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

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, Patrik Rorsman, Anne Clark and Frances M. Ashcroft ()
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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

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13496

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