A Culprit Behind High Blood Sugar Identified

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Recently, resident blogger David Spero explored the role of an organ not often discussed relative to diabetes: the liver. In his popular blog entry, he described how, in many people with diabetes, the liver ignores the signals of insulin, releasing excessive glucose into the bloodstream and contributing to high blood glucose levels. Now, in research funded by the National Institutes of Health, scientists have discovered an important protein that regulates the liver’s management of insulin and glucose production, potentially opening the door for new diabetes treatments that target the liver.

Typically, the liver stores excess glucose in a storage form of carbohydrate known as glycogen. When blood glucose levels are low, such as during the night, the liver converts this glycogen into glucose and makes it available for the body to use. In people with diabetes, however, the liver continues to release glucose even when blood glucose levels are high and insulin has been administered, according to study author H. Henry Dong, PhD.

In order to understand the underlying mechanism behind this liver dysfunction, Dr. Dong and his fellow researchers from the Children’s Hospital of Pittsburgh of UPMC and the University of Pittsburgh School of Medicine looked at a type of protein known as Forkhead box 06, or FOX06. Mice engineered to make too much FOX06 developed signs of the metabolic syndrome, the precursor to Type 2 diabetes, including impaired glucose tolerance and high blood glucose and insulin levels during fasting. Mice with too little FOX06, on the other hand, had unusually low blood glucose levels while fasting.

In mice with normal levels of FOX06, Dr. Dong noted, an injection of glucose causes an initial rise in blood glucose levels, with a return to normal levels within two hours. In the mice that made excess FOX06, however, the ability to regulate blood glucose was lost, and levels did not return to normal within the two-hour window. Moreover, other experiments showed that mice with diabetes have abnormally high levels of FOX06 in their livers, and that blocking this protein results in a substantial — although not complete — reduction in the liver’s glucose production.

Further tests looking at the effects of FOX06 in human liver cells supported these findings.

According to Dr. Dong “The liver is very important for glucose metabolism in our bodies. 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… These findings strongly suggest that FOX06 has potential to be developed as a therapeutic target.”

To learn more about the study, read the article “Key Protein Causing Excess Liver Production of Glucose in Diabetes Identified” or see the study in the journal Diabetes (a free download of the full study is also available at this link.) And to join in the discussion on “leaky” liver and its role in diabetes, click here.

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