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Free keywords:
Animals
Blood Glucose
Cell Line
DNA-Binding Proteins/deficiency/*genetics/metabolism
Diabetes Mellitus, Type 2/blood/*genetics/metabolism/pathology
Female
Gene Expression
Gene Silencing
Genetic Loci
Genetic Variation
Humans
Insulin/blood/metabolism/*secretion
Insulin-Secreting Cells/metabolism/secretion
Islets of Langerhans/metabolism
Male
Mice
Mice, Transgenic
Middle Aged
Mitochondria/metabolism
Mitochondrial Proteins/deficiency/*genetics/metabolism
Muscle, Skeletal/metabolism
Quantitative Trait Loci
RNA, Messenger/genetics/metabolism
Transcription Factors/deficiency/*genetics/metabolism
Abstract:
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.
