The Metabolic-Epigenetic Nexus in Type 2 Diabetes Mellitus

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The prevalence of type 2 diabetes mellitus (T2DM) continues to rise globally. Yet the aetiology and pathophysiology of this noncommunicable, polygenic disease, is poorly understood. Lifestyle factors, such as poor dietary intake, lack of exercise, and abnormal glycaemia, are purported to play a role in disease onset and progression, and these environmental factors may disrupt specific epigenetic mechanisms, leading to a reprogramming of gene transcription. The hyperglycaemic cell per se, alters epigenetics through chemical modifications to DNA and histones via metabolic intermediates such as succinate, α-ketoglutarate and O-GlcNAc. To illustrate, α-ketoglutarate is considered a salient co-factor in the activation of the ten-eleven translocation (TET) dioxygenases, which drives DNA demethylation. On the contrary, succinate and other mitochondrial tricarboxylic acid cycle intermediates, inhibit TET activity predisposing to a state of hypermethylation. Hyperglycaemia depletes intracellular ascorbic acid, and damages DNA by enhancing the production of reactive oxygen species (ROS); this compromised cell milieu exacerbates the oxidation of 5-methylcytosine alongside a destabilisation of TET. These metabolic connections may regulate DNA methylation, affecting gene transcription and pancreatic islet β-cell function in T2DM. This complex interrelationship between metabolism and epigenetic alterations may provide a conceptual foundation for understanding how pathologic stimuli modify and control the intricacies of T2DM. As such, this narrative review will comprehensively evaluate and detail the interplay between metabolism and epigenetic modifications in T2DM.
Original languageEnglish
Pages (from-to)194-206
Number of pages13
JournalFree Radical Biology and Medicine
Early online date8 Jan 2021
Publication statusPublished (in print/issue) - 31 Jul 2021

Bibliographical note

Publisher Copyright:
© 2021


  • epigenetics
  • metabolism
  • diabetes
  • DNA Methylation
  • Histone modifications
  • Type 2 diabetes mellitus
  • Diabetes Mellitus
  • 5-Methylcytosine
  • Epigenesis, Genetic
  • Humans
  • Histones/metabolism
  • Type 2/genetics


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