A Common Variant in TFB1M Is Associated with Reduced Insulin Secretion and Increased Future Risk of Type 2 Diabetes

作者：Koeck Thomas; Olsson Anders H; Nitert Marloes Dekker; Sharoyko Vladimir V; Ladenvall Claes; Kotova Olga; Reiling Erwin; Ronn Tina; Parikh Hemang; Taneera Jalal; Eriksson Johan G; Metodiev Metodi D; Larsson Nils Goran; Balhuizen Alexander; Luthman Holger; Stancakova Alena; Kuusisto Johanna; Laakso Markku; Poulsen Pernille; Vaag Allan; Groop Leif; Lyssenko Valeriya; Mulder Hindrik; Ling Charlotte^*

来源：Cell Metabolism, 2011, 13(1): 80-91.

DOI：10.1016/j.cmet.2010.12.007

Type 2 diabetes (T2D) evolves when insulin secretion fails. Insulin release from the pancreatic beta 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 beta 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.

• 出版日期2011-1-5