Misfolded Insulin Proteins May Contribute to Diabetes Progression

Researchers have identified a protein problem within insulin-producing cells that could offer a new approach to slowing diabetes-related damage. Proteins inside cells must fold into precise three-dimensional structures to function correctly. This process can break down as prediabetes progresses toward diabetes.

Misfolded and defective proteins accumulate inside cells. This creates stress that can harm the pancreatic cells responsible for producing insulin. Scientists from Sanford Burnham Prebys Medical Discovery Institute and the University of Michigan published these findings on June 1, 2026. Their work appeared in the journal *Proceedings of the National Academy of Sciences*.

The study reveals how insulin-producing cells coordinate protein folding. It also shows what happens when this system becomes unbalanced. The research suggests that strengthening the cellular machinery responsible for protein folding could protect these cells from damage. Pancreatic beta cells monitor blood sugar levels. They produce additional insulin when glucose rises. This helps return blood sugar to a normal range.

As diabetes advances, beta cells struggle to meet the body's insulin demand. Previous research linked this decline to the misfolding of proinsulin. Proinsulin is the precursor protein cells use to make insulin. Improperly folded proinsulin accumulates during diabetes. This stresses pancreatic beta cells. The researchers aimed to understand how partner proteins coordinate proinsulin folding. They also wanted to know how these proteins remove misfolded mistakes. These steps are essential for the health of insulin-producing cells.

The team genetically modified mice to study the interactions of binding immunoglobulin protein (BiP). BiP is a chaperone protein. The results highlighted the important role of p58IPK. This is one of BiP's cochaperone proteins. When p58IPK was removed from cell lines, misfolded proinsulin accumulated at higher levels. Mice engineered without p58IPK produced smaller amounts of proinsulin and insulin. Restoring p58IPK improved the cells' ability to fold and transport proinsulin. This also reduced the accumulation of improperly folded copies. However, these improvements only occurred when BiP was also present.

Most current diabetes medications do not directly correct protein-folding problems. They primarily control the disease by helping tissues absorb more glucose. They also prompt the pancreas to release more insulin. No current therapies are designed to improve proinsulin folding. Such therapies could preserve the health and function of beta cells. Influencing the coordinated activity of BiP could be a promising treatment strategy. This could intervene early to prevent or reduce damage to insulin-producing cells. The National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Cancer Institute, and Breakthrough T1D supported the study. The research was led by Randal J. Kaufman and Insook Jang.