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.
authors.affiliation: Department of Clinical Sciences, Lund University Diabetes Centre, CRC, Scania University Hospital, 205 02 Malmö, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Koeck
authors.forename: Anders H
authors.initials: AH
authors.lastname: Olsson
authors.forename: Marloes Dekker
authors.initials: MD
authors.lastname: Nitert
authors.forename: Vladimir V
authors.initials: VV
authors.lastname: Sharoyko
authors.forename: Claes
authors.initials: C
authors.lastname: Ladenvall
authors.forename: Olga
authors.initials: O
authors.lastname: Kotova
authors.forename: Erwin
authors.initials: E
authors.lastname: Reiling
authors.forename: Tina
authors.initials: T
authors.lastname: Rönn
authors.forename: Hemang
authors.initials: H
authors.lastname: Parikh
authors.forename: Jalal
authors.initials: J
authors.lastname: Taneera
authors.forename: Johan G
authors.initials: JG
authors.lastname: Eriksson
authors.forename: Metodi D
authors.initials: MD
authors.lastname: Metodiev
authors.forename: Nils-Göran
authors.initials: NG
authors.lastname: Larsson
authors.forename: Alexander
authors.initials: A
authors.lastname: Balhuizen
authors.forename: Holger
authors.initials: H
authors.lastname: Luthman
authors.forename: Alena
authors.initials: A
authors.lastname: Stančáková
authors.forename: Johanna
authors.initials: J
authors.lastname: Kuusisto
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Pernille
authors.initials: P
authors.lastname: Poulsen
authors.forename: Allan
authors.initials: A
authors.lastname: Vaag
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: Valeriya
authors.initials: V
authors.lastname: Lyssenko
authors.forename: Hindrik
authors.initials: H
authors.lastname: Mulder
authors.forename: Charlotte
authors.initials: C
authors.lastname: Ling
mesh_terms: D000818:Animals; D001786:Blood Glucose; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D020868:Gene Silencing; D056426:Genetic Loci; D014644:Genetic Variation; D006801:Humans; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D004268:DNA-Binding Proteins; D007328:Insulin; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C499632:TFB1M protein, human; D014157:Transcription Factors