A research team at the John G. Rangos Sr. Research Center at Children’s Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine has discovered a molecular pathway responsible for regulating management of insulin in the liver as well as the production of new glucose. The team published their findings in the American Diabetes Association’s journal “Diabetes.”
The liver typically stores excess blood glucose as glycogen and releases that energy during periods of fasting, such as sleeping, to ensure that blood sugar levels remain within the proper range. According to H. Henry Dong, Ph.D., head of the study and associate professor of Pediatrics at the Pitt School of Medicine, in individuals with diabetes the liver continues producing glucose even when the patient is supplemented with insulin treatments.
“Scientists have been trying to find the factors that contribute to this liver overproduction of glucose for decades,” says Dr. Dong. “If we can control that pathway, we should be able to help reduce the abnormally high blood sugar levels seen in patients with diabetes.”
Dr. Dong’s research team has been investigating the Forkhead box family of proteins, also known as FOX. This particular study was focused on the protein FOX06. When mice took too much FOX06, they developed symptoms of metabolic syndrome, a series of complications such as elevated blood glucose, increased insulin levels, and impaired glucose tolerance that typically precedes diabetes. Similarly, mice who produced lower levels of FOX06 displayed very low levels of blood glucose when fasting.
“In a normal animal, a glucose injection causes blood sugar level to rise initially and then it goes back to normal range within two hours,” said Dr. Dong. “In animals that made too much FOX06, blood sugar after a glucose injection doesn’t normalize within two hours. They have lost the ability to regulate the level while the liver keeps making unneeded glucose.” The protein appeared to affect the animals’ ability to respond to elevated blood glucose levels properly by using insulin to shuttle it away from the bloodstream.
The research team also conducted tests on human liver cells that confirmed the effects of FOX06 on glucose production.
“These findings strongly suggest that FOX06 has potential to be developed as a therapeutic target,” said Dr. Dong. “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.”
The study received funding from the National Institutes of Health. Co-authors on the study included lead author Dae Hyun Kim, Ph.D., as well as researchers from the Pedatrics and Pathology departments of the University of Pittsburgh.
The University of Pittsburgh is one of the leading academic centers for biomedical research in the U.S., consistently placing in the top 10 recipients for funding from the National Institutes of Health since 1997. The school system’s progress in research and development is primarily headed by the School of Medicine and its affiliates.
The Forkhead box (FOX) family of proteins is a series of transcription factors that play a role in the expression of certain genes related to cell growth, differentiation, longevity, and proliferation. Also known as the winged helix, the family is named after the forkhead box, a sequence of amino acids that form a motif which binds to genetic material (DNA).