Solving Insulin-signaling Mystery

Critical nodes form an important part of the signaling network that functions downstream of the insulin receptor (IR) (black arrows) and the insulin growth factor-1 receptor (IGF1R) (blue arrows). Signaling pathways that are activated by cytokines such as tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and leptin interfere with insulin signaling through crosstalk (orange and red arrows). (graphic courtesy C. Ronald Kahn, Harvard University)

Critical nodes form an important part of the signaling network that functions downstream of the insulin receptor (IR) (black arrows) and the insulin growth factor-1 receptor (IGF1R) (blue arrows). Signaling pathways that are activated by cytokines such as tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), and leptin interfere with insulin signaling through crosstalk (orange and red arrows). (graphic courtesy C. Ronald Kahn, Harvard University)

American children are more sedentary than at any time in our nation’s history and gaining weight at alarming rates, all of which is leading to an epidemic of diabetes, particularly type II diabetes.

Though researchers have sought effective treatments for obesity and diabetes for decades, the medications that are currently available are effective in only about 60 percent of patients. Diabetes can lead to eye, kidney, nerve, gums and teeth problems. More seriously, someone with diabetes is more than twice as likely to have heart disease or a stroke.

So Pfizer, a leading pharmaceutical company, has taken the unusual step of funding basic research into the biology of insulin-signaling in cells that involves a consortium of universities and private companies. UCSB’s Frank Doyle, a chemical engineer and associate director of the UCSB-led, Army-funded Institute for Collaborative Biotechnologies, heads the effort.

Called the Insulin Resistance Pathway (IRP) project, the three-year, $14 million effort involves UCSB, MIT, Caltech, the University of Massachusetts, Pfizer Laboratories and Entelos, a physiological modeling firm based in the San Francisco Bay area.

“The IRP Project is a new paradigm in two respects,” Doyle explains. “First, its methodology is a true departure from the way fundamental research on human disease has been done and then applied to the development of new therapies in the past. Second, this consortium also represents a sea change in how industry and academia collaborate in research and product development in the pharmaceutical area.”

Doyle has spent most of his career working on type I diabetes research, sometimes referred to as insulin-dependent diabetes. (In type II diabetes, there is a malfunction in how the body’s cells process insulin. In type I diabetes, the body stops producing insulin in most cases.)

Then, in early 2007, UCSB hosted Pfizer officials during a two-day meeting organized by Leslie Edwards, business development director for engineering and the sciences. The meeting culminated in a dinner at which Doyle happened to sit next to C. Preston Hensley, a senior executive with Pfizer. Hensley, a UCSB alumnus, and Doyle spent the dinner talking about the ICB, systems biology and the type II diabetes problem. By the time dessert was finished, they had the makings of a collaborative plan that became the IRP.

UCSB and its partners in the ICB, the University of Massachusetts and Entelos were brought in. Linda Petzold, from the UCSB departments of mechanical engineering and computer science, is part of the computational side of the project, which Doyle leads. Forest White at MIT is leading the experimental aspects of the project. All the UCSB teams include graduate students. The project’s conditions allow the academic partners to publish and/or patent any basic biology discoveries that come out of the research, an extraordinary and unusual opportunity, Doyle says.

Diabetes is a disease that occurs when the body’s cells can’t process glucose, the simple sugar in food that is the main source of energy for the body. Cells need insulin, a hormone produced by the pancreas, to take in the glucose and convert it to energy. When the pancreas doesn’t produce enough insulin, or the cell is unable to use the insulin that’s present, glucose builds up in the bloodstream and ultimately leads to diabetes. Being overweight compromises the body’s ability to use insulin, thus the epidemic of obesity in Americans, particularly youngsters, is contributing to an alarming increase in type II diabetes.

“The cell is like an information processing network,” Doyle explains. “We’re using experimental modeling and systems understanding to look at the network and figure out what’s going on. It’s very likely a combination of things that’s happening, and it will take a combination of strategies to solve it.”

“We’re really drilling down to the chemical reactions in the cell,” Doyle adds. “We’re doing fundamental research right now, and what we find out will become the platform to build upon in future years. It is the chance to do systems biology for a really compelling problem, in a partnership that’s going to push us toward a real solution.”

After the first three years of basic research, Pfizer expects to fund another three years of applied research. Ultimately, the company hopes to develop new drugs to treat the disease.

“Clearly, I’d love for new insights to be brought to bear on type II diabetes,” Doyle says. As the associate director of the ICB, he sees long-term benefits for UCSB: “This also reflects our ability, our versatility, to put together a team to do very-directed research with applied outcomes.”