Science paper showed that the hexosamine biosynthetic pathway prevents phophorylation of CRTC2, which in turn promotes gluconeogenis.

Researchers discover the pathway through which high blood sugar levels disable a protien that normally shuts off sugar production in the liver in response to rising levels of insulin.

Normally, the rise in insulin after a meal activates SIK2. This liver enzyme chemically tags CRTC2, which is inactivated in type 2 diabetics, with a phosphate group, marooning the protein outside the cell’s nucleus. This renders CRTC2 unable to reach the genes involved in gluconeogenesis, and glucose production in the liver ceases.

The scientists focused on the role of hexosamine biosynthetic pathway in insulin resistance. They found that in the presence of excessive glucose levels, the hexosamine biosynthetic pathway is activated and blocks crucial phosporylation sites on CRTC2 through O-glycosylation. CRTC2 can no longer be phosphorylated in response to rising insulin levels and becomes free to slip into the nucleus and keep the gluconeogenic program going.

The team was also able to demonstrate that glucose tolerance and insulin sensitivity markedly improved in insulin-resistant diabetic mice and mice fed a high fat diet when they decreased the activity of the hexosamine biosynthetic pathway in the liver of these animals.

The research was conducted by investigators from the Salk Institute for Biological Studies, Cell Signaling Technology, and The Scripps Research Institute. The study is published in the March 7 issue of Science.

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