Neonatal diabetes: a KATP channelopathy
Professor Frances Ashcroft
Head of Department Seminar Series
Friday, 07 November 2014, 1pm to 1.30pm
Sherrington Large Lecture Theatre, Sherrington Building, off South Parks Road OX1 3PT
If you have a question about this talk, please contact Sarah Noujaim.
ATP -sensitive potassium (KATP) channels conduct potassium ions across cell membranes and thereby couple cellular energy metabolism to membrane electrical activity. They play important functional roles in a variety of tissues, from insulin secretion from pancreatic beta-cells to electrical activity of brain neurones. As a result, mutations in KATP channel genes result in a range of diseases including neonatal diabetes (ND), hyperinsulinism, epilepsy and cardiomyopathy. The KATP channel is also the target for the antidiabetic sulphonylurea drugs, which stimulate insulin secretion by closing the channel. Indeed, many patients born with neonatal diabetes can be successfully switched from insulin therapy to sulphonylurea drugs, with considerable improvement in both their clinical condition and quality of life.
We generated an inducible mouse model selectively expressing an ND gain-of-function mutation (Kir6.2-V59M) in pancreatic β-cells (βV59M mice). Gene induction at 12 weeks of age led to rapid diabetes, due to impaired insulin secretion. Chronic KATP channel activation was associated with reduced insulin and increased glucagon content in βV59M islets, and marked alterations in pancreatic islet morphology and ultrastructure. Importantly, this did not reflect alterations in or - or β-cell turnover as lineage tracing revealed that β-cells start to express glucagon. Hyperglycaemia, rather than KATP channel activation, underlies the morphological and gene expression changes because they can be prevented by sulphonylurea treatment; insulin therapy was also effective. Strikingly, changes associated with 4 weeks of diabetes can be reversed by sulphonylureas, which may explain some of the clinical features of ND patients managed on sulphonylureas. The KATP channel is also involved in glucagon secretion from -cells and its overactivity in diabetes may underlie the hyperglucagonaemia associated with diabetes. Finally, this lecture will briefly discuss the neurological deficits associated with severe gain-of-function KATP channel mutations and the extent to which these can be ameliorated by sulphonylurea therapy.