Scientists at Sanford Burnham Prebys Medical Discovery Institute and the University of Michigan published findings on June 1 in the Proceedings of the National Academy of Sciences that reveal new insights into how insulin-producing cells manage protein folding, and how this system can be disrupted. The study suggests that enhancing these protein-folding processes may help protect insulin-producing cells from harm.
Beta cells in the pancreas detect changes in blood sugar and produce more insulin as sugar levels rise to restore normal blood glucose. As diabetes progresses, beta cells struggle to meet the demand for insulin. Previous research has implicated misfolding of proinsulin, a precursor molecule necessary for insulin production, but it was unclear which other proteins were involved or how they interacted.
"Our goal was to examine how these partner proteins coordinate proinsulin folding and remove any misfolded mistakes, as these steps are essential for the health of insulin-producing cells," said Insook Jang, PhD, a staff scientist in the Kaufman lab and lead author of the manuscript.
The research team genetically modified mice so that their beta cell binding immunoglobulin protein (BiP) included an extra peptide tag. This allowed BiP to be easily detected during experiments. Their results highlighted an important role for one of BiP's cochaperone proteins called p58IPK. Removing p58IPK led to increased accumulation of misfolded proinsulin in two different cell lines. Mice genetically altered not to produce p58IPK had beta cells that produced less proinsulin and insulin.
Reintroducing p58IPK improved folding and trafficking of proinsulin in altered cell lines and prevented buildup of misfolded copies; however, these improvements did not occur unless BiP was present. Overexpressing BiP alone only modestly improved folding when p58IPK was absent; both partners at normal levels yielded better results.
"Like a single tennis player trying to play a doubles match, we found that BiP cannot just go it alone in maintaining the proper folding of proinsulin," said Jang. The investigators also identified other partner proteins involved in this process but noted further research is needed to understand their roles.
