Building on work published earlier this year, U-M researchers have furthered their understanding of what goes awry at the cellular level in Type 2 diabetes.

Their results, described in two papers published online Nov. 7 in the journal Biochemistry, reveal why a protein known as Islet Amyloid Polypeptide Protein (IAPP), or amylin, kills insulin-producing cells in the pancreas.

By comparing the human form of IAPP to the rat version, which does not cause cell death, Associate Professor of Chemistry and Biophysics Ayyalusamy Ramamoorthy and co-workers showed that a difference of a single amino acid (protein building block) at a position designated as residue 18 accounts for the difference in toxicity. They also elucidated the structures of human and rat IAPP and then tested the ability of the two proteins to damage membranes (the process by which human IAPP kills insulin-producing cells).

Their results suggest that the reason rat IAPP is non-toxic, while the human version is a cell killer, has to do with differences in how the two proteins fold, which in turn is dictated by the particular amino acid at residue 18. The new work also confirms their previous finding (published in the Journal of the American Chemical Society) that human IAPP does not form fibrils to kill cells, as amyloid peptides in general have been thought to do.