Controlling liver protein could help diabetics manage sugar

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When contending with diabetes, most people focus concern on the pancreas, where insulin is produced, often in inadequate quantities.

But with Type 1 and Type 2 diabetes, a key culprit could be the liver.

So says H. Henry Dong, who holds a doctoral degree and serves as associate professor of pediatrics at the University of Pittsburgh School of Medicine.

His research team has discovered an important protein and "molecular pathway" involved in management of insulin and glucose production in the liver.

The protein -- known as FOX06, part of the Forkhead box family of proteins -- serves a role in priming the liver for glucose production during times of starvation or fasting. Those times include overnight, when the body has little food to process and must rely on glucose produced in the liver for sustenance.

But the protein also can raise blood-sugar levels in people with either type of diabetes. So improving blood-glucose levels, Mr. Dong said, could be accomplished by controlling the protein.

"The liver is very important for glucose metabolism in our bodies," he said. "Glucose overproduction in the liver is a major contributing factor for high blood sugar in diabetes, Type 1 and 2. If you inhibit glucose production in the liver, you can improve glucose control."

The research, published in the American Diabetes Association's journal, Diabetes, was funded with a National Institutes of Health grant. Mr. Dong's research team is based at Pitt Medicine and at John G. Rangos Sr. Research Center at Children's Hospital of Pittsburgh of UPMC.

Normally, the liver stores excess blood sugar as glycogen, which the pancreas doles out overnight to the liver during sleep and other periods of fasting to keep glucose levels within a normal physiological range, Mr. Dong said.

But in diabetes, the liver continues to pump out glucose even when insulin is provided as a treatment for diabetes, thus elevating blood-sugar levels.

In studying the FOX family of proteins, his team eventually focused on FOX06 and found that mice engineered to make too much of the protein developed signs of metabolic syndrome, or pre-diabetes, in which blood-glucose levels are elevated in people prone to developing Type 2 diabetes.

Mice that produced too little of the protein had low blood sugar levels during fasting.

Blocking the FOX06 protein markedly reduced liver production of glucose, although blood sugar did not completely normalize. But within two weeks of treatment, there was significant improvement in blood sugar and glucose metabolism in diabetic mice, explains a news release on the research.

Tests with human liver cells echoed FOX06's role in glucose production. Controlling the protein could help with control in both forms of diabetes, Mr. Dong said.

The lead author in the study was Dae Hyun Kim, along with other researchers from Pitt's departments of pediatrics and pathology. Future research, Mr. Dong said, will focus on developing a drug to control FOX06 production.

"These findings strongly suggest that FOX06 has potential to be developed as a therapeutic target," he said. "If we can inhibit its activity, we can possibly slow the liver's production of glucose in patients with diabetes and better control blood sugar levels."


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