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 imageswhich 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
|Contact: Jessica Studeny|
Case Western Reserve University