Ashcroft Group

01865 285810
frances.ashcroft@dpag.ox.ac.uk

ATP-sensitive potassium (K-ATP) channels, insulin secretion and diabetes

Ion channels, Diabetes and Obesity

Type-2 diabetes is a serious metabolic disease that is reaching epidemic proportions in Western societies and is predicted to affect 300 million people worldwide by 2025. In the UK, over 1.5 million people have type-2 diabetes and many more have impaired glucose tolerance. Diabetes is associated with serious chronic ill health and premature mortality. It is characterised by elevated blood glucose concentrations, usually presents in middle age, and is exacerbated by obesity.

It is generally agreed that the primary defect in diabetes lies in the beta cells of the pancreas, which do not secrete enough insulin to meet the needs of the body. Age and obesity (which lead to insulin resistance) exacerbate the disease by placing a greater demand on the beta cell that it is unable to match. Thus the primary aims of our research are to elucidate the molecular mechanisms by which glucose stimulates insulin secretion from pancreatic beta cells, and to identify the defects in this process that occur in type-2 and neonatal diabetes. This work is expected to facilitate the development of new therapies and preventative strategies.

Current Research Programme

There are two main threads to our current research.

The ATP-sensitive potassium (K-_ATP) channel, a plasma membrane protein that plays a key role in insulin secretion and is the target for the sulphonylurea drugs used to treat type-2 diabetes. We are interested in how the function of the K_-ATP channel relates to its atomic structure, how cell metabolism regulates channel activity, and how mutations/polymorphisms in K_-ATPchannel genes cause human diseases such as neonatal diabetes, type-2 diabetes and congenital hyperinsulinism.
The mechanism of insulin secretion, with an emphasis on the role of metabolism and metabolic regulation of K-_ATP channels. We study mouse models of diabetes and human type-2 diabetic beta cells, as well as normal beta cells. Recent studies with Prof. Cox revealed that nicotinamide nucleotide transhydrogenase (Nnt), a protein previously thought to be involved only in free radical detoxification, is important for insulin secretion: our current studies focus on the function of this protein.

Because diabetes is strongly linked to obesity, we are also increasingly interested in how feeding is regulated and what causes obesity.

In our studies, we employ protein biochemistry, molecular biology, cell culture, radioligand binding assays, flux assays, single-cell fluorescence imaging, electrophysiology (patch-clamping), and measurements of insulin secretion and metabolism. We also collaborate with scientists using electron microscopy, X-ray crystallography, and molecular modelling.

We hope that our research will provide novel insights into a number of scientific areas, such as how ion channels work; how insulin secretion is regulated; and the molecular basis of the insulin secretory defect in diabetes. It is expected that this will lead to novel therapeutic targets/strategies. Indeed, our recent work with Prof. Hattersley has provided the scientific basis that has enabled patients with diabetes due to mutations in K_ATPchannel genes to be treated with sulphonylureas not insulin injections. This has had clinical benefits and made their lives easier. We have also shown that some sulphonylureas are specific for beta cells and do not act on the heart; and the Medical Research Council is exploring Nnt as a new target for antidiabetic drugs. Better therapy for diabetes is expected to have economic benefits: the NHS currently spends 5% of its annual budget (~£11 million/day) on direct diabetes care.