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ATP-sensitive potassium channels: from atomic structure to human disease

Final 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 >500 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. Understanding how insulin secretion is controlled is thus of fundamental importance.

Our studies focus on a protein called the KATP channel. This tiny gated pore sits in the membrane of the pancreatic beta-cells 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 aims of this project were 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 if the KATP channel plays a role in 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 the extent to which these can be alleviated by sulphonylurea therapy. We made significant advances in all these areas.

We 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 made significant progress towards identifying these partner proteins. We discovered the channel is present at neuronal synapses, which may explain why its mutation can cause neurological problems.

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 elucidated how chronic hyperglycaemia (such as occurs in diabetes) impairs beta-cell structure and function. We also showed that chronic hyperglycaemia rapidly impairs cardiac function. These effects can be reversed if normal blood glucose levels are quickly restored.

We showed that successful transfer of ND patients to sulphonylurea therapy depends on the functional effect of the mutation and the age at transfer, being less frequent for diabetes of longer duration. 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.