Just as paper must be folded into the right shape to create an origami sculpture, proteins inside cells must form precise three-dimensional structures before they can function properly.
As prediabetes progresses toward type 2 diabetes, this highly regulated process can begin to fail. Misfolded and defective proteins build up inside cells, triggering stress that can damage pancreatic beta cells, the insulin-producing cells responsible for regulating blood sugar.
Researchers at Sanford Burnham Prebys Medical Discovery Institute and the University of Michigan reported new insights into this process on June 1, 2026, in the Proceedings of the National Academy of Sciences. Their study explains how insulin-producing beta cells coordinate proinsulin folding and what happens when this cellular quality-control system becomes disrupted. The findings suggest that strengthening the proteins responsible for folding and managing proinsulin could help protect beta cells from diabetes-related damage.
Why Insulin-Producing Beta Cells Become Overwhelmed
Pancreatic beta cells monitor blood glucose levels. When blood sugar rises, they respond by producing more insulin, the hormone that helps move glucose from the bloodstream into tissues and restore healthy blood sugar levels.
As diabetes develops, beta cells increasingly struggle to produce enough insulin to meet the body’s demands.
Earlier studies have connected this decline to the misfolding of proinsulin, the precursor protein that beta cells use to produce insulin. Scientists knew that misfolded proinsulin accumulates during diabetes and places stress on pancreatic beta cells. However, it remained unclear which additional proteins regulate proinsulin folding and how these proteins 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 misfolded proteins, because both processes are essential for maintaining the health of insulin-producing beta cells.”
Tracking a Key Protein Inside Pancreatic Beta Cells
To investigate how binding immunoglobulin protein (BiP) interacts with other proteins, researchers genetically modified mice so that BiP in their pancreatic beta cells carried an additional amino acid sequence called a peptide tag.
The marker contained three copies of an eight-amino-acid sequence known as a 3xFLAG tag. This molecular beacon enabled the researchers to detect, track and isolate BiP more easily during laboratory experiments.
The findings highlighted an especially important role for p58IPK, a cochaperone protein that works with BiP to support protein folding.
When the researchers genetically removed p58IPK from two different cell lines, misfolded proinsulin accumulated at higher levels. Experiments in mice engineered to lack p58IPK produced similar results. Their pancreatic beta cells made lower amounts of both proinsulin and insulin.
BiP and p58IPK Must Work Together
The researchers then restored p58IPK in one of the modified cell lines. Reintroducing the cochaperone improved the cells’ ability to fold and transport proinsulin while reducing the buildup of misfolded protein.
However, p58IPK could not perform BiP’s central function on its own. The improvements occurred only when BiP was also present.
The team next examined whether increasing BiP levels could compensate for the absence of p58IPK. Cells that produced extra BiP without p58IPK showed only modest improvements in proinsulin folding and transport. The strongest benefits occurred 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 researchers also identified other partner proteins that help fold and transport proinsulin, detect misfolded versions and manage damaged proteins. Additional studies are needed to determine exactly how these proteins affect insulin production and contribute to 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 Treatment Strategy for Diabetes
Most current diabetes medications do not directly address the protein-folding problems that may contribute to pancreatic beta cell failure. Instead, these treatments primarily lower blood sugar by helping tissues absorb more glucose or encouraging the pancreas to release additional insulin.
No approved therapies are specifically designed to improve proinsulin folding and preserve the health and function of insulin-producing 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).
Source: www.sciencedaily.com