Key regulator of blood glucose levels discovered

September 9, 2005

Key regulator of blood glucose levels discovered

September 9, 2005

La Jolla, CA – In many patients with type 2 diabetes, the liver acts like a sugar factory on overtime, churning out glucose throughout the day, even when blood sugar levels are high. Scientists at the Salk Institute for Biological Studies discovered a key cellular switch that controls glucose production in liver cells.

This switch may be a potential new target for the development of highly specific diabetes drugs that signal the liver to reduce the production of sugar. The Salk researchers, led by 马克·蒙特米尼, a professor 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 in the liver is regulated. Now, we can try to improve the way how type 2 diabetics handle blood sugar,” says Montminy.

The newly discovered switch, a protein named TORC2, turns on the expression of genes necessary for glucose production in liver cells.

When describing glucose’s role in health and disease, Montminy compares the human body to a hybrid car that runs on a mix of fuels depending on its activity status: gas, or glucose, is used for high-energy activities, and battery power, or body fat, for low-energy activities. During the day, when food refuels the “gas tank,” the body burns mainly glucose, and during sleep, it burns primarily fat.

The body switches from glucose to fat burning mainly in response to two key hormones – insulin and glucagon – that are produced by the pancreas. During feeding, the pancreas releases insulin, which promotes the burning of glucose. At night, however, the pancreas releases glucagon into the bloodstream, which signals the body to fire up the fat burner.

But even during sleep, our brain needs a constant supply of glucose to function properly. For that reason, our body actually manufactures 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 produce glucose. In individuals with Type II diabetes, however, insulin is unable to inhibit sugar production in the liver, “either because the pancreas is not producing enough insulin or because insulin’s signal can’t be ‘heard,'” says Montminy. When the liver is unable to hear the insulin signal, excess glucose builds up in the bloodstream.

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

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

Most of the time, TORC2 sits in the cellular compartment that surrounds the nucleus, where all the genes are located. When a glucagon signal arrives, the TORC2 switch crosses the nuclear membrane, teams up with the transcriptional activator CREB and turns on all the genes necessary for gluconeogenesis. “Being located in a different part of the cell is what keeps the TORC2 switch off,” explains Montminy.

The researchers also discovered that a chemical modification on TORC2 itself sequesters the protein in the cytoplasm, the viscous substance inside the cell that surrounds the nucleus. “Since we now know the molecular mechanism by which TORC2 is inactivated we can start looking for small molecules that do the same thing,” says Montminy.

加利福尼亚州拉霍亚的索尔克生物学研究所（Salk Institute for Biological Studies）是一个独立的非营利组织，致力于在生命科学领域做出基础性发现，改善人类健康，并培养未来的研究人员。其脊髓灰质炎疫苗几乎根除了1955年令人衰弱的脊髓灰质炎疾病的乔纳斯·索尔克医学博士于1965年创立了该研究所，得到了圣地亚哥市赠送的土地以及“March of Dimes”组织的财政支持。.