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

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 Hb...

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Veröffentlicht in:Nature communications Jg. 14; H. 1; S. 8040 - 21
Hauptverfasser: Rönn, Tina, Ofori, Jones K., Perfilyev, Alexander, Hamilton, Alexander, Pircs, Karolina, Eichelmann, Fabian, Garcia-Calzon, Sonia, Karagiannopoulos, Alexandros, Stenlund, Hans, Wendt, Anna, Volkov, Petr, Schulze, Matthias B., Mulder, Hindrik, Eliasson, Lena, Ruhrmann, Sabrina, Bacos, Karl, Ling, Charlotte
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 12.12.2023
Nature Publishing Group
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Adenosine diphosphate
Animals
Beta cells
Calcium (mitochondrial)
Calcium ions
Clinical Medicine
Diabetes
Diabetes mellitus (non-insulin dependent)
Diabetes Mellitus, Type 2 - genetics
Diabetes Mellitus, Type 2 - metabolism
DNA Methylation
Electron transport
Endocrinology and Diabetes
Endokrinologi och diabetes
Enhancers
Epigenesis, Genetic
Epigenetics
Forkhead Transcription Factors - metabolism
Foxp1 protein
Glycine
Humanities and Social Sciences
Humans
Hyperglycemia
Insulin
Insulin - metabolism
Insulin resistance
Insulin Secretion
Insulin-Secreting Cells - metabolism
Islets of Langerhans - metabolism
Klinisk medicin
Medical and Health Sciences
Medicin och hälsovetenskap
Metabolites
Mitochondria
Mitochondria - genetics
Mitochondria - metabolism
multidisciplinary
Pancreas
Proline
Rats
Repressor Proteins - metabolism
Science
Science (multidisciplinary)
Secretion
Transcription factors
Transcription Factors - metabolism
γ-Aminobutyric acid
ISSN:2041-1723, 2041-1723
Online-Zugang:Volltext
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Zusammenfassung: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. Type 2 diabetes (T2D) is characterized by hyperglycemia caused by insufficient insulin release from pancreatic islets, often in combination with insulin resistance. Here the authors present an epigenetic case-control study in human pancreatic islets revealing changes that contribute to type 2 diabetes development, e.g., epigenetic downregulation of RHOT1.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-023-43719-9