Much like paper must be folded into the correct shape to create an origami sculpture, proteins inside cells must form precise three-dimensional structures before they can function properly.
As prediabetes advances toward diabetes, this delicate process can begin to break down. Misfolded and defective proteins accumulate inside cells, creating stress that can damage the pancreatic cells responsible for producing insulin.
Researchers from Sanford Burnham Prebys Medical Discovery Institute and the University of Michigan reported new details about this process on June 1, 2026, in the Proceedings of the National Academy of Sciences. Their findings reveal how insulin-producing cells coordinate protein folding and what happens when that system falls out of balance. The work suggests that strengthening the cellular machinery responsible for folding proteins could help protect these cells from damage.
Why Insulin-Producing Beta Cells Become Overwhelmed
Beta cells in the pancreas monitor blood sugar levels. When glucose rises, they respond by producing additional insulin, which helps return blood sugar to a normal range.
As diabetes progresses, however, beta cells increasingly struggle to meet the body’s demand for insulin.
Previous research has linked this decline to the misfolding of proinsulin, the precursor protein cells use to make insulin. Scientists already knew that improperly folded proinsulin accumulates during diabetes and places stress on pancreatic beta cells. What remained uncertain was which additional proteins help control the process and how they work together.
“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.”
Tracking a Key Protein Inside Beta Cells
To study the interactions of binding immunoglobulin protein (BiP), the researchers genetically modified mice so that BiP in their beta cells carried an additional amino acid chain called a peptide.
The added marker consisted of three copies of an eight-amino-acid sequence known as a 3xFLAG-tag. It acted like a molecular beacon, allowing scientists to detect and isolate BiP more easily during experiments.
The results pointed to an especially important role for p58IPK, one of BiP’s cochaperone proteins.
When researchers genetically removed p58IPK from two different cell lines, misfolded proinsulin accumulated at higher levels. Tests in mice engineered not to produce p58IPK produced similar evidence. Their beta cells made smaller amounts of both proinsulin and insulin.
BiP and p58IPK Must Work Together
The team then restored p58IPK in one of the modified cell lines. Reintroducing the protein improved the cells’ ability to fold and transport proinsulin while reducing the accumulation of improperly folded copies.
However, p58IPK could not replace BiP’s central role. Those improvements did not occur unless BiP was also present.
The researchers next investigated whether increasing BiP could compensate for the absence of p58IPK. When cells produced extra BiP but lacked p58IPK, they showed only modest gains in proinsulin folding and its movement out of the cell. The improvements were substantially greater when both proteins were present at normal levels.
“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 identified additional partner proteins involved in folding and transporting proinsulin, as well as detecting and managing misfolded versions. More research will be needed to determine precisely how these proteins influence insulin production and the 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.
A Potential New Diabetes Treatment Strategy
Most existing diabetes medications do not directly correct the protein-folding problems that may contribute to beta cell failure. Instead, they primarily control the disease by helping tissues absorb more glucose or prompting the pancreas to release more insulin.
No current therapies are designed to improve proinsulin folding in order to preserve the health and function of beta cells.
“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 and 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).
