In 1998, Glaser et al. (1) described a mutation in the glucokinase gene (GCK) that caused autosomal-dominant hyperinsulinism. At the time, syndromic hyperinsulinemic hypoglycemia in adults was known only to be caused by mutations affecting KATP channel function but not glucokinase. Instead, GCK mutations were known to cause maturity-onset diabetes of the young (MODY) and persistent neonatal diabetes, suggesting that all GCK mutations were detrimental to enzyme function (2). The discovery of GCK mutations that activated the enzyme was not just surprising, it stimulated decades of research with the goal of developing pharmaceutical activators of glucokinase, now referred to as GKAs.
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