A Culprit Behind High Blood Sugar Identified

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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  • Donna

    In reading these articles… interesting, but the protein that should be avoided for liver control is not named in either… So not sure if there is a protein that we can use… it is probably another medicine that is being developed…

    Also I take metaforim, 2000 per day (4 tablets), 5 glimpride, and a new pill onglaza, which is suppose to enhance the metaforim… I also have tried taking the metaforim at different times of the day, especially at night, instead of taking 2 at a time.. I take one at 4 different times, and seem to have better glucose control, which would substantiate the “leaky liver” theory…

  • Angela Norton

    Whilst this discovery is very interesting, and may be benificial to the development of new, and more effective medications for diabetes, I am more interested in the why’s.
    Why does the liver produce too much FOX06?
    If we could figure that out, perhaps we could find a cure, or a sure prevention, for diabetes.
    Why 100 years ago, was there less overproduction of this protein?

  • BK CDE

    There may have been overproduction of this protein 100 years ago also. The body tries to keep up by releasing more insulin to move the sugar into the cells so we can use it for energy or store it as fat, but in diabetes, eventually our insulin production just can’t keep up. Other factors also affect this. 100 years ago, people did not live as long, they ate differently, they did more physical labor… all factors that decreased risk for type 2 diabetes. And who knows if there are also environmental exposures that have changed how all this works in our bodies too?

  • David Taylor

    I have been Type1 for 63 years and now have a pump.

    I have been teling my diabetes team about this “phenomenon” for over 5 years now and they simply tell me to counter the “sugar” with more and more insulin. I actually counter it by reducing my insulin requirement by 10% for a few days and the glycogen effect gradually dissapears. How long depends on how long the Glycogen has been being produced. Now that I have found the solution to the problem my “highs” last about 12 hours only.

    Its taken me a long time to find out this remedy and my team simply look at me and my charts with disbelief. The breakthrough came by injecting 3units insulin and retesting after 1 hour to find the sugar level had increased; perversely I ate 40 grams carbohydrate and found the sugar level went down. My team said I simply pee’d it away!!