Researchers use fruit flies to unlock mysteries of human diabetes

August 7, 2014, Stanford University Medical Center
Fruit Fly
Fruit Fly. Credit: UCSD

For the first time, the tiny fruit fly can be used to study how mutations associated with the development of diabetes affect the production and secretion of the vital hormone insulin.

The advance is due to a new technique devised by researchers at the Stanford University School of Medicine that allows scientists to measure levels in the insects with extremely high sensitivity and reproducibility.

The experimental model is likely to transform the field of diabetes research by bringing the staggering power of fruit fly genetics, honed over 100 years of research, to bear on the devastating condition that affects millions of Americans. Until now, scientists wishing to study the effect of specific mutations on insulin had to rely on the laborious, lengthy and expensive genetic engineering of laboratory mice or other mammals.

In contrast, tiny, short-lived can be bred in dizzying combinations by the tens of thousands in just days or weeks in small flasks on a laboratory bench.

"I normally avoid the term, but I think Dr. Park's new technique is a true breakthrough," said Seung Kim, MD, PhD, professor of developmental biology. "Only in selected mammals can researchers measure insulin with this degree of sensitivity."

Kim, who is also a Howard Hughes Medical Institute investigator, is the senior author of the paper describing the research. Research associate Sangbin Park, PhD, is the lead author of the paper, which will be published Aug. 7 in PLOS Genetics.

The power of a tiny model system

Insulin is an ancient molecule used by nearly all animals to regulate metabolism, growth and development. Diabetes in humans occurs when insulin-making cells in the pancreas fail to produce the hormone or when other cells in the body grow resistant to its effects. In 2002, Kim, his lab team and fellow Stanford researchers discovered that fruit flies develop a diabetes-like condition when their insulin-producing cells are destroyed.

"Studies of diabetes in fruit flies represent a relatively new area of investigation," said Carl Thummel, PhD, professor of genetics at the University of Utah School of Medicine. Thummel uses the insect to study energy metabolism and metabolic disorders.

"Needless to say, fruit flies are very small, and only tiny amounts of blood can be extracted from their bodies," he said. "Our inability to measure the amounts of circulating insulin has been a major drawback in the field. The technique developed by Dr. Kim's group will allow researchers to rapidly test the effect of diabetes risk factors, and establishes fruit flies as an effective tool for studies of diabetes."

Developed by Park, the new technique uses a chemical tag to label an insulin-like peptide called Ilp2 in fruit flies. The tag allows researchers to use an antibody-based assay to measure insulin concentrations in the insect's blood and cells at the picomolar level—the level at which insulin concentrations are measured in humans.

Using the technique, the researchers were able to quickly identify what a mutation associated with type-2 diabetes in humans actually does: It regulates insulin secretion, but not production.

Understanding the effect of each mutation

Parsing the effect of each mutation on the way the body produces, secretes and responds (or not) to insulin is critical to further understand the disease and to devise new therapeutic approaches. "I was stunned that this technique worked so well to identify the effect of specific mutations," said Park. "Many of the genes we studied seem to have similar functions in governing insulin production or secretion in flies and in humans."

Previous efforts to tag Ilp2 have been hampered by the fact that the protein undergoes a complex series of modifications and folding events on its way to becoming the active form of the molecule. Tags that disrupt this process can cause inappropriate expression of the molecule or render it inactive, interfering with the very metabolic pathway researchers want to study.

Park capitalized on the knowledge that overexpression of the active form of the Ilp2 protein is lethal. He then randomly inserted chemical tags along the length of the molecule to create a panel of molecules tagged in many different places. Testing them individually, he looked for those that were still able to kill the flies—indicating that the molecule's activity had not been compromised. Eventually he found two locations on Ilp2 that were ideal. He could then use antibodies that recognized the tags to quantify levels of Ilp2 with the antibody-based assay.

"Once you know that the modifications, or tags, don't affect the expression or activity of the molecule, you have a lot more power to interpret your experiments," said Kim. "You can begin to track the insulin assembly line, from the transcription of RNA from the gene, to the production of the protein, to the storing and eventual secretion of the protein in response to metabolic signals. You have the opportunity to figure out the mechanisms controlling each of those steps in detail."

In flies, Ilp2 is produced and secreted by specialized neurons in the brain. This makes it relatively easy to compare levels of circulating Ilp2 with the amount of mature but unsecreted Ilp2: simply compare the amount of Ilp2 in the insects' bodies to the amount in their brains.

Park found that the amount of secreted Ilp2 increased from about 0.1 percent to about 0.35 percent of the total available during the first three days of a fruit fly's life. Furthermore, like in humans, circulating Ilp2 concentrations were relatively low in fasting flies, but peaked and then declined after a subsequent meal. Finally he showed that, in flies with only one working copy of the insulin receptor gene (they normally have two, as do humans), was increased in an apparent attempt to compensate for the deficiency—mirroring the development of insulin resistance in humans and mice.

Park and his colleagues then turned their attention to mutations associated with type-2 diabetes in genome-wide studies in humans. These studies don't reveal how a specific mutation might work to affect development of a disease; they show only that people with the condition are more likely than those without it to have certain mutations in their genome. Hundreds of candidate-susceptibility genes have been identified in this way.

Tip of the iceberg

The researchers found that blocking the expression of a fly version of a human protein called GLIS3, known to affect in mammals, and linked both to type-2 and type-1 diabetes in humans, also affected the production of Ilp2 in flies. A mutation in another protein, BCL11A, was known to be associated with the development of the disease in humans, but its mechanism of action was unclear. Park and his colleagues found that blocking the expression of the fly version of BCL11A did not affect the flies' ability to make Ilp2, but caused it to secrete abnormally high levels of Ilp2 into the bloodstream.

The researchers emphasize that these findings are just the tip of the iceberg. Many more mutations can be studied alone and in combination under a myriad of experimental conditions. A single fruit fly can lay several hundred eggs during its approximately 40-day life span; eggs develop into adults in only 10 days. They plan to continue to use the fruit fly system to complement and inform their ongoing studies in mammals and humans.

"We're really taking advantage of a century of work done by generations of other researchers," said Kim. "Historically the fly has been used to understand developmental biology by looking at its genes and its cells and observing how they change over time. Now we've shown we can accurately and precisely measure levels of a crucial hormone in these insects, and use that to identify new targets for diabetes investigation in mice and humans."

Explore further: 'Diabetic flies' can speed up disease-fighting research

Related Stories

'Diabetic flies' can speed up disease-fighting research

November 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 ...

Therapeutic agent reduces age-related sleep problems in fruit flies

April 1, 2014
Elderly flies do not sleep well – they frequently wake up during the night and wander around restlessly. The same is true of humans. For researchers at the Max Planck Institute for Biology of Ageing in Cologne, the sleeplessness ...

Inducing insulin resistance: Human iPS cell model offers new look at key driver of type 2 diabetes

August 1, 2014
(Medical Xpress)—Harvard Medical School researchers at Joslin Diabetes Center have created the first induced pluripotent stem cells (iPSCs) that offer a human model of insulin resistance, a key driver of type 2 diabetes.

Loss of function of a single gene linked to diabetes in mice

January 4, 2014
Researchers from the University of Illinois at Chicago College of Medicine have found that dysfunction in a single gene in mice causes fasting hyperglycemia, one of the major symptoms of type 2 diabetes. Their findings were ...

Novel drug target linked to insulin secretion and type 2 diabetes treatment

May 26, 2014
A signal that promotes insulin secretion and reduces hyperglycemia in a type 2 diabetes animal model is enhanced by the inhibition of a novel enzyme discovered by CHUM Research Centre (CRCHUM) and University of Montreal researchers. ...

Researchers discover new explanation for diabetes and poor growth

April 23, 2013
A group of researchers from the University of Copenhagen has taken a significant step towards understanding the reasons for both diabetes and growth hormone deficiency. Their new discoveries centre on the body's ability to ...

Recommended for you

Peers' genes may help friends stay in school, new study finds

January 18, 2018
While there's scientific evidence to suggest that your genes have something to do with how far you'll go in school, new research by a team from Stanford and elsewhere says the DNA of your classmates also plays a role.

A centuries-old math equation used to solve a modern-day genetics challenge

January 18, 2018
Researchers developed a new mathematical tool to validate and improve methods used by medical professionals to interpret results from clinical genetic tests. The work was published this month in Genetics in Medicine.

Can mice really mirror humans when it comes to cancer?

January 18, 2018
A new Michigan State University study is helping to answer a pressing question among scientists of just how close mice are to people when it comes to researching cancer.

Group recreates DNA of man who died in 1827 despite having no body to work with

January 16, 2018
An international team of researchers led by a group with deCODE Genetics, a biopharmaceutical company in Iceland, has partly recreated the DNA of a man who died in 1827, despite having no body to take tissue samples from. ...

Epigenetics study helps focus search for autism risk factors

January 16, 2018
Scientists have long tried to pin down the causes of autism spectrum disorder. Recent studies have expanded the search for genetic links from identifying genes toward epigenetics, the study of factors that control gene expression ...

The surprising role of gene architecture in cell fate decisions

January 16, 2018
Scientists read the code of life—the genome—as a sequence of letters, but now researchers have also started exploring its three-dimensional organisation. In a paper published in Nature Genetics, an interdisciplinary research ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.