Frances Ashcroft and colleagues have identified mutations in a potassium channel as the cause of neonatal diabetes. His discovery greatly improved treatment for patients.
General description of the conversation:
Diabetes is a devastating disease that has a huge cost both in human life and in health spending throughout the world. Dr. Frances Ashcroft begins her talk by explaining that blood glucose should be controlled within narrow limits. In a healthy person, insulin is released from pancreatic beta cells in response to an increase in blood sugar, which stimulates the uptake of glucose in muscle, liver and fat, and thus restores blood glucose to its rest level. Diabetes occurs when beta cells do not release enough insulin, resulting in chronic blood sugar levels. There are several types of diabetes: type 1 occurs because the beta cells are damaged by an autoimmune attack; Type 2, the most common form, is usually due to a combination of insulin resistance and decreased insulin secretion and is aggravated by obesity and age; Monogenic diabetes results from a mutation in a single gene. Neonatal diabetes is a rare monogenic form of diabetes that occurs at birth, or soon after. Ashcroft explains that in 1984, she and her colleagues discovered that the function of an ATP-sensitive potassium channel (KATP channel) in the plasma membrane of pancreatic beta cells is essential to link the increase in blood glucose levels with the insulin secretion. They postulated that a mutation that caused the KATP channel to open permanently would affect the release of insulin. Twenty years later, these mutations were identified and proved to be the cause of neonatal diabetes.
In his second lecture, Ashcroft expands what is known about the KATP channel and its role in insulin secretion. It is an octomeric complex composed of 4 subunits Kir6.2 and 4 subunits SUR1. ATP binds to both proteins and changes in the metabolism of the metabolically generated ATP pair to the activity of the KATP channel. Functional studies showed that mutations of the KATP channel found in neonatal diabetes affect the ability of ATP to close the channel and stimulate insulin release. This suggested that drugs that could shut down the KATP channel directly would stimulate insulin release and could be a good therapy for neonatal diabetes. It was known that sulfonylurea drugs directly closed the KATP channel and have been used safely to treat type 2 diabetes for many years. According to this knowledge, many patients with neonatal diabetes have now switched from insulin injections to sulphonylurea medications by mouth. This has resulted in better glucose control. Ashcroft continues to explain how perceptions of the study of neonatal diabetes have also led to a better understanding of the impact of chronic hyperglycemia in type 2 diabetes.
Biography of the speaker:
Professor Dame Frances Ashcroft is a research professor at the Royal Society of GlaxoSmithKline in the Department of Physiology, Anatomy and Genetics and a member of Trinity College at the University of Oxford.
Ashcroft earned his bachelor's and doctorate from the University of Cambridge and was a postdoctoral fellow at the University of Leicester and the University of California at Los Angeles. When he established his own laboratory in Oxford, Ashcroft began to study how an increase in blood sugar levels leads to the release of insulin from pancreatic beta cells, and what fails with this process in diabetes. Ashcroft's most recent research has focused on neonatal diabetes, a rare genetic form of the disease that usually develops shortly after birth. Together with her colleagues, she has shown that mutations in an ATP-sensitive potassium channel in the plasma membrane are responsible for this disease. The understanding of the mechanism of action of this potassium channel has allowed many patients to switch from insulin injections to oral pharmacological treatment. In addition, the information obtained from the study of neonatal diabetes has implications for the understanding and treatment of type 2 diabetes, a much more common disease.
Ashcroft was elected to the Royal Society in 1999 and in 2012 she was awarded the L'Oréal-UNESCO European Women's Award in Science. Learn more about Ashcroft's research here:
Video credits to iBiology YouTube channel