COLLEGE PARK, Md.—A team of medical researchers at theUniversity of Maryland say they have created fruit flies as a model system tounravel what genes and gene pathways are involved in the metabolic changes thatlead to insulin resistance and full-blown diabetes in humans.
In research published last month in the Proceedings ofthe National Academy of Sciences, LesliePick, an associate professor in the department of entomology, and colleaguesdescribe how they altered genes in fruit flies to model the loss of insulinproduction, as seen in human type 1 diabetes.
The research was funded primarily by the National Institutesof Health. Pick and her team, which included University of Maryland researchersHua Zhang, Jingnan Liu, and Caroline Li, Bahram Momen, associate professor ofbiostatistics and environmental science, and former Johns Hopkins UniversityAssociate Professor Dr. Ronald Kohanski, used genetic approaches to delete acluster of five genes encoding insulin-like peptides (Drosophila insulin-likepeptides, DILPs) in the Drosophila melanogaster fruit fly.
"When we compare the mutants with a normal fly that has beenstarved, they look the same in that they are both breaking down their fat toget energy," Pick explains.
According to Pick, this mimics a clinical feature ofdiabetic patients resulting from the fact that nutrients are present but thebody cannot utilize them and thus mounts a starvation response, breaking downenergy stores to obtain nutrients.
"We can use these genetically manipulated flies as a modelto understand defects underlying human diabetes and to identify genes andtarget points for pharmacological intervention," suggests Pick.
While sedentary lifestyles and diets high in sugar and fatcontribute significantly to the rise in diabetes rates, genetic factors maymake some people more vulnerable than others to developing diabetes,researchers say.
"These mutant flies show symptoms that look very similar tohuman diabetes," explains Pick. "They have the hallmark characteristic which iselevated blood sugar levels. They are also lethargic and appear to be breakingdown their fat tissue to get energy, even while they are eating—a situation inwhich normal animals would be storing fat, not breaking it down."
Pick notes that one advantage to working with Drosophila(fruit flies) is that researchers can breed lots of flies with the samegenotype or genetic defect, and then expose them to different treatments andsee how this effects them.
"These different treatments could be drugs, different foods,different environments, or really anything. In this way, we can set up'screens' to expose flies to many different compounds under very controlledconditions," she notes. "With this approach, we could use flies that havedefects in insulins or insulin signaling and screen for compounds that improvethese defects.
Researchers can similarly screen for mutations in othergenes that lessen the symptoms that they see. "These kinds of 'genetic screens'were used to find many new genes in Drosophila and these genes turned out to beimportant in human development and disease," Pick adds.
Pick says the work with type 2 diabetes is in its earlystages.
"We are making specific mutations in the insulinreceptor—the protein on the cell surface that insulin binds to—to carry out itsbiochemical functions," she points out. "We would like to see if we can findspecific mutations that affect sugar metabolism and lead to a condition equivalentto human insulin resistance, where insulin is present, but the body tissues donot respond to it. This type of insulin resistance is associated with type 2diabetes and often is a warning sign that diabetes is developing."
Model organisms have proven enormously valuable for studiesof human disease mechanisms because regulatory pathways and physiology are sohighly conserved throughout the animal kingdom. The relationship between flyand human genes is so close that human genes, including disease genes, canoften be matched against their fly counterparts.
"Way more is shared between flies and humans than we everwould have expected before we started identifying the genes," says Pick.
Using flies as a model system has advantages over studies inother animals, such as mice, because the experiments can be done quickly inthousands of flies and because scientists can combine different mutations muchmore easily. This could prove valuable in understanding the genesis of type 2diabetes in which scientists believe multiple genes play a role.
"When we made the genetic mutation that deleted these genes,we asked would these flies have any symptoms of human diabetes, and it turnsout they do," Pick says. "That tells us that there are some things going onthat are very similar. Our hope is that this provides a valuable resource forthe scientific community to identify gene targets for diabetes treatment."
Moving forward, Pick said the team would like to know thecauses of increased circulating sugar levels in these "diabetic" flies.
"In humans, insulin promotes the uptake of sugar from theblood and it also inhibits the breakdown of storage products," she says. "Weare now asking if insulins in Drosophila have these same functions."
Moving forward, there are some specific goals that willserve as benchmarks for continued success for the research, Pick concludes.
"If we can figure out the biochemical cause of the diabeticsymptoms in our mutant flies, and if we can find mutations in the insulinreceptor that produce diabetic symptoms, these would be big steps forward forus," she says.