Diabetic fruit flies and lessons they teach us

To solve a modern health crisis, Jon Graff, MD, PhD, is looking back millions of years.

Dr. Graff, Professor of Developmental Biology, and his colleagues genetically alter fruit flies to have diabetes or obesity.

Jon Graff, MD, PhD

“We’re interested in unraveling the basis of metabolism,” Dr. Graff said. “Our ability to control fat and glucose levels are basic, ancient functions. We try to explore the evolutionary underpinnings.” At the center of Dr. Graff’s work is the concept of evolutionary conservation—the principle that once a gene appears in a species, it remains similar in other species that evolve from it. Ancestral mammals diverged from ancestral flies about 300 million years ago, but today, modern humans and modern flies share many genes.

Dr. Graff and his colleagues focus on the fruit fly Drosophila melanogaster, the roundworm C. elegans, and mice.

By inducing mutations and selecting for flies that have disorders in sugar metabolism—a condition he calls “flyabetes”—the researchers can identify genes that may prove relevant to human disease. Flies don’t have blood, having instead a bloodlike substance called hemolymph, but fundamentally, their glucose regulation is comparable to a mammal’s.

In Drosophila and mice, the researchers found that a single gene called adipose regulates fat and insulin resistance. In mice, they found that fat stem cells reside in the blood vessel walls of fatty tissue, but not in vessels of other types of tissues.

“If we understand how adipocytes (fat cells) form and how they function, we can hopefully find therapeutic targets to treat obesity-related diseases in humans,” Dr. Graff said. For instance, if the triggers can be found that signal stem cells to become fat cells, it may be possible to turn off the process.

His research involves animal models, but Dr. Graff keeps humans and human health in mind. “We have our eyes on what could be of use clinically,” he said.

He cofounded a company called Reata Pharmaceuticals that now has an experimental anti-inflammatory drug, bardoxolone methyl, in Phase III clinical trials. The trial is testing the efficacy and safety of bardoxolone methyl in people with chronic kidney disease and type 2 diabetes.

“We’re trying to understand a public health problem of obesity and diabetes,” he said. “The problem is well enumerated, and the vast majority of people understand that this is a burden physically, socially, and medically. It’s a huge cost for the country.”