title: Hyperglycaemia induces metabolic dysfunction and glycogen accumulation in pancreatic β-cells.
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.
authors.affiliation: Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Melissa F
authors.initials: MF
authors.lastname: Brereton
authors.affiliation: Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Rohm
authors.affiliation: Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Kenju
authors.initials: K
authors.lastname: Shimomura
authors.affiliation: Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Christian
authors.initials: C
authors.lastname: Holland
authors.affiliation: Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Sharona
authors.initials: S
authors.lastname: Tornovsky-Babeay
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Daniela
authors.initials: D
authors.lastname: Dadon
authors.affiliation: Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Michaela
authors.initials: M
authors.lastname: Iberl
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Margarita V
authors.initials: MV
authors.lastname: Chibalina
authors.affiliation: Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Sheena
authors.initials: S
authors.lastname: Lee
authors.affiliation: Endocrinology and Metabolism Service, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Glaser
authors.affiliation: Department of Developmental Biology and Cancer Research, The Institute for Medical Research Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Yuval
authors.initials: Y
authors.lastname: Dor
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LJ, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Clark
authors.affiliation: Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Frances M
authors.initials: FM
authors.lastname: Ashcroft
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D004195:Disease Models, Animal; D005941:Glucokinase / Q000235:genetics; D006003:Glycogen / Q000378:metabolism*; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases / Q000378:metabolism*; D007328:Insulin / Q000494:pharmacology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009154:Mutation; D051381:Rats; D013453:Sulfonylurea Compounds / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D013453:Sulfonylurea Compounds; D006003:Glycogen; D005941:Glucokinase