Epigenetic programming of glucose-regulated insulin release.

Abstract

Pancreatic β cells support glucose homeostasis with great precision by matching insulin release to the metabolic needs of the moment. Previous gene-expression analysis indicates that adult β cells not only produce cell-specific proteins, but also repress a small set of housekeeping genes - such as those encoding lactate dehydrogenase A (LDHA), solute transporter MCT1, and hexokinase 1 (HK1) - that would otherwise interfere with normal β cell function. In this issue of the JCI, Dhawan et al. elucidate a molecular mechanism involved in β cell-specific repression of Ldha and Hk1 that is mediated by induction of the de novo DNA methyltransferase DNMT3A during the first weeks after birth. Failure to induce DNMT3A-dependent methylation disrupts normal glucose-induced insulin release in adult life. The results of this study reinforce the idea that the phenotype of adult β cells has two faces and that failure to achieve selective gene repression undermines β cell support of normal glucose homeostasis.