A study has identified a key player in the body's ability to respond to insulin action in the brain by ratcheting down the export of blood sugar from the liver.
The findings point to a potential new drug target for the treatment of type 2 diabetes.

The researchers found evidence in mice that the gene STAT3 in liver mediates the effects of brain insulin. The STAT3 response depends upon interleukin-6, a chemical involved in the body's reaction to stresses.

Earlier evidence by the researchers showed that the gene STAT3 controls glucose balance by limiting the activity of genes that manufacture glucose in the liver. However, the mechanism by which nutritional and hormonal status controls hepatic STAT3 had remained unknown, said study author Masato Kasuga of Kobe University Graduate School of Medicine in Japan.

Insulin secreted by the pancreas after a meal normally allows body tissues, such as muscle and fat, to take up the blood sugar glucose. " In liver, which is responsible for minute-by-minute regulation of blood glucose levels and can export glucose as well as store it, insulin not only promotes the storage of glucose but also inhibits the production of sugar for export," explained Martin Myers, in a preview. The brain participates in the regulation of glucose production and insulin response by sensing and responding to nutrient levels and hormonal signals of energy intake and storage.

In those with diabetes due to a lack of normal insulin or insulin resistance, blood sugar rises, a condition that can lead to tissue damage. An increase in glucose issued from the liver is largely responsible, Kasuga said.

Now, the researchers have found in mice that an increase in blood insulin levels, achieved by administering glucose or insulin, leads to the activation of STAT3 in liver. The response depends upon the hormone's effects in the brain and an increase in interleukin-6. Animals lacking STAT3 only in the liver and those deficient for interleukin-6 lost the ability to respond normally to brain insulin by lowering the production of glucose.

The current findings provide a "first glimpse" into the mechanisms that operate within the liver to decrease glucose output in response to insulin action in the brain, Myers said.

" Given that disregulation of glucose production in the liver is an important pathophysiological feature of type 2 diabetes, the mechanism uncovered in this study may serve as a therapeutic target for this increasingly prevalent condition," the research team wrote.

Source: Cell Metabolism, 2006
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