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

Rönn, Tina LU ; Ofori, Jones K. LU ; Perfilyev, Alexander LU orcid ; Hamilton, Alexander LU ; Pircs, Karolina LU orcid ; Eichelmann, Fabian ; Garcia-Calzon, Sonia LU ; Karagiannopoulos, Alexandros LU orcid ; Stenlund, Hans and Wendt, Anna LU , et al. (2023) In Nature Communications 14(1).
Abstract

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,... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
14
issue
1
article number
8040
publisher
Nature Publishing Group
external identifiers
  • pmid:38086799
  • scopus:85179645980
ISSN
2041-1723
DOI
10.1038/s41467-023-43719-9
language
English
LU publication?
yes
id
4bfc32c6-4ec8-4bcd-bf57-f66db28f2085
date added to LUP
2024-01-04 11:36:13
date last changed
2024-04-19 07:51:56
@article{4bfc32c6-4ec8-4bcd-bf57-f66db28f2085,
  abstract     = {{<p>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<sup>2+</sup>, 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.</p>}},
  author       = {{Rönn, Tina and Ofori, Jones K. and Perfilyev, Alexander and Hamilton, Alexander and Pircs, Karolina and Eichelmann, Fabian and Garcia-Calzon, Sonia and Karagiannopoulos, Alexandros and Stenlund, Hans and Wendt, Anna and Volkov, Petr and Schulze, Matthias B. and Mulder, Hindrik and Eliasson, Lena and Ruhrmann, Sabrina and Bacos, Karl and Ling, Charlotte}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Genes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes}},
  url          = {{http://dx.doi.org/10.1038/s41467-023-43719-9}},
  doi          = {{10.1038/s41467-023-43719-9}},
  volume       = {{14}},
  year         = {{2023}},
}