Lack of Protein Shown to Cause Diabetes-Like Effects
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
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
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
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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