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Hyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic β-cells

Author

Listed:
  • Melissa F. Brereton

    (Anatomy and Genetics and OXION, University of Oxford)

  • Maria Rohm

    (Anatomy and Genetics and OXION, University of Oxford)

  • Kenju Shimomura

    (Anatomy and Genetics and OXION, University of Oxford)

  • Christian Holland

    (Anatomy and Genetics and OXION, University of Oxford)

  • Sharona Tornovsky-Babeay

    (Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center)

  • Daniela Dadon

    (The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School)

  • Michaela Iberl

    (Anatomy and Genetics and OXION, University of Oxford)

  • Margarita V. Chibalina

    (Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital)

  • Sheena Lee

    (Anatomy and Genetics and OXION, University of Oxford)

  • Benjamin Glaser

    (Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center)

  • Yuval Dor

    (The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School)

  • Patrik Rorsman

    (Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital)

  • Anne Clark

    (Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital)

  • Frances M. Ashcroft

    (Anatomy and Genetics and OXION, University of Oxford)

Abstract

Insulin secretion from pancreatic β-cells is impaired in all forms of diabetes. The resultant hyperglycaemia has deleterious effects on many tissues, including β-cells. Here we show that chronic hyperglycaemia impairs glucose metabolism and alters expression of metabolic genes in pancreatic islets. In a mouse model of human neonatal diabetes, hyperglycaemia results in marked glycogen accumulation, and increased apoptosis in β-cells. Sulphonylurea therapy rapidly normalizes blood glucose levels, dissipates glycogen stores, increases autophagy and restores β-cell metabolism. Insulin therapy has the same effect but with slower kinetics. Similar changes are observed in mice expressing an activating glucokinase mutation, in in vitro models of hyperglycaemia, and in islets from type-2 diabetic patients. Altered β-cell metabolism may underlie both the progressive impairment of insulin secretion and reduced β-cell mass in diabetes.

Suggested Citation

  • Melissa F. Brereton & Maria Rohm & Kenju Shimomura & Christian Holland & Sharona Tornovsky-Babeay & Daniela Dadon & Michaela Iberl & Margarita V. Chibalina & Sheena Lee & Benjamin Glaser & Yuval Dor &, 2016. "Hyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic β-cells," Nature Communications, Nature, vol. 7(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13496
    DOI: 10.1038/ncomms13496
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