Origami masters turn simple sheets of paper into ornate sculptures. In the origami of life, our cells must fold proteins into specific three-dimensional shapes before they can carry out their biological jobs.
This folding process goes awry as prediabetes progresses into diabetes. Misfolded and dysfunctional proteins then build up in cells like discarded wads of paper in an origami student's recycling bin. This abnormal accumulation stresses out the cells responsible for producing insulin.
Scientists at Sanford Burnham Prebys Medical Discovery Institute and the University of Michigan published findings June 1, 2026, in the Proceedings of the National Academy of Sciences revealing new insights into how insulin-producing cells manage protein folding—and how this system can be thrown out of balance. The results suggest that giving these protein-folding processes a boost may help prevent harm to insulin-producing cells.
Beta cells in the pancreas detect changes in blood sugar. They produce more insulin hormone as sugar levels go up to restore a normal amount of blood glucose. As diabetes progresses, beta cells are unable to keep up with the demand for insulin.
Research has implicated the misfolding of the protein proinsulin, a precursor molecule required for insulin production. While it had been shown that misfolding of proinsulin occurs during diabetes and stresses beta cells in the pancreas, it was unclear which other proteins were involved and how they interacted.
"We knew that the system for preventing proinsulin misfolding depended on a chaperone protein called binding immunoglobulin protein and a number of cochaperones," said Randal J. Kaufman, PhD , a professor in the Center for Metabolic and Liver Diseases at Sanford Burnham Prebys and senior and corresponding author of the study.
"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."
To enable their studies of binding immunoglobulin protein (BiP) interactions, the research team genetically modified mice so that the BiP in their beta cells featured an extra chain of amino acids known as a peptide. This addition—three sets of an eight-amino-acid sequence called a 3xFLAG-tag—served as a beacon enabling BiP to be easily detected and isolated during experiments.
The research team's results highlighted an important role for one of BiP's cochaperone proteins called p58IPK. In two different cell lines, genetically removing p58IPK led to an increased accumulation of misfolded proinsulin. The scientists then conducted tests with mice genetically altered to not produce p58IPK and found that their beta cells produced less proinsulin and insulin.
Upon returning to one of the cell lines altered to be unable to produce p58IPK, the researchers demonstrated that reintroducing p58IPK enhanced the cells' ability to fold and traffic proinsulin and prevented the buildup of misfolded copies. The investigators also showed that p58IPK is unable to take over BiP's leading role in proinsulin folding, as none of these changes occur unless BiP is present.
Next, the scientists tested whether extra BiP could cover for a lack of its partner protein. When BiP was overexpressed and p58IPK was absent, cells experienced only modest improvements in the folding of proinsulin and shipping it out of the cell. In tests where both partners were expressed at normal levels, the protein folding and trafficking improvements were markedly better.
"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 Insook Jang, PhD, a staff scientist in the Kaufman lab and lead author of the manuscript.
The investigators also found other partner proteins that play a role in the folding and shipping of proinsulin and quality control of misfolded versions. Further research is needed to understand what parts they play in the production of insulin and progression of diabetes.
"Our studies highlight that proinsulin folding is vulnerable to many of the same cellular stresses that cause beta cell failure in type 2 diabetes," said Kaufman.
Current treatments don't address this root cause. Instead, most current medications manage symptoms by helping tissues absorb more sugar or increasing insulin secretion. There are no therapies that promote proper proinsulin folding to maintain beta cell health and function.
"If we can learn how to influence the coordinated activity of BiP as a key regulator of proinsulin folding, we may find a promising treatment strategy for intervening early to prevent or reduce damage to insulin-producing cells," said Kaufman.
Additional authors include:
- Alec Duffey and Pamela Itkin-Ansari at Sanford Burnham Prebys
- Peter Arvan at the University of Michigan
The study was supported by the National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Cancer Institute and Breakthrough T1D (formerly JDRF).
The study's DOI is 10.1073/pnas.2533617123 .
