Genes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes

Nat Commun. 2023 Dec 12;14(1):8040. doi: 10.1038/s41467-023-43719-9.


Epigenetic dysregulation may influence disease progression. Here we explore whether epigenetic alterations in human pancreatic islets impact insulin secretion and type 2 diabetes (T2D). In islets, 5,584 DNA methylation sites exhibit alterations in T2D cases versus controls and are associated with HbA1c in individuals not diagnosed with T2D. T2D-associated methylation changes are found in enhancers and regions bound by β-cell-specific transcription factors and associated with reduced expression of e.g. CABLES1, FOXP1, GABRA2, GLR1A, RHOT1, and TBC1D4. We find RHOT1 (MIRO1) to be a key regulator of insulin secretion in human islets. Rhot1-deficiency in β-cells leads to reduced insulin secretion, ATP/ADP ratio, mitochondrial mass, Ca2+, and respiration. Regulators of mitochondrial dynamics and metabolites, including L-proline, glycine, GABA, and carnitines, are altered in Rhot1-deficient β-cells. Islets from diabetic GK rats present Rhot1-deficiency. Finally, RHOT1methylation in blood is associated with future T2D. Together, individuals with T2D exhibit epigenetic alterations linked to mitochondrial dysfunction in pancreatic islets.

MeSH terms

  • Animals
  • DNA Methylation
  • Diabetes Mellitus, Type 2* / genetics
  • Diabetes Mellitus, Type 2* / metabolism
  • Epigenesis, Genetic
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells* / metabolism
  • Islets of Langerhans* / metabolism
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Rats
  • Repressor Proteins / metabolism
  • Transcription Factors / metabolism


  • Insulin
  • Transcription Factors
  • FOXP1 protein, human
  • Repressor Proteins
  • Forkhead Transcription Factors