A florid hormone may predict your risk for developing diabetes
by Helene Ragovin

A hormone that looks like a bouquet of flowers could help physicians identify patients who are likely to develop Type 2 diabetes, a disease that has reached epidemic status in the United States.

Chemist David Lee, right, works on his diabetes research with Shinji Suzuki, who received his M.S. in chemistry from Tufts in May. © JEFF BEERS

The hormone, known as adiponectin, has captured the interest of researchers—including Tufts chemist David H. Lee—who hope it can help explain the biochemical connection between Type 2 diabetes, obesity and cardiovascular disease—and, eventually, aid in the early detection of diabetes.

Adiponectin “has so much potential,” said Lee, assistant professor of chemistry. Most recently, Lee and his students have been analyzing the molecular structure of a specific form of adiponectin that appears to be most closely associated with the development of Type 2 diabetes, the most common form of the disease.

A hormone is a molecule that stimulates activity in a cell. “The main purpose of a hormone is information transfer in your body,” Lee said. “It’s a way of conveying information through the circulatory system.” Most non-scientists are familiar with hormones such as insulin, estrogen or testosterone, but there are scores of hormones that regulate all manner of bodily functions.

Much of the initial work on adiponectin, which was just identified in the mid-1990s, was done by Harvey Lodish of the Whitehead Institute for Biomedical Research in Cambridge. Lodish invited Lee to collaborate on tackling some of the biochemical aspects of the research, such as describing the hormone’s molecular structure.

A hormone from fat
“What’s really interesting,” Lee said, is that adiponectin is made by adipose tissue—the substance that’s familiar to most as body fat. “There used to be the notion that fat [tissue] was just a storage place for fat [cells]. As it turns out, fat tissue secrets lots of different hormones that affect metabolism, and adiponectin is one of them,” Lee said.

Adiponectin comes in three different molecular forms, each apparently with its own role to play in the metabolic process. Each form is made of subunits: a trimer, which has three subunits; a hexamer, with six subunits, and a “high-molecular weight” form, with numerous subunits—until recently, little was known about the exact structure of this form. Research from Lee’s lab, published earlier this year in the journal FEBS (Federation of European Biochemical Societies) Letters, found that this “heavy” molecule was an “octadecamer”—in other words, 18 subunits, or an “18-mer.”

Viewed under an electron microscope, adiponectin has a rather unusual chemical structure, with the oval subunits clustered together, atop a “rod-like” bottom. The 18-mer, in particular, “looks like a bouquet of flowers,” Lee said. What this peculiar molecular architecture means, and how it affects the hormone’s biochemical interactions, is a subject for further research.

But it’s this 18-mer that appears to be particularly significant for Type 2 diabetes. “It’s known that people with Type 2 diabetes have low levels of adiponectin,” Lee said, especially the adiponectin that contains the 18 subunits. Existing diabetes drugs in the thiazolidinedione class—which include rosiglitazone and pioglitazone, marketed in the United States as Avandia and Actos—are known to increase the ratio of the 18-mer in the blood.

“So, the idea is that if you can measure how much 18-mer [is present in blood serum] compared to other forms of adiponectin, if the 18-mer level is low,” it could foreshadow the onset of Type 2 diabetes. “It might be a good early marker,” Lee said, and a key to developing therapies for prevention.

A national epidemic
Roughly 15 million Americans have Type 2 diabetes. And that number is growing at a rate that has earned it the label of “epidemic”—a term that has been used by medical authorities from the National Institutes of Health to the Centers for Disease Control to the New England Journal of Medicine. Increased rates of obesity and inactivity are most often cited for the rise in Type 2 cases, although the disease also has a genetic component. Once referred to as adult-onset diabetes, it is now surfacing in significant numbers of children and teens.

In Type 2 diabetes—unlike Type 1, or “juvenile” diabetes—the body is able to produce some insulin, but cannot use it effectively to metabolize sugar in the bloodstream. Sugar fuels the cells in our bodies, and insulin is the instrument that allows us to process sugar into energy. When glucose builds up in the blood instead of going into cells, it can starve cells of energy, and, over time, damage the eyes, kidneys, nerves or heart.

Of course, the question remains: Do low levels of the 18-mer adiponectin presage the development of Type 2 diabetes, or does having diabetes somehow lower the hormone levels?

Right now, that’s an unknown, Lee said. But other researchers have shown that when obese, non-diabetic people lose weight, their adiponectin levels—particularly the 18-mer variety—increase. And, low levels of adiponectin have been observed in obese people and in those with cardiovascular disease—two conditions often associated with Type 2 diabetes.

“It’s well known that obesity and diabetes and heart disease all correlate, but why that should be is unknown,” Lee said. “Now we have established that these diseases are all connected with low levels of a hormone that affects different relevant metabolic pathways. We think that’s the missing link.”

What’s next?
For the future, Lee’s lab has two major research goals: identifying the chemical features of the 18-mer—why are they bundled and why are there 18 subunits—and clarifying the roles of the different forms of adiponectin.

Several undergraduate research assistants in Lee’s lab have been instrumental in this work. Leading the effort to identify the chemical features are biochemistry majors Martha Simmons and Alan West, both A08. They already have identified critical amino acid residues and structural features of adiponectin, Lee said. A recent graduate, Cory Rillahan, A07, who was a 2006 Summer Scholar in Lee’s lab, led the group in developing a method to measure the different adiponectin complexes in blood samples; this work was recently submitted for publication.

Lee and his students are now establishing collaborations with clinical researchers to study variations in adiponectin complexes in patients with metabolic disorders. By looking at the distribution of the different forms of adiponectin in these people, the scientists may be able to define physiological activities for each form. And, Lee’s lab is collaborating with cell biologists to track changes in adiponectin and insulin in mice that have been fed a high-fat diet in an attempt to understand more about the relationship between adiponectin, insulin and insulin resistance, and to study the effects of low-fat diets, weight loss and exercise on adiponectin distribution.

Researchers are excited about where this work could lead, Lee said. “In 2002, there were maybe 100 papers [that had been published] on this hormone,” he said. “In the past five years, there are now almost 2,800 publications. That tells you how important this molecule is.”

Helene Ragovin is a senior writer in Tufts’ Office of Publications. She can be reached at helene.ragovin@tufts.edu. This story appeared in the September 2007 issue of the Tufts Journal.