Reading between the (Genetic) Lines: How Epigenetics is Unlocking Novel Therapies for Type 1 Diabetes

Abstract

Type 1 diabetes (T1D) is an autoimmune condition where the body's immune cells destroy their insulin-producing pancreatic beta cells leading to dysregulated glycaemia. Individuals with T1D control their blood glucose through exogenous insulin replacement therapy, often using multiple daily injections or pumps. However, failure to accurately mimic intrinsic glucose regulation results in glucose fluctuations and long-term complications impacting key organs such as the heart, kidneys, and/or the eyes. It is well established that genetic and environmental factors contribute to the initiation and progression of T1D, but recent studies show that epigenetic modifications are also important. Here, we discuss key epigenetic modifications associated with T1D pathogenesis and discuss how recent research is finding ways to harness epigenetic mechanisms to prevent, reverse, or manage T1D.

Keywords: DNA methylation; chromatin; epigenetics; histone modifications; metaboloepigenetics; miRNA; therapy; type 1 diabetes.

Figure 1

Gene regulation by DNA methylation. DNA is methylated by the covalent addition of a methyl group to CpG dinucleotides by DNA methyltransferases. This process is generally associated with gene silencing.

Figure 2

Histone modifications and chromatin structure. Histone methylation at lysine residues is associated with both gene expression and silencing, while acetylation is associated with repression.

Figure 3

MicroRNA (miRNA) biogenesis and mechanism of action. miRNAs are transcribed in the nucleus as primary miRNA (pri-miRNA) and then cleaved into precursor miRNA (pre-miRNA) by the DORSHA–DGCR8 microprocessor complex. Pre-miRNA is then processed in the cytoplasm by the DICER enzyme, forming a bioactive miRNA duplex which can be bound by the RNA-induced silencing complex ready to target the complementary mRNA for silencing.