'Diabetic Flies' Can Speed Up Disease-Fighting Research
Nov. 6, 2013 — In a finding
that has the potential to significantly speed up diabetes research,
scientists at the University of Maryland have discovered that fruit
flies respond to insulin at the cellular level much like humans do,
making these common, easily bred insects good subjects for laboratory
experiments in new treatments for diabetes.
The fruit
fly on the right, genetically altered to disable insulin-like genes and
fed a high sugar diet, has symptoms comparable to type 2 diabetes in
humans. It is smaller and less able to reproduce than the normal fruit
fly on the left, but healthy enough for use in testing diabetes
treatments. (Credit: Jingnan Liu and Hua Zhang)
The common fruit fly Drosophila melanogaster looks like a
sesame seed with wings, produces offspring by the thousands, and lives
for around a month. These creatures don't resemble humans in any obvious
way, but they share more than sixty percent of our genetic code. And
scientists like UMD's Leslie Pick and Georgeta Crivat are finding that
those similarities control basic biological processes that work alike in
both species.
Drosophila melanogaster is easy to breed, raise and study in
the laboratory, so it's widely used in research. Pick, chairman of the
UMD Entomology Department, conducts experiments that use information
about the fruit fly's relatively simple genome to illuminate biological
processes in humans. Her recent research focuses on whether fruit flies
use the hormone insulin the same way humans and other mammals do.
"We hope to use all the genetic tools we have available for flies,
and the fact that we can breed them in huge numbers, very fast, to set
up efficient screening tests for assessing new diabetes treatments,"
Pick said.
In a new study published Nov. 6 in the peer-reviewed online journal PLOS One,
Pick and her co-authors found the basic mechanisms that humans use to
regulate blood sugar -- the process that goes awry in diabetes -- are
indeed shared with flies.
In humans, insulin controls the production and movement of glucose,
the form of sugar that fuels mammalian cells. The movement of glucose
into individual cells begins when insulin binds to a specialized insulin
receptor on a cell. That causes a sugar transporter called GLUT4 to
move from the cell interior to its membrane, allowing glucose to flow
through the membrane, moving from the bloodstream into the cell. In
diabetics, this process fails and sugar accumulates in the blood. In the
main types of diabetes -- Type 1, in which the body cannot produce
insulin, and Type 2, in which the cells stop responding to insulin --
high blood sugar levels can gravely damage many organs. The disease is
one of the world's most serious health problems.
Fruit flies' systems are very different than humans. Glucose is not
their main form of sugar, and they don't have blood like mammals do, so
researchers were not sure whether insulin played a role in their cells
that is similar to humans. But in a 2009 experiment, Pick and colleagues
used genetic engineering techniques to disable five insulin-like fruit
fly genes.
The resulting "diabetic flies" had many symptoms of diabetes in
humans, Pick said. "They were very, very small and sluggish; they had
decreased body fat and higher levels of circulating blood sugar; and
they did not reproduce very well." Other researchers trying to
understand diabetes have performed similar experiments on mammals, which
usually did not survive the genetic alteration, Pick said.
"The flies are not fine, but they do live," Pick said. That meant
more diabetes-related experiments, using flies instead of mammals, might
be possible.
To be sure, the researchers needed to know whether the cellular
processes taking place were the same in both species. Pick and her
colleagues turned to Samuel Cushman of the National Institutes of
Health, the co-discoverer of the glucose transport process involving
GLUT4 in humans. Combining their expertise, the two research teams
inserted GLUT4 into fruit flies, using a fluorescent tag to mark the
GLUT4 molecules.
To the scientists' surprise, although this protein is foreign to the
fruit flies, their cells moved GLUT4 to the cell membrane exactly as
human cells do in response to insulin. Under a high powered microscope
that picks up the fluorescent GLUT4,"You can actually track its movement
onto the cell membrane."
"It's pretty amazing," Pick said. "We hoped that would happen, but
there are so many differences between flies and mammals that we
ourselves were skeptical."
The researchers' next step is to find the sugar transporter that
fills the role of GLUT4 in fruit flies, Pick said, and "to use the fly
model to see if we can screen for compounds that promote sugar uptake,
alone or working together with insulin, to treat diabetes more
effectively."