Misfolded insulin may be quietly driving diabetes
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- Researchers from Sanford Burnham Prebys and the University of Michigan reported in the Proceedings of the National Academy of Sciences on June 1, 2026, that pancreatic beta cells rely on the chaperone protein BiP and its cochaperone p58IPK to fold proinsulin correctly before it becomes functional insulin.
- Genetically removing p58IPK from two different cell lines and from mice caused misfolded proinsulin to accumulate and led beta cells to produce smaller amounts of both proinsulin and insulin.
- Randal J. Kaufman, senior author and professor in Sanford Burnham Prebys' Center for Metabolic and Liver Diseases, said BiP "cannot just go it alone" — reintroducing p58IPK only improved proinsulin folding and transport when BiP was also present.
- Lead author Insook Jang, a staff scientist in the Kaufman lab, compared the BiP-p58IPK dynamic to "a single tennis player trying to play a doubles match," and adding extra BiP without p58IPK produced only modest gains.
- Existing diabetes medications primarily help tissues absorb more glucose or prompt the pancreas to release more insulin; none are designed to correct proinsulin-folding problems that contribute to beta cell failure.
- 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).
- Additional partner proteins involved in folding, transporting, and clearing misfolded proinsulin were identified, though the researchers said more work is needed to determine how precisely they influence insulin production and disease progression.
Why it matters: Every existing diabetes drug on the market either improves glucose uptake or stimulates insulin release — none are designed to fix the underlying beta cell decline. If researchers can find a way to strengthen the BiP-p58IPK folding partnership, that opens the first treatment pathway aimed at preserving insulin-producing cells themselves rather than just managing blood sugar around the damage.
