Reversible changes in pancreatic islet structure and function produced by elevated blood glucose

Melissa F. Brereton, Michaela Iberl, Kenju Shimomura, Quan Zhang, Alice E. Adriaenssens, Peter Proks, Ioannis I. Spiliotis, William Dace, Katia K. Mattis, Reshma Ramracheya, Fiona M. Gribble, Frank Reimann, Anne Clark, Patrik Rorsman and Frances M. Ashcroft ()
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Melissa F. Brereton: Henry Wellcome Centre for Gene Function, Anatomy and Genetics and OXION, University of Oxford
Michaela Iberl: Henry Wellcome Centre for Gene Function, Anatomy and Genetics and OXION, University of Oxford
Kenju Shimomura: Henry Wellcome Centre for Gene Function, Anatomy and Genetics and OXION, University of Oxford
Quan Zhang: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital
Alice E. Adriaenssens: Cambridge Institute for Medical Research, Addenbrooke’s Hospital
Peter Proks: Henry Wellcome Centre for Gene Function, Anatomy and Genetics and OXION, University of Oxford
Ioannis I. Spiliotis: Henry Wellcome Centre for Gene Function, Anatomy and Genetics and OXION, University of Oxford
William Dace: Henry Wellcome Centre for Gene Function, Anatomy and Genetics and OXION, University of Oxford
Katia K. Mattis: Henry Wellcome Centre for Gene Function, Anatomy and Genetics and OXION, University of Oxford
Reshma Ramracheya: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital
Fiona M. Gribble: Cambridge Institute for Medical Research, Addenbrooke’s Hospital
Frank Reimann: Cambridge Institute for Medical Research, Addenbrooke’s Hospital
Anne Clark: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital
Patrik Rorsman: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital
Frances M. Ashcroft: Henry Wellcome Centre for Gene Function, Anatomy and Genetics and OXION, University of Oxford

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5639

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