Epigenetic programming of glucose-regulated insulin release

Pancreatic beta 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 beta 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 beta cell function. In this issue of the JCI, Dhawan et al. elucidate a molecular mechanism involved in beta 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 beta cells has two faces and that failure to achieve selective gene repression undermines beta cell support of normal glucose homeostasis.