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Banting Medal awardee makes the case for glucokinase as a novel target in type 2 diabetes


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Frances Ashcroft, PhD
Frances M. Ashcroft, DBE, FRS, FMedSci

A growing body of in vitro, mouse, and human mutation data suggest that inhibiting the activity of glucokinase in beta cells may restore insulin secretion and reduce hyperglycemia in type 2 diabetes, according to Frances M. Ashcroft, DBE, FRS, FMedSci, recipient of the ADA’s 2022 Banting Medal for Scientific Achievement.

“In type 2 diabetes, glucose pours into beta cells, triggering the activity of glucose metabolites and reducing insulin secretion,” explained Dr. Ashcroft, Royal Society GlaxoSmithKline Research Professor at the University Laboratory of Physiology, University of Oxford, United Kingdom. “Chronic hyperglycemia results in a dramatic loss of insulin secretion but not a loss of beta cells. The question is whether we can reverse the progressive decline in beta-cell function. The answer appears to be a qualified yes.”

Dr. Ashcroft explored her decades-long journey into the mechanisms of insulin secretion on Sunday, June 5, during her Banting Medal lecture Metabolic Regulation of Insulin Secretion in Health and Disease. The session was livestreamed and can be viewed on-demand by registered meeting participants at If you haven’t registered for the 82nd Scientific Sessions, register today to access the valuable meeting content.

Dr. Ashcroft’s research journey began with an initial interest in electrical activity at the cellular level. Beta cells were attractive because glucose stimulates electrical activity. She found that glucose closes specific potassium channels in rat beta cells. Adenosine triphosphate (ATP) closes the same channel, dubbed the ATP-sensitive potassium (KATP) channel. When beta-cell metabolism is low, KATP channels open and no insulin is secreted But when beta-cell metabolism is high, KATP channels close, depolarizing the cell membrane to allow insulin secretion.

In theory, mechanisms that impair the KATP channel would dysregulate insulin secretion, resulting in diabetes. That’s what happens in some forms of neonatal diabetes, Dr. Ashcroft explained. Gain-of-function mutations to KATP channel genes cause about 50% of neonatal diabetes.

“The beta cell is essentially switched off (by mutation) and causes neonatal diabetes,” Dr. Ashcroft said. “It’s very rare—1 in 200,000 live births—and causes markedly high blood glucose within six months of birth.”

Neonatal diabetes was long thought to be a rare form of type 1 diabetes and treated with insulin. The realization that existing sulfonylurea drugs close KATP channels and stimulate insulin secretion transformed management. If started early, oral sulfonylurea can restore normal insulin secretion and normal blood glucose levels for about 90% of children with neonatal diabetes.

“As a basic scientist, one never expects one’s work to change peoples’ lives in one’s own lifetime,” Dr. Ashcroft said. “As a scientist, I have seen many wonderful things, but none so wonderful as the change in life for the children and families with neonatal diabetes.”

There could be more wonders to come. Nearly 200 distinct genetic mutations are known to be involved in neonatal diabetes. One of them, E23K, reduces ATP sensitivity and increases susceptibility for type 2 diabetes. In mouse models and in humans, gain-of-function mutations reduce insulin secretion, which impairs glucose tolerance and increases diabetes risk.

Chronic hyperglycemia impairs beta-cell function over time, Dr. Ashcroft continued. When type 2 diabetes is diagnosed, about half of beta-cell function remains.

“Beta cells do not die in type 2 diabetes, they lose their insulin content and change their metabolism,” Dr. Ashcroft explained. “Loss of insulin staining does not mean loss of beta cells.”

In type 2 diabetes, beta cells flooded with glucose accumulate glycogen, which downregulates mitochondrial metabolism to reduce oxygen consumption and ATP production. These metabolic changes inhibit insulin secretion, boosting blood glucose, which further disrupts insulin secretion as diabetes progresses. The culprit is not glucose, but accumulation of glucokinase, a glucose metabolite.

“Rather than enhancing glucokinase activity, we should be reducing it,” Dr. Ashcroft said. “This may prevent beta-cell decline and reduce complications caused by chronic hyperglycemia. We can see this in vitro, in mouse models, and in humans with loss-of-function mutations in glucokinase. These individuals have mild hyperglycemia that does not progress and there is no increase in the rate of diabetic complications. The aim of therapy would be to reduce glucokinase activity to the level found in normal beta cells.”