Misfolded Molecules: Key to Diabetes?

University of Michigan scientists may have found a new culprit in diabetes: improperly folded molecules of proinsulin, the precursor molecule for insulin.

Peter Arvan Photo: Paul Jaronski

Too many misfolded molecules can clog a cell’s internal waste disposal system, putting stress on cells and even killing them. If this happens with proinsulin in the pancreatic beta cells that produce insulin, it could be an important factor leading to the development of diabetes, according to Peter Arvan, M.D., Ph.D., the William K. and Delores S. Brehm Professor of Type 1 Diabetes Research.

Pancreatic beta cells make insulin by folding long molecules of proinsulin into a specific shape, so chemical bonds can form, and then chopping them up to make active insulin. If the folding process is defective, the cells must work extra hard to generate additional insulin needed to regulate the amount of glucose in the bloodstream.

According to Arvan, this continual stress on beta cells could explain why people with diabetes make less insulin and why the cells eventually die. Destruction of pancreatic beta cells is the hallmark of both type 1 (juvenile) and type 2 (adult) diabetes.

In a study published in the Journal of Biological Chemistry, Arvan’s research team found that normal rat and human beta cells produce misfolded, as well as normally folded, proinsulin. But mice with gene mutations that made them prone to diabetes and mice that produced mutant forms of proinsulin had much higher levels of misfolded molecules. Misfolded molecules were much less likely to leave the cell.

“We’ve shown that misfolded forms of proinsulin are made under normal conditions, and in higher abundance under diabetic conditions,” Arvan says. “The next step is to see how they affect cell function.”

—KG

Read an expanded version of the story:
www.med.umich.edu/opm/newspage/2005/insulin.htm

For more information on the Brehm Center and U-M diabetes research:
www.med.umich.edu/brehm