Key Regulator Of Blood Glucose Levels Discovered

This switch may be a potential new target for the development ofhighly specific diabetes drugs that signal the liver to reduce theproduction of sugar. The Salk researchers, led by Marc Montminy, aprofessor in the Clayton Foundation Laboratories for Peptide Biology,published their findings in the Sept. 7th online issue of Nature.

"It is very exciting to understand how glucose production inthe liver is regulated. Now, we can try to improve the way how type 2diabetics handle blood sugar," says Montminy.

The newly discovered switch, a protein named TORC2, turns onthe expression of genes necessary for glucose production in livercells.

When describing glucose's role in health and disease, Montminycompares the human body to a hybrid car that runs on a mix of fuelsdepending on its activity status: gas, or glucose, is used forhigh-energy activities, and battery power, or body fat, for low-energyactivities. During the day, when food refuels the "gas tank," the bodyburns mainly glucose, and during sleep, it burns primarily fat.

The body switches from glucose to fat burning mainly inresponse to two key hormones -- insulin and glucagon -- that areproduced by the pancreas. During feeding, the pancreas releasesinsulin, which promotes the burning of glucose. At night, however, thepancreas releases glucagon into the bloodstream, which signals the bodyto fire up the fat burner.

But even during sleep, our brain needs a constant supply ofglucose to function properly. For that reason, our body actuallymanufactures glucose during sleep or when we are fasting. That process,called gluconeogenesis, is carried out mainly in the liver.

Insulin normally shuts down the ability of the liver to produceglucose. In individuals with Type II diabetes, however, insulin isunable to inhibit sugar production in the liver, "either because thepancreas is not producing enough insulin or because insulin's signalcan't be 'heard,'" says Montminy. When the liver is unable to hear theinsulin signal, excess glucose builds up in the bloodstream.

In addition to so-called insulin sensitizing drugs that allowinsulin to work better, researchers are looking for alternative ways toshut down the production of glucose in the liver of diabetics."Figuring out how to control glucose production in the liver iscritical because many complications of diabetes, such as heart disease,kidney failure and blindness, can be reduced by maintaining a verytight control over blood sugar levels," he says.

As glucose levels run low during fasting, the pancreas sendsout the hormone glucagon and instructs the liver to produce glucose.This increase in glucagon turns on the TORC2 switch and allows theliver to make more glucose. Mice that were genetically modified to makemore or less TORC2 produced more or less glucose depending on theamount of available TORC2 (transducer of regulated CREB activity).

Most of the time, TORC2 sits in the cellular compartment thatsurrounds the nucleus, where all the genes are located. When a glucagonsignal arrives, the TORC2 switch crosses the nuclear membrane, teams upwith the transcriptional activator CREB and turns on all the genesnecessary for gluconeogenesis. "Being located in a different part ofthe cell is what keeps the TORC2 switch off," explains Montminy.

The researchers also discovered that a chemical modificationon TORC2 itself sequesters the protein in the cytoplasm, the viscoussubstance inside the cell that surrounds the nucleus. "Since we nowknow the molecular mechanism by which TORC2 is inactivated we can startlooking for small molecules that do the same thing," says Montminy.

The Salk Institute for Biological Studies in La Jolla, California,is an independent nonprofit organization dedicated to fundamentaldiscoveries in the life sciences, the improvement of human health andthe training of future generations of researchers. Jonas Salk, M.D.,whose polio vaccine all but eradicated the crippling diseasepoliomyelitis in 1955, opened the Institute in 1965 with a gift of landfrom the City of San Diego and the financial support of the March ofDimes.