title: Reversible changes in pancreatic islet structure and function produced by elevated blood glucose.
abstract: Diabetes is characterized by hyperglycaemia due to impaired insulin secretion and aberrant glucagon secretion resulting from changes in pancreatic islet cell function and/or mass. The extent to which hyperglycaemia per se underlies these alterations remains poorly understood. Here we show that β-cell-specific expression of a human activating KATP channel mutation in adult mice leads to rapid diabetes and marked alterations in islet morphology, ultrastructure and gene expression. Chronic hyperglycaemia is associated with a dramatic reduction in insulin-positive cells and an increase in glucagon-positive cells in islets, without alterations in cell turnover. Furthermore, some β-cells begin expressing glucagon, whilst retaining many β-cell characteristics. Hyperglycaemia, rather than KATP channel activation, underlies these changes, as they are prevented by insulin therapy and fully reversed by sulphonylureas. Our data suggest that many changes in islet structure and function associated with diabetes are attributable to hyperglycaemia alone and are reversed when blood glucose is normalized.
authors.affiliation: Henry Wellcome Centre for Gene Function, 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: 1] Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford OX1 3PT, UK [2].
authors.forename: Michaela
authors.initials: M
authors.lastname: Iberl
authors.affiliation: 1] Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford OX1 3PT, UK [2].
authors.forename: Kenju
authors.initials: K
authors.lastname: Shimomura
authors.affiliation: 1] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK [2].
authors.forename: Quan
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: 1] Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK [2].
authors.forename: Alice E
authors.initials: AE
authors.lastname: Adriaenssens
authors.affiliation: Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Proks
authors.affiliation: Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Ioannis I
authors.initials: II
authors.lastname: Spiliotis
authors.affiliation: Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: William
authors.initials: W
authors.lastname: Dace
authors.affiliation: Henry Wellcome Centre for Gene Function, Department of Physiology, Anatomy and Genetics and OXION, University of Oxford, Parks Road, Oxford OX1 3PT, UK.
authors.forename: Katia K
authors.initials: KK
authors.lastname: Mattis
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
authors.forename: Reshma
authors.initials: R
authors.lastname: Ramracheya
authors.affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Fiona M
authors.initials: FM
authors.lastname: Gribble
authors.affiliation: Cambridge Institute for Medical Research, Addenbrooke's Hospital, Hills Road, Cambridge CB2 0XY, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Reimann
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
authors.forename: Anne
authors.initials: A
authors.lastname: Clark
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Oxford OX3 7LE, UK.
authors.forename: Patrik
authors.initials: P
authors.lastname: Rorsman
authors.affiliation: Henry Wellcome Centre for Gene Function, 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; D001786:Blood Glucose / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D004195:Disease Models, Animal; D004594:Electrophysiology / Q000379:methods; D005905:Glyburide / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D007328:Insulin / Q000494:pharmacology; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure*; D054086:KATP Channels / Q000037:antagonists & inhibitors / Q000378:metabolism; D008822:Mice, Transgenic; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D000099161:Kcnj11 Channel
chemical_list: D001786:Blood Glucose; D005905:Glyburide; D007328:Insulin; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D000099161:Kcnj11 Channel