Published June 1, 2026 in Proceedings of the National Academy of Sciences by researchers at Sanford Burnham Prebys Medical Discovery Institute and the University of Michigan. Senior author: Randal J. Kaufman, PhD.
The Core Problem
In healthy beta cells, proteins must fold into precise 3D shapes to work — like origami. As prediabetes progresses to diabetes, proinsulin, the precursor to insulin, often misfolds. Misfolded proinsulin builds up, stresses beta cells, and contributes to their failure to meet insulin demand.
What They Studied
The team investigated how beta cells manage proinsulin folding, focusing on the chaperone protein binding immunoglobulin protein (BiP) and its partner proteins. To track BiP, they engineered mice with a 3xFLAG-tagged version of BiP in beta cells.
Key Findings
- p58IPK is a critical helper: Removing p58IPK, a BiP cochaperone, caused misfolded proinsulin to accumulate in cell lines. Mice lacking p58IPK made less proinsulin and insulin.
- p58IPK can’t replace BiP, but helps it: Reintroducing p58IPK restored proper proinsulin folding and trafficking, but only when BiP was also present. Overexpressing BiP without p58IPK gave only modest improvements.
- It’s a team effort: “Like a single tennis player trying to play a doubles match, BiP cannot just go it alone,” said lead author Insook Jang, PhD.
- Other players involved: Additional partner proteins also help with proinsulin folding and quality control, but their exact roles need more study.
Why It Matters
Current diabetes drugs mainly help tissues absorb sugar or boost insulin release — they don’t fix the root problem of beta cell stress from misfolded proteins. This work shows proinsulin folding is vulnerable to the same cellular stresses that drive type 2 diabetes.
If researchers can figure out how to support BiP and its cochaperones like p58IPK, they may develop treatments that promote proper proinsulin folding, protect beta cells, and intervene earlier in diabetes progression.