‘Counterintuitive’ glucokinase inhibition may help prevent, reverse type 2 diabetes
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NEW ORLEANS — A novel “counterintuitive” intervention that reduces glucokinase activity and limits the buildup of metabolites may enhance insulin secretion and ultimately prevent or even reverse type 2 diabetes, according to a speaker.
Genome-wide association studies indicate many genes enhance diabetes risk, yet it has been difficult to understand why type 2 diabetes develops later in life, Frances Ashcroft, PhD, ScD, professor of physiology at the University of Oxford and fellow of Trinity College Oxford, said during the Banting Lecture at the American Diabetes Association Scientific Sessions. Chronic hyperglycemia drives a progressive decline in beta cell function. Several factors, such as genetic predisposition, combined with stressors such as insulin resistance, age or pregnancy, may cause a small increase in blood glucose, causing only mild glucose intolerance that may persist for many years.
“The problem is that, with time, the chronic hyperglycemia causes accumulating changes in gene and protein expression that eventually impair beta cell metabolism and reduce insulin secretion,” Ashcroft said. “This will exacerbate hyperglycemia, raising blood glucose even higher, initiating a vicious spiral that accelerates exponentially and underlies the progression to frank diabetes and the continuing decline in beta cell function.”
Ashcroft said a key question in research is whether the deleterious effects of chronic hyperglycemia can be prevented or even reversed.
“The answer appears to be a qualified yes,” Ashcroft said. “We know that most neonatal diabetes patients can switch to drug therapy and that the drug dose required sometimes decreases with time, as if their beta cells may be recovering. We also know that type 2 diabetes can be reversed, for example, with intensive insulin therapy, very low-calorie diets and after bariatric surgery.”
‘We have been looking at things the wrong way’
Interventions that can prevent or reverse diabetes are characterized by reduced plasma glucose levels, Ashcroft said, yet they are far from perfect solutions. Compliance with very low-calorie diets is challenging; bariatric surgery and intensive insulin therapy are not available to all who could benefit.
Instead, Ashcroft proposed what she called a “provocative and, at first, counterintuitive way” to help protect and restore beta cell function in diabetes: reducing glucokinase activity.
In diabetes, a rise in glucose leads to a buildup of glycolytic metabolites that trigger a chain of events that ultimately change gene and protein expression and activity, impairing beta cell metabolism, Ashcroft said. By limiting the buildup of these metabolites, the gradual decline in beta cell function seen in diabetes could be prevented, she said.
This can be done by reducing glucokinase activity in diabetes to levels found in non-diabetic beta cells to prevent the buildup of downstream signaling metabolites.
“Glucokinase is the best target, as it is confined to beta cells, the liver and a few neurons and endocrine cells,” Ashcroft said.
In experiments, mannoheptulose, a naturally occurring sugar found in avocado, prevented the effects of chronic hyperglycemia. In cells cultured at high glucose, insulin secretion was “strikingly enhanced” when mannoheptulose was present, both during culture and secretion assays, Ashcroft said.
“These data show partial glucokinase inhibition may be beneficial in diabetes, but they also explain why glucokinase activators were unsuccessful as a diabetes therapy,” Ashcroft said. “They simply exacerbated the metabolic effects of high glucose. Perhaps we have been looking at things the wrong way.”
Rather than increasing glucokinase activity, reducing it may help prevent beta cell decline in diabetes and reduce secondary complications caused by chronic hyperglycemia, Ashcroft said. In mouse models, glucokinase inhibition restored and preserved beta cell function in diabetes. Additionally, human patients with loss-of-function mutations in glucokinase also provide real-world, proof-of-concept evidence that a reduction in glucokinase activity is not harmful, she said.
“These individuals show mild, fasting hyperglycemia that often goes undiagnosed,” Ashcroft said. “No treatment is needed; the hyperglycemia does not progress and there is no increase in rate of diabetic complications. The counterregulatory response to hypoglycemia is also improved. This suggests that even as much as 50% loss of glucokinase activity is not harmful, and crucially, despite mild hyperglycemia, it appears to prevent progressive deterioration of beta cell function.”
Lessons learned
Ashcroft said she hoped researchers can take lessons from discoveries in neonatal diabetes where another therapy that seemed counterintuitive — sulfonylurea therapy — has been nothing short of transformative. Today, more than 90% of patients with neonatal diabetes caused by calcium channel mutations have transferred from insulin to sulfonylurea therapy, some even after many years of diabetes, proving that beta cells remain viable. Both their clinical condition and quality of life have improved, Ashcroft said.
“As a basic scientist, wanting to understand how things work is what drives your research, and you never expect that your work will impact people’s lives in your own lifetime, despite what you write in your grant applications,” Ashcroft said. “It has been an immense privilege that this has happened to me. Although it is a huge honor to be awarded the Banting medal, the true reward is seeing the patients’ lives improve.”
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Ashcroft F. MSB-01. Presented at: American Diabetes Association Scientific Sessions; June 3-7, 2022; New Orleans (hybrid meeting).
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