Lack of Protein Shown to Cause Diabetes-Like Effects in Mice

(Philadelphia, PA) - Researchers have mimicked the effects of insulin resistance of human type 2 diabetes by creating mice that lack a functional gene for the enzyme Akt2. According to Morris J. Birnbaum, MD, PhD, of the University of Pennsylvania School of Medicine and Howard Hughes Medical Institute, the experiment establishes Akt2, a signaling enzyme also found in humans, as essential for maintaining blood sugar levels. Birnbaum and his colleagues publish their findings in the June 1st issue of the journal Science.

Although most of the biochemical reactions have not yet been defined, researchers believe that insulin causes a series of events initiated by triggering proteins on the surfaces of muscle and liver cells.

"We have found that Akt2 serves as a crucial gateway for insulin in the pathway to lower blood sugar levels," said Birnbaum, associate director of the Penn Diabetes Center in the Penn Departments of Medicine and Cell and Molecular Biology. "When Akt2 does not work, it is like trying to open an office door with a broken lock - you won't end up getting much work done."

Type 2 diabetes is a complicated disorder that occurs when sufferers develop a resistance to otherwise perfectly normal insulin. The insulin secreting cells of the pancreas are unable to compensate by making more of the hormone. In healthy individuals, insulin triggers a series of events that allows certain cells to take in sugar, in the form of glucose, from blood. High glucose levels, in turn, can lead to cardiovascular disease, blindness, and kidney disorders.

With a disease such as type 2 diabetes, which affects numerous organs throughout the body, it is difficult to chart out exactly what went wrong - a case of too many possible pathways and no clear maps. The difficulty has been compounded by conflicting research on the roles of various proteins within the pathway. "Diabetes is a disease that affects multiple organs, so it helps to look at the disease in terms of an entire organism," said Birnbaum. "It also helps to have a model - in this case, mice."

Humans and mice share nearly identical copies of three closely related kinase enzymes that researchers thought were likely candidates. Birnbaum and his colleagues had previously found that one of the enzymes, Akt2, could create some of the same effects as insulin when overproduced, so the researchers bred mice that lacked the gene for the protein.

Without functional Akt2, the mice exhibited many of the symptoms of diabetes, most importantly elevated blood sugar. Their investigation revealed that Akt2-deficient mice were incapable of increasing their glucose uptake in response to insulin and unable to halt the production of even more glucose in their liver cells. The mice could still produce insulin, however. In fact, the mice produced even greater amounts of insulin as pancreatic cells reacted to the higher amounts of glucose in the blood. In addition, the presence of the other two related kinases did not compensate completely for the absence of Akt2.

The study provides definitive evidence of the importance of Akt2 in the function of insulin. The researchers believe such knowledge will help open up the rest of the biochemical pathway to science.
"These findings represent a crucial step in understanding the basic science of type 2 diabetes," said Birnbaum. "Part of the process in developing a treatment is charting exactly how the pathways would work in a healthy individual."

Han Cho, PhD, of the Penn Department of Biology was the lead author of the study and Jason K. Kim, PhD and Gerald I. Shulman, MD, of the Yale University School of Medicine were among the contributors to the finding presented in this paper. Funding for this research was provided by the Howard Hughes Medical Institute and the National Institutes of Health.

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