In the new paper, published online before print publication in the Proceedings of the National Academy of Sciences, the team details its findings and proposes that proinsulin 'blobs' might lead to beta cell dysfunction and death, which in turn can lead to the start, or progression, of diabetes.
Senior author Peter Arvan, M.D., Ph.D., says, "We believe that in the insulin production factory, misfolded copies of newly-made proinsulin can gum up the works in several ways. This paper shows that one of the first things that can happen is that misfolded proinsulin can stick to other proinsulin in the very first stages of production within the endoplasmic reticulum, the area of the cell where proteins are made.
Arvan, who is chief of Metabolism, Endocrinology and Diabetes at the U-M Medical School and director of the Michigan Comprehensive Diabetes Center, explains that this chain reaction can start with just a few misfolded proinsulin molecules. It can then lead to beta cell shutdown and an insulin shortage. The misfolded proinsulin does not get exported from the factory, and neither does the normally folded proinsulin made after it, he says. Pretty soon, pancreatic beta cells are running out of insulin to secrete in response to the customer's demand for the product that is, an increase in blood glucose. And that is a key hallmark of diabetes.
Arvan, who is the William and Delores Brehm Professor of Type 1 Diabetes Research, and first author Ming Liu, M.D., Ph.D., led the research team in developing the techniques needed to visualize proinsulin production and then study problems with the process by following misfolded molecules through the production pathway.
First, the team engineered the gene for human proinsulin to insert a tag that makes the protein fluorescent, but does not interfere with the production, function or secretion o
|Contact: Kara Gavin|
University of Michigan Health System