Soothing Stressed Protein-Folding in Beta Cells Shows Promise in Treating Diabetes
By using a stem cell model to closely examine a rare disorder, Wolfram syndrome, scientists have shed light on more common forms of diabetes, which share a key feature of Wolfram syndrome—beta-cell dysfunction. The model has allowed the scientists to relate beta-cell dysfunction to endoplasmic reticulum (ER) stress. In addition, they found that 4-phenyl butyric acid, a chemical that relieves ER stress, prevents the cells from failing, suggesting a target for clinical intervention.
The scientists, affiliated with the New York Stem Cell Foundation (NYSCF) Research Institute and Columbia University, published their findings November 13 in Diabetes, in an article entitled “Beta cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome.”
In their paper, the authors describe how clinicians from Columbia’s Naomi Berrie Diabetes Center recruited Wolfram syndrome patients to donate skin samples, as well as how researchers from the NYSCF reprogrammed cells from these samples to obtain induced pluripotent stem (iPS) cells. (These researchers used an iPS cell line generated from a healthy individual as a normal control.)
Then the NYSCF researchers undertook the delicate task of differentiating the iPS cells from the Wolfram subjects and the controls into beta cells. After implanting both Wolfram and control iPS cell-derived beta cells under the kidney capsule of immunocompromised mice, the NYSCF scientists confirmed that the beta cells from the Wolfram subjects produced less insulin in the culture dish and secreted less insulin into the bloodstream of the mice when they were challenged with high blood-sugar levels.
Further experiments with these beta cells revealed “increased levels of ER stress molecules, and decreased insulin content,” wrote the authors of the Diabetes paper. “Upon exposure to experimental ER stress, Wolfram beta cells showed impaired insulin processing and failed to increase insulin secretion in response to glucose and other secretagogues.”
An even more interesting observation was that 4-phenyl butyric acid, a chemical protein folding and trafficking chaperone, restored normal insulin synthesis and the ability to upregulate insulin secretion.
Direct evidence in mice, as well as circumstantial evidence in humans with both type 1 and type 2 diabetes, highlights the role of the ER stress response mechanism in the survival of insulin-producing beta cells. The ER stress response mechanisms oppose both the stress of immune assault in type 1 diabetes and the metabolic stress of high blood glucose in both types of diabetes. When the ER stress response fails cell death occurs, potentially reducing the number of insulin-producing cells.
“This report highlights again the utility of close examination of rare human disorders as a path to elucidating more common ones,” said study co-author Rudolph L. Leibel, M.D., the Christopher J. Murphy Professor of Diabetes Research and co-director of the Naomi Berrie Diabetes Center. “Our ability to create functional insulin-producing cells using stem cell techniques on skin cells from patients with Wolfram’s syndrome has helped to uncover the role of ER stress in the pathogenesis of diabetes. The use of drugs that reduce such stress may prove useful in the prevention and treatment of diabetes.”