Endocrine Abstracts

Mitochondria are essential for the fuel-stimulated processes in beta-cells that control insulin secretion. Indeed, mutations in mitochondrial DNA underlie rare forms of maternally-inherited diabetes, where insulin secretion is impaired. Studies in human islets have identified several perturbations of mitochondrial function but whether they are causal or not has not been determined. Mining data from genome-wide association studies led us to the discovery of a variant of TFB1M, which encodes a protein that controls translation of mitochondrial proteins. Risk variant carriers exhibit elevated plasma glucose levels, reduced insulin secretion, lower TFB1M protein levels and impaired mitochondrial function, as well as increased risk of type 2 diabetes. Mice with a heterozygous general knock out or beta-cell-specific knock out of Tfb1m become glucose intolerant and ultimately hyperglycemic. Functional studies of islets from such mice or clonal beta-cells, where Tfb1m has been silenced, revealed abrogated fuel-stimulated insulin secretion, loss of mitochondrial proteins, impaired respiration and reduced ATP generation. Beta-cell-specific homozygous and heterozygous knock out of Tfb2m, a paralogue of Tfb1m and a bona fide transcription factor, exhibited an even more pronounced phenotype, with rapidly evolving diabetes and mitochondrial dysfunction. These studies demonstrate, on a functional and molecular level, the critical role of mitochondria in control of beta-cell function and insulin secretion. Human genetics lends support to the notion that mitochondrial dysfunction plays a contributing, but causal, role in the deterioration of beta-cell function in type 2 diabetes.