Proteins have a job to do, and for insulin-producing cells, that job starts with folding. Before insulin can help regulate blood sugar, proinsulin must twist into a specific three-dimensional shape.
It’s a delicate process.
As prediabetes creeps toward type 2 diabetes, that folding machinery breaks down. Defective proteins pile up. Stress builds. The insulin-producing beta cells buckle.
A new study published in the Proceedings of the National Academy of Sciences by researchers at Sanford Burnham Prebys and the University of Michigan maps this failure. They found that strengthening the cell’s protein-folding system could protect these cells. It might even slow the disease.
The Misfolding Mechanism in Beta Cells
Pancreatic beta cells watch glucose levels like hawks. Sugar rises. Insulin is released.
This works until it doesn’t.
In type 2 diabetes, beta cells can’t keep up. They stop producing enough insulin. Why? Because proinsulin starts misfolding. It accumulates. It stresses the cell.
Previous studies knew proinsulin misfolding was a problem. They didn’t know how the cellular machinery handled it. Or which proteins were actually coordinating the folding and cleanup.
“We knew that the system for preventing prosign misfolding depended on a chopper protein called binding immunoglobulin protein (Bi) and a number of cochaperons,” said Randal J. Kaufmann, PhD. He’s a professor at Sanford Burnham Prebys.
The goal was simple: see how these partner proteins work together. Keep the mistakes out. Save the cell.
Tagging BiP to Find the Partners
You can’t study what you can’t see.
So, the researchers modified mice. They gave their beta cells’ BiP protein a tag. Specifically, three copies of an eight-amino-acid chain. A 3xFLAG tag.
This made BiP easy to isolate. Easy to track.
Then they looked at who BiP talked to. Who did it partner with to fold proinsulin?
The experiments pinpointed a key player: p58IPK. It’s one of the cochaperone proteins. It hangs out with BiP.
Why p58IPK is Essential for Insulin Production
When the researchers genetically removed p58IPK from cell lines, things got messy.
Misfolded proinsulin accumulated. Lots of it.
Mice without p58IPK produced less proinsulin. And significantly less insulin.
When they put p58IPK back in one cell line, things improved. The cells folded proinsulin better. Transported it out of the cell more effectively. Less junk piled up.
But there was a catch.
p58IPK couldn’t replace BiP. It wasn’t the main regulator. If BiP was missing, nothing improved.
Can Extra BiP Compensate for Missing p58IPK?
That’s the question.
Cells with extra BiP but zero p58IPK showed slight improvements. Barely anything.
Cells with normal levels of both? Big improvements. Much better folding. Better transport.
“Like a single tennis player trying a doubles match, BiP cannot go it alone,” said lead author Insook Jang.
They aren’t meant to work solo. They need each other.
The team identified more partner proteins involved in folding and defect detection. We still don’t know every role each one plays. But the core relationship between BiP and p58IPK seems critical for proinsulin folding.
Why Current Treatments Miss the Mark
Most diabetes meds don’t fix the root cause.
They boost insulin secretion. They help tissues absorb sugar. They manage symptoms.
They do not target protein folding.
No current therapy improves proinsulin folding. No therapy actively preserves beta cell health in that specific way.
“If we can learn how to influence coordinated BiP activity… we may find a promising treatment for early intervention,” Kaufman said.
Preventing the damage before the cells fail. That’s the hope.
What This Means for Diabetes Management
Proinsulin folding is vulnerable.
It fails under the same cellular stress that causes beta cell failure in type 2 diabetics.
Understanding this vulnerability opens new doors. It highlights specific molecular targets. BiP and p58IPK are among them.
The study was supported by the NIH, NIDDK, NCI, and Breakthrough T1D.
Reference: “Coordinated expression and assembly of Bip, p58IPK, ER chaperone complexes maximize prosign folding in pancreatic beta cells” by Insook J, Duffey A, Itkin-Ansari P, Arvan P, Kaufman RJ. 1 June 2025, PNAS.
DOI: 10.073/pnas.233361713
We still have a long way to go before these findings become pills in a bottle. But knowing the failure mode is half the battle.
The question is: will we act on it?
