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Glucose metabolism is a central process in mammalian energy homeostasis. Its deregulation is a key factor in development of metabolic disease like diabetes and cancer. In recent decades, our understanding of gene regulation at the signaling, chromatin and posttranscriptional levels has seen dramatic developments.A number of epigenetic mechanisms that do not affect the genetic code can be assessed with new technologies. However, increasing complexity becomes a major challenge for translation into clinical application.The current review provides an update of transcriptional control of glucose metabolism, focusing on epigenetic regulators, DNA-methylation, histone modifications and noncoding RNAs. Recent studies heavily support the importance of those mechanisms for future therapeutics and preventive efforts for metabolic diseases.