Insulin resistance and epigenetic regulation: insights from human studies and prospects for future research

In this study, we review the current knowledge and recent insights on the role of epigenetic factors in the development of human insulin resistance (IR)- and metabolic syndrome (MS)-related phenotypes, and attempt to lay a framework to consider IR as a potentially reversible incapacity to control metabolic homeostasis that is strongly influenced by the interplay between external and internal cues. We summarize the evidence on how tissue-specific epigenetic markers participate either by activating or repressing the gene expression programs to modulate IR- and MS-associated traits. Some additional data are provided about how the exploration of DNA methylation markers in peripheral blood mononuclear cells potentially offers appealing information about the impact of epigenetics in the pathogenesis of IR. Clues about the relation between IR and impaired intrauterine growth explained by fetal metabolic programming and epigenetic modifications are shown, including novel findings about the impact of histone modifications. For instance, we observed that specific epigenetic factors in genes associated with mitochondrial biogenesis may be associated with birth weight. Furthermore, some prospective ideas about the functional consequences of genetic variation modulated by allele-specific epigenetic markers and its impact on MS susceptibility are also illustrated. Finally, we summarize the current knowledge of epigenetics as the biological rationale for potential therapeutic intervention in IR and MS.