Hopkins Researchers Discover Potential New Approach To Treating Diabetes

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Source: s Hopkins Medical Institutions

Posted: June 7, 2006

Hopkins Researchers Discover Potential New Approach To Treating Diabetes

Scientists at s 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 like

diabetes.

The discovery by researchers in Hopkins' Institute of Basic

Biomedical Sciences and McKusick-s Institute for Genetic

Medicine reveals that a protein called GCN5 is critical for

controlling a domino-like 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, " says the report's

senior author, Pere Puigserver, Ph.D., an assistant professor of cell

biology at Hopkins.

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, which 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, " says Carles Lerin, Ph.D., a

postdoctoral fellow in cell biology at Hopkins 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 says.

The body keeps blood sugar â� " known as glucose â� " 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 body.

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 â� " 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 " says Lerin. " 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 release glucose into the

bloodstream. Introducing GCN5 into their livers, however, causes

blood glucose levels in these mice to be reduced.

" These results show that changing GCN5 is sufficient to control the

sugar balance in mice, " says Puigserver. " 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.

Authors on the paper are Lerin, ph Rodgers, Dario Kalume, Seung-

hee Kim, Akhilesh Pandey, and Puigserver, all of Hopkins.

http://www.sciencedaily.com/releases/2006/06/060607151532.htm