Mutations of the gene that encodes glucokinase have been previously linked to an autosomal dominant form of diabetes mellitus, maturity-onset diabetes of the young type 2 (MODY2). In MODY2 patients, loss-of-function mutations decrease the rate at which glucokinase phosphorylates glucose in pancreatic β-cells and hepatocytes. On the basis of these data, Grimsby et al. proposed that upregulating glucokinase activity might clinically benefit sufferers of type 2 diabetes. As such, they set out to find activators of this key homeostatic enzyme.

A screen of 120,000 structurally diverse synthetic compounds identified one small molecule that enhanced the activity of glucokinase. Chemical optimization produced a racemic mixture, the R enantiomer of which — RO-28-1675 — potently activated recombinant human glucokinase in a dose-dependent manner. This enhanced activity was a function of an increase in the maximal velocity of the enzyme, in combination with an increased affinity for its glucose substrate. These effects of RO-28-1675 were specific for glucokinase — the activity of hexokinase isozymes of brain and muscle was not enhanced in its presence.

In isolated rat pancreatic islets, the threshold concentration of glucose required to induce the release of insulin progressively decreased in the presence of increasing concentrations of RO-28-1675. In vivo, a single oral dose of RO-28-1675 reduced blood glucose levels in wild-type mice, and in both rat and mouse models of type 2 diabetes. This glucose-lowering effect was accompanied by increasing plasma insulin levels.

The authors showed that in addition to modulating pancreatic function, RO-28-1675 increases the rate at which glucose is utilized in the liver. This dual mechanism of action targeting two of the hallmarks of diabetes — impaired insulin secretion and enhanced hepatic glucose production — is a highly favourable feature of potential therapeutics. If, as the authors suggest, the results of these animal studies with RO-28-1675 can be reproduced in human trials, safe and effective new treatments for diabetes based on activation of glucokinase might make it to the end of the drug development pipeline.