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Diabetes

Ramping up kinase restores the balance

Nature Reviews Drug Discovery volume 2, page 688 (2003)Cite this article

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.

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ORIGINAL RESEARCH PAPER

  1. Grimsby, J. et al. Allosteric activators of glucokinase: potential role in diabetes therapy. Science 301, 370–373 (2003)

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Authors
  1. Suzanne Farley
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Insulin action: molecular basis of diabetes

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Farley, S. Ramping up kinase restores the balance. Nat Rev Drug Discov 2, 688 (2003). https://doi.org/10.1038/nrd1186

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