Constant High Blood Sugar Disables Insulin 'Off' Switch

THURSDAY, March 6 (HealthDay News) — Chronically high blood glucose levels disable the molecular switch that normally turns off sugar production in the liver in response to increasing insulin levels, a California study finds.

This finding suggests that inhibiting the enzymatic pathway that disables the "sugar-off" switch (CRTC2) may help lower glucose levels in people with diabetes and reduce long-term complications associated with the disease, the researchers said.

The study, by researchers at the Salk Institute for Biological Studies, in La Jolla, Calif., is published in the March 7 issue of Science.

In healthy people, the CRTC2 switch turns on glucose production in the liver when blood glucose levels decline during the night. After a meal, insulin shuts down CRTC2, thus ensuring that blood sugar levels don't rise too high.

But in many people with type 2 diabetes, CRTC2 no longer responds to increasing insulin levels. As a result, the liver keeps on pumping out glucose, even if blood glucose levels are already elevated.

In research with mice, the Salk team focused on the hexosamine biosynthetic pathway. Activation of this pathway promotes the addition of sugar molecules to proteins, a process called O-glycosylation.

"It had been known that increases in the concentration of circulating glucose activate the hexosamine biosynthetic pathway. But we had no idea that the resulting O-glycosylation would lock CRTC2 in the 'on' position," study first author Renaud Dentin said in a prepared statement.

Dentin's team decreased the activity of the hexosamine biosynthetic pathway in insulin-resistant diabetic mice and in mice fed a high-fat diet (both groups had high blood sugar levels) and found a marked improvement in glucose tolerance and insulin sensitivity.

—Robert Preidt

SOURCE: Salk Institute for Biological Studies, news release, March 6, 2008

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