||Researchers at the University
of Pennsylvania School of Medicine have discovered
a potential new target for treating type 2 diabetes.
||This study shows that when insulin is
present, as it is after a meal, the protein Akt2/PKB adds
a phosphate group to its molecular partner PGC-1a. When this
happens, PGC-1a cannot activate the genes needed for fat
||The findings suggest that if a drug could
induce Akt2/PKB to add the phosphate group (phosphorylation)
to PGC-1a, then the liver of a diabetic might be “fooled” into
stopping the oxidation of fat stores.
||This study appeared online this
week in Nature.
(PHILADELPHIA) – Researchers at the University
of Pennsylvania School of Medicine have discovered a potential new target for treating
2 diabetes, according to a new study that appeared online
this week in Nature. The target is a protein, along with its molecular
partner, that regulates fat metabolism.
“Over the last 10 years, we have begun to understand the importance
of fat metabolism in diabetes,” notes lead author Morris
J. Birnbaum, MD, PhD, the Willard and Rhoda Ware Professor of Diabetes and Metabolic
Diseases at Penn and an Investigator of the Howard
Hughes Medical Institute. “Type
2 diabetics are at a higher risk for cardiovascular
disease because they
also have disorders in fat metabolism as a result of obesity and abnormal
insulin action.” Birnbaum is also the Associate Director of the
Type 2 Diabetes
Unit for Penn’s Institute
for Diabetes, Obesity, and Metabolism.
When a person eats a meal, the pancreas usually responds by secreting
insulin that signals the liver to stop making glucose and burning fat.
When a type 2 diabetic eats a meal, insulin cannot stop the manufacture
of glucose in the liver, but it can stop the burning of fat stores. This
gives the diabetic person a “double whammy:” fatty acids
accumulate from food and from the liver. Consequently, more fat is deposited
in tissues and obesity worsens.
Until now there was no clear connection between insulin and the control
of fat metabolism. This study shows that when insulin is present, as
it is after a meal, the protein Akt2/PKB adds a phosphate group to its
molecular partner PGC-1a. When this happens, PGC-1a cannot activate the
genes needed for fat metabolism.
The findings suggest that if a drug could induce Akt2/PKB to add the
phosphate group (phosphorylation) to PGC-1a, then the liver of a diabetic
might be “fooled” into stopping the oxidation of fat stores. “Muscle
and fat tissue also burn fat stores, and we are currently investigating
whether PGC-1a and Akt2/PKB have the same role in those tissues,” says
The researchers also found that insulin-stimulated phosphorylation of
PGC-1a was blunted in mice that had non-functional Akt2/PKB. Finally,
they showed that livers with too much PGC-1a or with PGC-1a that could
not be phosphorylated put out many copies of the genes for fat metabolism.
Each approach pointed to the same conclusion: PGC-1a had phosphate groups
added to it by Akt2/PKB in the presence of insulin and this prevented
the turning on of genes that make fat.
There are currently no drugs that target PGC-1a and Akt2/PKB. “We
hope that drug companies will look for new ways to modify fat metabolism
in type 2 diabetics using these possible targets,” says Birnbaum.
Co-authors are first author Xinghai Li and Bobby Monks, both of Penn
and Qingyuan Ge of Cell Signaling
Technology, Inc. Dr. Birnbaum as an
Investigator of the Howard Hughes Medical Institute and receives additional
support for this work from the National
Institute of Diabetes and Digestive and Kidney Diseases.
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