Community Research and Development Information Service - CORDIS


KATP-DIABETES Report Summary

Project ID: 322620
Funded under: FP7-IDEAS-ERC
Country: United Kingdom

Mid-Term Report Summary - KATP-DIABETES (ATP-sensitive potassium channels: from atomic structure to human disease)

Type 2 diabetes (T2DM) is reaching epidemic proportions in Western societies and is predicted to affect >300 million people worldwide by 2025. All types of diabetes are characterized by an elevated blood sugar level, which is deleterious to many cells and gives rise to kidney disease, eye disease, heart disease and loss of sensation in the peripheral limbs. A key element in development of diabetes is the inability of the beta-cells of the pancreas to secrete enough insulin when the blood sugar rises. Insulin is the only hormone that can lower blood glucose, which is why an insufficiency has such devastating effects. Thus understanding how insulin secretion is controlled is of fundamental importance.
Our studies focus on a protein called the KATP channel. This tiny gated pore sits in the membrane of the beta-cell and plays a key role in insulin secretion. At low blood glucose, the pore is open. Glucose (via its metabolism), or the sulphonylurea drugs used to treat T2DM, stimulate insulin release by closing the channel. Mutations in KATP channel genes may cause a rare inherited form of diabetes (neonatal diabetes or ND), which presents within the first six months of life. The mutant channels are no longer closed properly by glucose, impairing insulin release. However, sulphonylurea drugs are usually still effective. This has enabled most ND patients to switch from insulin injections to tablet therapy, with considerable improvement in their clinical condition and quality of life.

The aim of this project is to: (i) understand how glucose metabolites (such as the nucleotides ATP and MgADP), and sulphonylurea drugs, interact with the KATP channel to influence its opening and closing; (ii) determine how ND mutations affect secretion of the glucose-increasing hormone glucagon from pancreatic alpha cells; (iii) explore how sulphonylurea therapy affects glucose homeostasis in ND; and (vi) investigate how severe ND mutations cause neurological problems as well as diabetes, and determine the extent to which these can be alleviated by SU therapy.
We have developed a novel assay that allows us to determine nucleotide binding to the KATP channel with high temporal and spatial resolution. This has provided fresh insights into how nucleotides regulate channel function, and demonstrated an important interaction between nucleotides and sulphonylurea action. There is evidence that the KATP channel is part of a much larger complex of interacting proteins and we have made significant progress towards identifying these partner proteins.
We showed KATP channels play an important role in glucagon secretion, and explained why their closure in response to glucose metabolism paradoxically inhibits glucagon release (whilst stimulating insulin secretion). We also demonstrated how chronic hyperglycaemia (such as occurs in diabetes) impairs beta-cell structure and function.
We showed that successful transfer of ND patients to SU therapy depends on the functional effect of the mutation and the age at transfer. We developed a highly sensitive method of measuring sulphonylurea concentration. We used this, together with an ND mouse model, to show sulphonylureas are rapidly pumped out of the brain, which may explain why they are not very effective at treating the neurological symptoms. We also showed sulphonylureas are present in the breast milk of sulphonylurea-treated mothers and can affect glucose homeostasis in newborns. This has implications for sulphonylurea therapy during pregnancy.

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United Kingdom
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