Just as paper must be folded into the correct shape to create origami sculptures, proteins in cells must form precise three-dimensional structures to function properly.
As prediabetes progresses to diabetes, this delicate process can begin to break down. When misfolded or defective proteins accumulate in cells, they create stress that damages pancreatic cells responsible for producing insulin.
Researchers from the Sanford Burnham Prebys Medical Discovery Institute and the University of Michigan reported new details about this process on June 1, 2026. Proceedings of the National Academy of Sciences. Their findings revealed how insulin-producing cells coordinate protein folding and what happens when that system is out of balance. This study suggests that strengthening the cellular machinery responsible for protein folding may help protect these cells from damage.
Why insulin-producing beta cells are overwhelmed
Beta cells in the pancreas monitor blood sugar levels. When glucose rises, your body responds by producing additional insulin, which helps bring blood sugar levels back into the normal range.
However, as diabetes progresses, beta cells have an increasingly difficult time meeting the body’s insulin needs.
Previous studies linked this decline to misfolding of proinsulin, the precursor protein that cells use to make insulin. Scientists already knew that during diabetes, improperly folded proinsulin accumulates and stresses the beta cells of the pancreas. What remained unclear was which additional proteins help control the process and how they work together.
“We knew that the system that prevents proinsulin from misfolding relies on chaperone proteins called binding immunoglobulin proteins and a number of cochaperones,” said Randall J. Kaufman, Ph.D., professor in the Sanford Burnham Prebys Center for Metabolic and Liver Diseases and senior corresponding author of the study.
“Our goal was to investigate how these partner proteins coordinate the folding of proinsulin and remove misfolding errors, as these steps are essential for the health of insulin-producing cells.”
Track important proteins within beta cells
To study the interactions of bound immunoglobulin proteins (BiP), researchers genetically modified mice so that BiP in beta cells carried additional amino acid chains called peptides.
The added marker consisted of three copies of an eight-amino acid sequence known as the 3xFLAG tag. This acted like a molecular beacon, allowing scientists to more easily detect and isolate BiP during experiments.
This result demonstrated a particularly important role for p58IPK, one of the cochaperone proteins of BiP.
When the researchers genetically removed p58IPK from two different cell lines, misfolded proinsulin accumulated at higher levels. Similar evidence was obtained in studies in mice engineered not to produce p58IPK. Their beta cells produced smaller amounts of proinsulin and insulin.
BiP and p58IPK need to work together
The team then restored p58IPK in one of the engineered cell lines. Reintroducing this protein improved the cells’ ability to fold and transport proinsulin, while reducing the accumulation of improperly folded copies.
However, p58IPK could not replace the central role of BiP. These improvements did not occur unless BiP was present.
The researchers next investigated whether increased BiP could compensate for the lack of p58IPK. When cells produced excess BiP but lacked p58IPK, there was only a small increase in proinsulin folding and movement out of the cell. The improvement was significantly greater when both proteins were present at normal levels.
“We found that BiP cannot do it alone to maintain proper folding of proinsulin, like a tennis player trying to play a doubles match,” said Insook Jang, Ph.D., a staff scientist in the Kaufman lab and first author of the manuscript.
The researchers also identified additional partner proteins involved in the folding and transport of proinsulin, as well as the detection and management of misfolded versions. Further research will be needed to determine exactly how these proteins influence insulin production and diabetes progression.
“Our study highlights that proinsulin folding is vulnerable to many of the same cellular stresses that cause beta-cell failure in type 2 diabetes,” Kaufman said.
Possibility of new diabetes treatment strategies
Most existing diabetes drugs do not directly correct protein folding problems that can contribute to beta-cell failure. Instead, they primarily control disease by helping tissues absorb more glucose or encouraging the pancreas to release more insulin.
Current treatments are not designed to improve 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 promising therapeutic strategies for early intervention to prevent or reduce damage to insulin-producing cells,” Professor Kaufman said.
Other authors include Alec Duffy and Pamela Itkin-Ansari of Sanford Burnham Prebys and Peter Irvan of the University of Michigan.
This research 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).
