - 13
SP - 80
EP - 91
JO - Cell Metabolism
JF - Cell Metabolism
IS - 1
ER -