June 01, 2001
Loss of Enzyme Produces Diabetes-Like Symptoms
Researchers have
identified a protein that appears to play an important role in signaling muscle
cells to take up glucose from the bloodstream.
In genetic studies in mice,
researchers knocked out the gene that produces the enzyme Akt2 and noted that
the mice developed insulin resistance and symptoms that resembled type 2
diabetes. Insulin resistance is caused by environmental factors and genetic
mutations that result in cells becoming resistant to insulin. Normally, cells
respond to insulin by taking up glucose from the bloodstream. Type 2 diabetes
mellitus ensues when the insulin-producing cells of the pancreas fail to
compensate for abnormalities in insulin action. Diabetes causes high blood
sugar levels, which can lead to cardiovascular disease, blindness and kidney
malfunction.
“No one believes that diabetes is caused by a defect in a single gene, but, nonetheless, it is striking that the phenotype we observed in these animals is so much like the multi-system effects of human diabetes.”
Morris J. Birnbaum
In an article published in
the June 1, 2001, issue of the journal
Science
, researchers led by Howard Hughes
Medical Institute investigator
Morris J.
Birnbaum
at the University of Pennsylvania School of Medicine reported that
they have pinned down a function for the somewhat enigmatic protein, Akt2.
"Dozens of papers have
been published arguing both for and against Akt2 as having a role in
insulin-stimulated signaling of glucose transport," he said. "Most
people agree that insulin's action on the insulin receptor activates the enzyme
PI 3-kinase which initiates a signaling cascade that somehow leads to the
movement of glucose transporters to the cell membrane.
"But PI 3-kinase was
the most downstream member of the signaling pathway for which there was a
consensus," he said. "The Holy Grail in this field is to link the
signal transduction cascade to the movement of glucose transporters."
Akt2 was not necessarily a
favorite candidate for being that downstream enzyme, said Birnbaum. In fact,
some researchers had begun to discount Akt2, arguing that other similar protein
kinases might play a more important role in insulin signaling. But in earlier
experiments, Birnbaum and his colleagues had shown that overactivation of Akt2
mimicked insulin action in mice.
"While the data in
those experiments were very clear, it was an artificial system that only showed
that Akt could be sufficient under certain conditions. But the experiments did
not address whether Akt2 was necessary for insulin-stimulated glucose
transport," he said. Other scientists had reduced Akt2 activity in tissue
culture cells, but their experiments proved inconclusive because they had not
managed to eliminate Akt activity completely in their experimental systems.
Birnbaum's colleague and
lead author on the
Science
paper, Han Cho, with the help of
HHMI investigator
Marisa S.
Bartolomei
, successfully created a strain of mice in which all Akt2
activity was eliminated. With Akt2 function abolished, the scientists found
that the mice grew normally, but had mildly elevated blood sugar a telling
symptom of diabetes. The researchers found that the elevated blood sugar was
not caused by inadequate insulin production in the pancreas. Studies of the
pancreas revealed that its insulin-producing cells had greatly increased, most
likely to compensate for an insulin resistance characteristic of type 2
diabetes, said Birnbaum.
When Birnbaum and his
colleagues studied the animals' muscle tissue, they discovered a partial defect
in insulin-stimulated glucose uptake. Co-authors Jason Kim and HHMI
investigator
Gerald
I. Shulman
at Yale University School of Medicine performed glucose
clamp studies to measure the liver production of glucose in response to
insulin. The researchers infused precise amounts of glucose and insulin through
a small catheter inserted into a mouse's vein and measured the blood glucose
levels. These experiments as well as studies using a radioactive glucose
tracer revealed that the livers of the Akt2 knockout mice did not respond to
insulin by lowering glucose production. Furthermore, the animals' tissues were
consuming less glucose in response to insulin.
"These findings are
important because they represent the first evidence in an intact animal of a
signaling pathway by which insulin shuts off hepatic glucose production,"
said Birnbaum. "And taken together, finding effects in both liver and
muscle are especially significant because dual abnormalities are exactly what
occurs in type 2 diabetes," he said.
"No one believes that
diabetes is caused by a defect in a single gene, but, nonetheless, it is
striking that the phenotype we observed in these animals is so much like the
multi-system effects of human diabetes," said Birnbaum.
Birnbaum and his colleagues
plan to knock out Akt2 in specific tissues such as muscle, liver and fat, and
study the effects on insulin signaling in those tissues. They also plan to
explore the signaling pathway downstream of Akt2, in an effort to determine
whether genetic defects in the Akt2 pathway could contribute to diabetes.
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