After all of those times fruit flies have literally bugged us at work or play, the teeny insects could someday be a lead player in two major breakthroughs for humans.

A reduced need for insulin shots, as well as getting the benefits of exercise – without exercising – are possible as the result of ongoing studies involving fruit flies at Wake Forest University. Good thing that drosophila (the scientific name for fruit flies) are a lot more like human beings than many of us know.

Humans’ and fruit flies’ similar biophysical and biochemical processes, including those that control sugar, enable researchers to manipulate blood sugar levels in fruit flies and trigger a reaction that could inform metabolic research.

“Fruit flies and human beings are wired similarly,” said Erik Johnson, associate professor of biology at Wake Forest and the study’s lead investigator. “They share 30 percent to 60 percent of the same genes. The big difference is that fruit flies are so much simpler than humans in the number of cells you’re looking at.”

Johnson said fruit flies have about 100,000 neurons, as opposed to approximately 11 billion in humans.

2005 discovery

Johnson and his team’s findings, recently published in the journal Genetics, reflect research that goes back seven years. The work “has been the most fun, scientifically, in my career,” he said.

He explained the roots of this scientific process and the discovery of similar reactions in fruit flies’ and humans’ brains: “The brain makes chemicals. An individual brain cell will make a chemical and release it, and that chemical will bind to its receptor on some other brain cell. Essentially, this is the means by which brain cells communicate.

“We were doing experiments in 2005, just mapping where some of these receptors were. Essentially, we were trying to identify what cells make a particular hormone, and what cells were responding to it. One of the things we found was a similar endocrine circuit that in our hypothalamus (a pearl-size area of our brain that produces various hormones and controls a wide variety of our physiology), there is one group of cells that produce one hormone, and they receive information from two other populations of cells.

“We saw the same thing happen in the fly brain when we were doing these mapping experiments. That was really kind of wild because it does say that some of the basic wiring diagrams are going to be similar.”

The key: AMPK

Johnson and his team investigated how fruit flies react when starved for food. They found that rather than becoming slower, the flies buzzed around frantically in search of something to eat.

He explained that this occurs due to the secretion of adipokinetic hormone, which functions the same way that glucagon does in humans by raising blood sugar levels (glucagon does the opposite of insulin, which lowers those levels). The elevated AKH prompts the flies to release more sugar to fuel their food search.

Researchers manipulated an enzyme called AMP-activated kinase – which causes the release of AKH – in the experiments. When they switched off AMPK in selected cells, less AKH was secreted. This decreased the sugar release, and the hyperactive behavior in the fruit flies all but stopped.

Exercise stimulates AMPK. So the theory is that if researchers can achieve predictable results by switching off AMPK in certain cells, they could someday develop a drug that turns on all AMP-activated kinase in the body and trick it into thinking it was exercising. The body would get all of the benefits without the work.

“The problem is, what we really have to do is target these potential drugs,” said Johnson, adding that it’s possible the exercise drug could be available within five or 10 years. “What we don’t want to have happen is to globally target AMPK in one way or the other because it’s doing different things in different tissues. … We turned off AMPK in only the cells that were of interest.”

Hope for diabetics

This ability to manipulate AMPK has resulted in its being targeted by drug companies as an anti-diabetic, Johnson said.

The study’s potential help for diabetics comes from the fact that AKH – the hormone that’s released by AMPK – functions in fruit flies the way that glucagon does in humans. Secreted in the human pancreas, glucagon raises blood sugar levels. But the study of glucagon systems in humans is challenging because it’s hard to separate the pancreatic cells.

The ability to study how this system works in the fruit fly could lead to a drug that targets the cells that cause glucagon to signal the body to release sugar into the blood. That would lessen the need for insulin shots in diabetics.

Jason Braco, a graduate student from Warren, N.J., who gathered a considerable amount of data for the experiment since beginning work on it two years ago, said the project underscores “the old-timey adage that ‘the devil is in the details.’

“When I started grad school, I had no idea what the failure rate of experiments was. You try to set up these experiments over and over again, and it’s hard to get things to the point where they are replicable. We’re trying to control for a lot of variables and very specific things. Getting it down to being able to replicate one experiment to another is so difficult.”

Braco said he understands the importance of the diabetes and weight-loss aspect as “selling points” but emphasized that “this is basic research. What we’re really trying to do is establish a foundation for metabolism, understanding it a lot better.

“We have all these crazy diets. The reason is because people really don’t have a good grasp of metabolism, in that we don’t understand the regulatory aspects of it. And that’s what this research is really pushing for, is trying to understand what’s going on, and how it’s going on. … We’re trying to establish a basis for future research in a lot of different fields that can be applied toward a lot of different things.”

A ways to go

Similarly, Johnson stressed that his team’s research is one small step in seeking a larger understanding of how all molecules work and interact.

“We’re learning a lot, but there’s still a lot left to learn,” said Johnson, who expects the fruit fly research to last perhaps decades. “AMPK does a lot, but there are other things that impact glucagon and impact insulin. Part of what we’re trying to do is figure out some of these other regulatory molecules.”

An even more ambitious quest: the search to fully understand the human brain.

“We’re really in the infancy of figuring out how the human brain works, which I think is one of the huge endeavors of our species,” Johnson said. “There’s a great quote (by neuroscientist Richard Restak) that says, ‘The human brain is the only organ in the known universe that seeks to understand itself.’ …

“We have to understand how 11 billion cells are talking to each other. We’re still far off from understanding even a fly brain and how 100,000 cells are talking to each other.”