During her Discovery Lecture on March 21, Professor Dame Frances Ashcroft, recipient of the 2023 Vanderbilt Prize in Biomedical Science, quoted from an exchange that heralded the discovery of Tutankhamen’s tomb in 1922.
Peering into the darkness, Lord Carnarvon asks, “Can you see anything?” To which British archaeologist Howard Carter responds, “Yes, wonderful things.”
“I have been fortunate,” Ashcroft said. “I have seen many wonderful things. Science has brought me much joy. Perhaps the most wonderful of all is to see improvements in the lives of patients.”
Ashcroft, professor of Physiology at the University of Oxford and a fellow of Trinity College Oxford, is known internationally for her work on insulin secretion, Type 2 diabetes and neonatal diabetes.
Her discoveries involving ion channels essential for insulin secretion have advanced the understanding of Type 2 diabetes and have enabled people with neonatal diabetes, a rare form of the disease that occurs within the first six months of life, to switch from insulin injections to oral drug therapy.
“As a basic scientist, it’s one thing to understand how things work,” Ashcroft said. “You never expect your results will have an impact on people’s lives in your own lifetime ― if at all.
“It’s been an immense privilege that this has happened to me,” she said. “It’s been a particular special joy to be able to meet some of these patients.”
Established in 2006, the Vanderbilt Prize in Biomedical Science recognizes internationally renowned scientists with a stellar record of research accomplishments who also are known for mentoring others in science.
Prize winners receive an honorarium, present a Discovery Lecture, and mentor a Vanderbilt Prize Scholar, a graduate student in the biomedical sciences in the School of Medicine.
Prior to the lecture, Yasminye Pettway, the 2023 Vanderbilt Prize Student Scholar who has been mentored by Ashcroft, discussed her research on the role that the transcription factor NKX2.2 plays in insulin secretion by the beta cells of the pancreas.
Ashcroft began her talk with a description of research that, in 1984, established how glucose stimulates insulin secretion. It closes a pore protein in the beta cell called the ATP-sensitive potassium (KATP) channel through which electrically charged potassium ions flow.
Later, in collaboration with Professor Andrew Hattersley at the University of Exeter, Ashcroft and their colleagues showed that mutations in KATP channel genes prevent the channel from closing, thereby blocking insulin secretion. These mutations account for about half of the cases of neonatal diabetes.
The researchers also found that most of the mutant channels responded to sulfonylurea drugs, which are used to treat Type 2 diabetes, and which stimulate insulin release by directly binding to, and closing, KATP channels.
This discovery led to a sea change in the clinical care of patients with neonatal diabetes. Switching from insulin injections to oral medication improved the control of blood glucose levels and significantly improved patients’ quality of life.
Ashcroft’s research now focuses on Type 2 diabetes, the most common form of the disease, which tends to develop later in life and is exacerbated by obesity. In Type 2 diabetes, the pancreas fails to secrete enough insulin for the body’s needs.
Because glucose must be metabolized ― broken down ― in the beta cell to stimulate insulin release, it was thought that drugs which stimulate glucokinase, the first enzyme in glucose metabolism, would enhance insulin secretion in diabetes. Those drugs, however, have not been effective.
Ashcroft presented evidence that the rise in blood levels of glucose alters beta cell metabolism, and that the hyperactivation of glucose metabolism, rather than glucose itself, underlies the progressive decline in beta cell function in diabetes.
Impaired beta cell metabolism and insulin secretion exacerbate hyperglycemia, and “you’ve got this vicious cycle that culminates in diabetes,” she said.
Evidence from Ashcroft’s lab suggests that the cycle can be broken by partially inhibiting glucokinase with a simple sugar, mannoheptulose. Data from human pancreatic islet studies indicates that mannoheptulose, by slowing glucose metabolism in the beta cell, can preserve insulin secretion under conditions of chronic hyperglycemia.
Partial inhibition of glucokinase, therefore, may represent a novel diabetes therapy, Ashcroft said.
A recording of Ashcroft lecture, which was sponsored by the Offices of the Chief Scientific and Strategy Officer and the Dean of Basic Sciences, will be posted to the Discovery Lecture website.
This site also has a complete schedule of upcoming Discovery Lectures and archived videos of other previous lectures.
