Scientists at Johns Hopkins have uncovered a
surprising and novel way of lowering blood sugar levels in
mice by manipulating the release of sugar by liver cells.
The results, published in the June issue of Cell
Metabolism, have implications for treating conditions
The discovery by researchers in Johns Hopkins'
Institute of Basic Biomedical Sciences and McKusick-Nathans
Institute for Genetic Medicine reveals that a protein
called GCN5 is critical for controlling a dominolike
cascade of molecular events that lead to the release of
sugar from liver cells into the bloodstream. Understanding
the role of GCN5 in maintaining blood sugar levels is
leading to a clearer picture of how the body uses sugar and
other nutrients to make, store and spend energy.
"Understanding the ways that energy production and use
are controlled is crucial to developing new drugs and
therapies," said the report's senior author, Pere
Puigserver, an assistant professor of
The inability to properly regulate blood sugar levels
leads to conditions like obesity and diabetes. Both type 1
and type 2 diabetes cause blood sugar levels to stay too
high, a condition that can lead to complications like
blindness, kidney failure and nerve damage.
"Diabetes is a really big problem, even when patients
are given insulin and stay on strict diets," said Carles
Lerin, a postdoctoral fellow in cell biology and an author
of the report. "In the absence of a cure for the disease,
we are really trying to focus on finding better treatment
because currently available methods just don't work that
efficiently," he said.
The body keeps blood sugar — known as glucose
— within a narrow range. Extra glucose floating
through the bloodstream, which is common after eating a
meal, is captured and kept in the liver. When blood glucose
runs low, the liver releases its stores back into the
bloodstream. When those reserves are tapped out, liver
cells turn on genes to make more glucose to fuel the
The research team found that GCN5 chemically alters
another protein called PGC-1alpha that normally turns on a
set of genes to manufacture enzymes required for glucose
release. When GCN5 is fully functional in liver cells, this
cascade is turned off and glucose is not released from
those cells. Removal of functional GCN5 from liver cells
restores the cells' ability to release glucose.
The researchers showed that GCN5 alters its target,
sabotaging it by adding a chemical tag called an acetyl
group. By using molecules that glow fluorescently, the
researchers saw under high-power microscopes that GCN5
carries its tagged target to a different location in the
cell's nucleus, sequestering it away from the genes it's
normally meant to turn on.
"GCN5 has been generally shown to turn on genes. No
one knew that GCN5 could be used to turn off pathways,"
Lerin said. "It was a bit of a surprise."
When the researchers put GCN5 into live mice, they
found that it can, in fact, decrease blood glucose levels.
Liver cells in mice that were given no food for 16 hours
actively released glucose into the bloodstream. Introducing
GCN5 into their livers, however, caused blood glucose
levels in these mice to be reduced.
"These results show that changing GCN5 is sufficient
to control the sugar balance in mice," Puigserver said.
"Therefore, GCN5 has the potential to be a target for
therapeutic drug design in the future."
The researchers were funded by the Secretaria de
Estado de Universidades e Investigacion del Ministerio de
Educacion y Ciencia of Spain, the Ellinson Medical
Foundation, the American Federation for Aging Research and
the American Diabetes Association.