When glucose levels are low, an inhibited form of GK associates with insulin-containing granules in pancreatic β cells. Rizzo and Piston have determined that this localization is mediated through interaction with neuronal nitric oxide synthase (nNOS). Insulin treatment disrupted this association through nitrosylation of a GK cysteine residue. Activation of nNOS and the resulting nitrosylation of GK may be mediated through a rise in intracellular calcium, a known response of β cells to insulin treatment. Release of the enzyme into the cytoplasm and the accompanying conformational change—both of which required NO production— activated GK.
GK induces secretion of the granules, thus promoting local increases in insulin levels. A recently developed drug for the treatment of type II diabetes is a GK activator. The new results suggest that the drug may activate GK by preventing granule binding. Piston plans to test this possibility in the near future. ▪