Melissa F. Brereton 1 , Michaela Iberl 1 , 4 , Kenju Shimomura 1 , 4 , Quan Zhang 2 , 4 , Alice E. Adriaenssens 3 , 4 , Peter Proks 1 , Ioannis I. Spiliotis 1 , William Dace 1 , Katia K. Mattis 1 , Reshma Ramracheya 2 , Fiona M. Gribble 3 , Frank Reimann 3 , Anne Clark 2 , Patrik Rorsman 2 , Frances M. Ashcroft a , 1
22 August 2014
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 K ATP 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 K ATP 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.
In patients with diabetes, insulin release from pancreatic β-cells is reduced due to altered islet structure and function. Here, Brereton et al. show that elevated blood glucose underlies these changes and is sufficient to reversibly alter β-cell identity in a mouse model of β-cell dysfunction.