Genes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes
(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.
(Less)
- author
- organization
-
- Diabetes - Epigenetics (research group)
- EXODIAB: Excellence of Diabetes Research in Sweden
- Diabetes - Islet Cell Exocytosis (research group)
- Molecular Neurogenetics (research group)
- MultiPark: Multidisciplinary research focused on Parkinson´s disease
- StemTherapy: National Initiative on Stem Cells for Regenerative Therapy
- LU Profile Area: Proactive Ageing
- Diabetic Complications (research group)
- Diabetes - Molecular Metabolism (research group)
- EpiHealth: Epidemiology for Health
- publishing date
- 2023-12
- 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}}, }