After decades of research, scientists unlock how insulin interacts with cells

(Press-News.org) The discovery of insulin nearly a century ago changed diabetes from a death sentence to a chronic disease.

Today a team that includes researchers from Case Western Reserve University School of Medicine announced a discovery that could lead to dramatic improvements in the lives of people managing diabetes.

After decades of speculation about exactly how insulin interacts with cells, the international group of scientists finally found a definitive answer: in an article published today in the journal Nature, the group describes how insulin binds to the cell to allow the cell to transform sugar into energy—and also how the insulin itself changes shape as a result of this connection.

"These findings carry profound implications for diabetes patients," said Case Western Reserve biochemistry professor and department chair Michael A. Weiss, MD, PhD, MBA, one of the leaders of the team. "This new information increases exponentially the chances that we can develop better treatments—in particular, oral medications instead of syringes, pens or pumps."

Weiss, also the Cowan-Blum Professor of Cancer Research at the School of Medicine, is renowned worldwide for his work on insulin. In 1991 he used nuclear magnetic resonance techniques to describe the structure of insulin; more recently he has developed a preliminary version of the hormone that does not need to be refrigerated, a critical breakthrough for those with diabetes in the developing world.

The results published today, however, represent among the most promising for Weiss and an entire generation of scientists devoted to enhancing care for those suffering from diabetes. They have sought to solve mystery of how the hormone bound to cells since 1969, when the late Dorothy Hodgkin and colleagues at the University of Oxford, first described insulin's structure.

"There's been a logjam in our understanding since then," Weiss said. "We hope that we've broken the logjam."

The magnitude of the challenge is, in part, evidenced by the diversity of the team required to overcome it. Weiss partnered with Associate Professor Mike Lawrence, of the Walter and Eliza Hall Institute of Medical Research in Melbourne, Australia, to lead the project. They, in turn, engaged scientists from the University of Chicago, the University of York in the United Kingdom, and the Institute of Organic Chemistry and Biochemistry in Prague in the Czech Republic.

The scientists recognized that cells absorb sugar from food as energy for the body, yet glucose can't penetrate a cell's membrane without help from insulin, a hormone secreted from endocrine cells in the pancreas. To absorb the sugar, most cells have insulin "receptors" that bind the hormone as it flows through the bloodstream.

The researchers tested structural models using molecular-genetic methods to insert probes that, in turn, are activated by ultra-violet light into the receptor. The procedure creates highly detailed, three-dimensional images—which provided critical answers for Weiss, Lawrence and their colleagues.

"Both insulin and its receptor undergo rearrangement as they interact," Lawrence said. "A piece of insulin folds out and key pieces within the receptor move to engage the insulin hormone. You might call it a 'molecular handshake.'"

Understanding the bonding mechanics offers possible advances in how diabetes is treated, now usually with daily, multiple insulin injections. The discovery, Weiss said, suggests that targeting small molecules "to the signaling clefts" of the receptor may allow for alternatives to injections, as well as fewer doses per day.

Diabetes patients develop high blood sugar from inadequate insulin production, imperfect cellular to insulin, or both. The disease can cause wide-ranging complications, from heart disease, stroke and high blood pressure to blindness and kidney problems.

Diabetes affects nearly 26 million—or more than 8 percent—of the U.S. population and rising, according to the Centers for Disease Control.

### The research team also included:

from Case Western Reserve, Jonathan Whittaker, PhD, associate professor of biochemistry, and research assistant Linda Whittaker; from the Walter and Eliza Hall Institute of Medical Research, professor Colin Ward and Dr. John Menting; from the University of York, the late Guy G. Dodson, Professor and Head, Crystallography; and from the University of Chicago, Donald G. Steiner, N. Pritzker Distinguished Service Professor Emeritus in the Departments of Medicine and Biochemistry and Molecular Biology. About Case Western Reserve University School of Medicine Founded in 1843, Case Western Reserve University School of Medicine is the largest medical research institution in Ohio and is among the nation's top medical schools for research funding from the National Institutes of Health. The School of Medicine is recognized throughout the international medical community for outstanding achievements in teaching. The School's innovative and pioneering Western Reserve2 curriculum interweaves four themes--research and scholarship, clinical mastery, leadership, and civic professionalism--to prepare students for the practice of evidence-based medicine in the rapidly changing health care environment of the 21st century. Nine Nobel Laureates have been affiliated with the School of Medicine.

Annually, the School of Medicine trains more than 800 MD and MD/PhD students and ranks in the top 25 among U.S. research-oriented medical schools as designated by U.S. News & World Report's "Guide to Graduate Education."

The School of Medicine's primary affiliate is University Hospitals Case Medical Center and is additionally affiliated with MetroHealth Medical Center, the Louis Stokes Cleveland Department of Veterans Affairs Medical Center, and the Cleveland Clinic, with which it established the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University in 2002. http://casemed.case.edu