[PHNUTR-L] Hopkins researchers discover potential new approach to treating diabetes

[Kathrynne Holden, MS, RD]

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Public release date: 7-Jun-2006
http://www.eurekalert.org/pub_releases/2006-06/jhmi-hrd060706.php

Contact: Audrey Huang
audrey at jhmi.edu
410-614-5105
Johns Hopkins Medical Institutions

Hopkins researchers discover potential new approach to treating diabetes

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 like diabetes.

The discovery by researchers in Hopkins' Institute of Basic Biomedical 
Sciences and McKusick-Nathans 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 � 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 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 � 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, Joseph Rodgers, Dario Kalume, Seung-hee 
Kim, Akhilesh Pandey, and Puigserver, all of Hopkins.

On the Web:
http://www.hopkinsmedicine.org/cellbio/profiles/profdisplay.cfm?senduserID=182&sendpage=directory 

-- 
Kathrynne Holden, MS, RD < fivestar at nutritionucanlivewith.com >
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