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, Ca 2+ , 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, RHOT1 methylation in blood is
associated with future T2D. Together, individuals with T2D exhibit epigenetic alterations
linked to mitochondrial dysfunction in pancreatic islets.
