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

Author

Listed:
  • Tina Rönn

    (Scania University Hospital)

  • Jones K. Ofori

    (Scania University Hospital)

  • Alexander Perfilyev

    (Scania University Hospital)

  • Alexander Hamilton

    (Scania University Hospital
    University of Copenhagen)

  • Karolina Pircs

    (Lund University
    Neurobiology and Neurodegenerative Diseases Research Group
    Semmelweis University)

  • Fabian Eichelmann

    (German Institute of Human Nutrition Potsdam-Rehbruecke
    German Center for Diabetes Research)

  • Sonia Garcia-Calzon

    (Scania University Hospital
    University of Navarra)

  • Alexandros Karagiannopoulos

    (Scania University Hospital)

  • Hans Stenlund

    (Umeå University)

  • Anna Wendt

    (Scania University Hospital)

  • Petr Volkov

    (Scania University Hospital)

  • Matthias B. Schulze

    (German Institute of Human Nutrition Potsdam-Rehbruecke
    German Center for Diabetes Research
    University of Potsdam)

  • Hindrik Mulder

    (Scania University Hospital)

  • Lena Eliasson

    (Scania University Hospital)

  • Sabrina Ruhrmann

    (Scania University Hospital)

  • Karl Bacos

    (Scania University Hospital)

  • Charlotte Ling

    (Scania University Hospital)

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, 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.

Suggested Citation

  • Tina Rönn & Jones K. Ofori & Alexander Perfilyev & Alexander Hamilton & Karolina Pircs & Fabian Eichelmann & Sonia Garcia-Calzon & Alexandros Karagiannopoulos & Hans Stenlund & Anna Wendt & Petr Volko, 2023. "Genes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-43719-9
    DOI: 10.1038/s41467-023-43719-9
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    References listed on IDEAS

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    1. Qin Yang & Timothy E. Graham & Nimesh Mody & Frederic Preitner & Odile D. Peroni & Janice M. Zabolotny & Ko Kotani & Loredana Quadro & Barbara B. Kahn, 2005. "Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes," Nature, Nature, vol. 436(7049), pages 356-362, July.
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