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

Rönn T, Ofori JK, Perfilyev A, Hamilton A, Pircs K, Eichelmann F, Garcia-Calzon S, Karagiannopoulos A, Stenlund H, Wendt A, Volkov P, Schulze MB, Mulder H, Eliasson L, Ruhrmann S, Bacos K, Ling C

Nat Commun 14 (1) 8040 [2023-12-12; online 2023-12-12]

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.

Swedish Metabolomics Centre (SMC) [Collaborative]

PubMed 38086799

DOI 10.1038/s41467-023-43719-9

Crossref 10.1038/s41467-023-43719-9

pmc: PMC10716521
pii: 10.1038/s41467-023-43719-9