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Unexpected function for a key regulator of blood glucose levels


An unexpected twist to a discovery reported just two months ago may significantly improve our understanding about the molecular origins of diabetes.

Scientists at the Salk Institute for Biological Studies then reported their discovery of a key cellular switch that instructs the liver to produce more glucose when blood sugar levels run low. Their paper was published in Nature.

Now, in the November issue of Cell Metabolism, they report that the very same switch limits its own activity to prevent the amount of produced glucose from overshooting healthy levels.

"This crucial fine-tuning is missing in diabetic individuals," explains Marc Montminy, a professor in the institute’s Clayton Foundation Laboratories for Peptide Biology. "When you measure glucose levels in diabetic patients in the morning or after they have been fasting, their glucose levels are very high because the body is unable to control the production of glucose," he adds.

Two hormones with opposite effects - insulin and glucagon - act together to maintain a steady level of glucose circulating in our bloodstream, to provide a constant and readily available energy supply for the cells in our body.

Right after a meal, when nutrient levels in the blood are high, the pancreas releases insulin, which tells muscle and liver cells to squirrel away glucose for later use. In addition, insulin stimulates the production of fat and shuts down the ability of the liver to produce glucose.

At night or between meals, however, when glucose supplies run low, the pancreas releases glucagon into the bloodstream, to signal the body to fire up the fat burner. But even during sleep, our brain relies solely on glucose for fuel. To keep the brain well supplied with energy, the liver actually manufactures glucose during sleep or when we are fasting.

In response to low blood sugar levels, the glucagon signal flips a switch that triggers glucose production in liver cells. This switch is a protein called TORC2 that, when activated by glucagon, turns on the expression of genes necessary to make glucose from scratch.

At the same time TORC2 sets the stage to be shut off quickly when glucose levels start rising. "We were quite surprised to find that activated TORC2 makes the liver more sensitive to insulin, allowing it to respond more effectively to rising glucose levels," says Salk research fellow and co-author Seung-Hoi Koo, who also is affiliated with the Sungkyunkwan University School of Medicine in Korea

TORC2 does so by increasing the amount of a protein called IRS2 (insulin receptor substrate 2) mainly in liver and pancreas cells. IRS2 acts as a molecular bridge between the insulin receptor and downstream targets in the insulin signaling pathway. With more IRS2 available, liver cells can react to minute amounts of insulin and stop churning out glucose.

Mice that lack IRS2 are severely diabetic since the insulin signal can’t "get through". However, when the Salk scientists treated them with gene therapy that delivered the missing gene for IRS2, healthy glucose levels were restored within a week.

"Understanding the regulation of insulin sensitivity represents a major challenge in the field of diabetes," says co-author Gianluca Canettieri, formerly a research fellow at Salk, now at the University of Rome, "La Sapienzia", Italy. "I think this finding could have significant implications in human therapy," he adds.

Other co-authors of the paper are Rebecca Berdeaux, Jose Heredia, Susan Hedrick and Xinmin Zhang, all at the Salk Institute for Biological Studies.

Cathy Yarbrough | EurekAlert!
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