Glowing mice illuminate diabetes
26 September 2007
Mice given a customised firefly gene that causes
their livers to glow in the presence of key chemicals formed during glucose
metabolism could help the development of new diabetes drugs.
at the Salk Institute for Biological Studies, California, report in a study
published in Nature that a protein called TORC2 serves as a key biochemical
control point linking feeding, insulin, and elevated blood sugar production
in the liver. With the help of the luciferase gene from the firefly they
made the livers of mice actively producing glucose light up. The findings
highlight TORC2 and an enzyme called SIK2 as potential drug targets for
treating type II diabetes.
Glowing mice on the left show glucose production in the liver
during fasting. Mice on the right show the response to feeding:
the mice produce insulin, which shuts down glucose production
in the liver. Photo courtesy of Dr. Renaud Dentin, Salk Institute
for Biological Studies
Diabetes is an incurable disease that can
lead to blindness, kidney failure, heart disease, and other serious
debilitations. According to the International Diabetes Federation, it
affects an estimated 246 million people worldwide and every year 3.8 million
people die from it. However, up to 80% of type 2 diabetes is preventable by
adopting a healthy diet and increasing physical activity. According to the
US Centers for Disease Control and Prevention, one in three Americans born
in 2000 will develop diabetes.
The problem starts during the process by which blood sugar is produced in
the liver — gluconeogenesis, explains Marc Montminy, PhD, a professor in the
Clayton Foundation Laboratories for Peptide Biology, who led the study.
During fasting, gluconeogenesis maintains blood sugar levels by increasing
After a meal, the hormone insulin normally turns down gluconeogenesis,
ensuring that blood sugar levels don’t rise too high. “But in people with
insulin resistance, blood sugar levels are elevated because gluconeogenesis
continues when it shouldn’t, increasing the risk of developing type II
diabetes,” Montminy says.
Twenty years ago, Montminy discovered a
metabolic switch, a protein called CREB that responds to various
physiological signals by turning on and off different gene networks in the
body. During periods of fasting when blood sugar stocks run low, for
example, CREB turns on gluceoneogenesis in the liver. Recently, Montminy’s
team identified a second essential component of the CREB switch, a protein
called TORC2, that binds to CREB and enables the switch to work.
researchers had established that TORC2 was essential to sugar production
during fasting, they were keenly interested in understanding the protein’s
role during feeding. That knowledge might clue them in to the causes of
To learn how feeding and insulin affect TORC2, the
researchers, led by post-doctoral fellows Renaud Dentin and Yi Liu, inserted
into laboratory mice the luciferase gene, which produces the glow of firefly
tails. They altered the gene so that it could only be turned on in the liver
by the CREB/TORC2 switch.
When the gene is turned on, the luciferase enzyme causes the liver to
light up. Using a sensitive camera, the light — a direct measure of
CREB/TORC2 activity — can be detected and measured from outside of the live
mice. Using biochemical and genetic techniques to change the levels of
various molecules in the pathway, including insulin and TORC2, the
researchers measured the effect of these changes on the amount of light
emitted from the liver.
The experiments revealed that the rise in insulin
during feeding turned off the CREB/TORC2 switch. Insulin first activated a
liver enzyme called SIK2, which in turn inactivated TORC2 by chemically
tagging it with a phosphate group. The extra phosphate group caused TORC2 to
leave the cell nucleus where it needed to be to turn on genes. Once the
protein left the nucleus, the researches discovered, it was destroyed by the
cell’s protein degradation machinery or proteasome.
“You need TORC2 to be
downregulated by phosphorylation during feeding. If you don’t do that, then
the whole gluconeogenic program stays on, and glucose levels go up,”
Understanding these key roles of TORC2 and SIK2 points to their potential
as drug targets for stemming the rising tide of fasting blood sugar. But the
glowing mice might one day do more than illuminate the relationship between
feeding, fasting, and the CREB/TORC2 switch. “Because the luciferase mice
provide a direct look at glucose metabolism in the liver, this imaging
approach may be useful in evaluating potential drugs for the treatment of
type II diabetes,” says Montminy.
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