Blocking cellular stress pathway may help preserve insulin-producing cells

Researchers at Weill Cornell Medicine have identified a molecular pathway that contributes to the death of insulin-producing beta cells in the pancreas.

Experiments with preclinical models and human pancreatic cells found that blocking certain proteins in the pathway helped protect beta cells from excessive cellular stress. The discovery, recently published in the Journal of Clinical Investigation, suggests a new strategy to preserve the cells that regulate blood sugar and potentially treat Type 2 diabetes.

Diabetes is a complex, chronic disease with two forms. In Type 1, the immune system attacks and destroys beta cells, leaving the body with little or no insulin. In Type 2, the body's cells become less responsive to insulin, so beta cells must churn out more of the hormone to keep blood sugar in check. Over time, beta cells can become dysfunctional, and some are lost through cell death, further compromising insulin production.

"The goal of this study was to understand the molecular pathways that cause overworked beta cells to die," said senior author Dr. Laura Alonso, chief of the division of endocrinology, diabetes and metabolism, director of the Weill Center for Metabolic Health and the E. Hugh Luckey Distinguished Professor in Medicine at Weill Cornell.

Stress response in overdrive

The researchers suspected the loss of overtaxed beta cells might involve the unfolded protein response (UPR) - a cellular system that helps cells cope when proteins accumulate faster than they can be properly processed. The UPR pathway temporarily adjusts protein production and triggers molecular chaperones, which help proteins fold correctly.

With collaborator Dr. Amy Lee of the University of Southern California, the team created mice whose beta cells lacked GRP78, a protein that keeps the UPR pathways in check under normal conditions. The effect was dramatic. Without GRP78, the beta cells' stress response kicks into overdrive and cells start to die. "By two weeks of age, the beta cells were starting to be lost, and by four weeks after birth, the mice were diabetic," said Alonso.

Although the UPR is meant to help beta cells produce and process insulin, keeping the pathway continuously activated is ultimately fatal.

Inhibitors to the rescue

With their sights set on the UPR, the researchers catalogued the genes and proteins with altered levels when GRP78 is missing. They found three proteins were significantly activated: IRE1α, JNK and p53. The findings suggest that excessive activation of the stress response triggered a signaling cascade in which IRE1α activates JNK, which in turn leads to p53 activation, helping trigger beta cell death.

Treating mice that lack GRP78 with a JNK inhibitor significantly reduced beta cell death. The treatment also protected beta cells in a second mouse model of diabetes, in which a mutation in the insulin gene causes misfolded insulin to accumulate and stress the cells.

The researchers - including first author Rohit Sharma, an assistant professor of molecular biology in medicine at Weill Cornell - saw a similar protective effect when treating donated human pancreatic islet cells. When GRP78 levels in these cells were reduced, inhibiting either JNK or p53 helped prevent human beta cell death.

"Preserving beta cell mass is a really important goal in diabetes research," said Alonso. "If we could safely administer a JNK or p53 inhibitor, we might be able to preserve the ability of beta cells to produce insulin and stave off diabetes."

Further research will be necessary to find a suitable JNK inhibitor for clinical use since the one used in the experiments acts on multiple forms of JNK and can damage kidney function.

"I would love to have a new drug to help preserve beta cells in my patients today," said Alonso, who is also an endocrinologist at NewYork-Presbyterian/Weill Cornell Medical Center. But for now, she and her team will continue pursuing the molecular causes of beta cell death. Her lab plans to test whether JNK inhibition protects beta cells in other models of diabetes, such as Type 2 diabetes brought on by a high-fat diet. She would also like to explore if a combination of JNK and p53 inhibitors can better minimize cell death and normalize blood sugar.

This study was funded by the National Institutes of Health.

Many Weill Cornell Medicine physicians and scientists maintain relationships and collaborate with external organizations to foster scientific innovation and provide expert guidance. The institution makes these disclosures public to ensure transparency. For this information, please see the profile for Dr. Laura Alonso.

Karen Hopkin is a freelance writer for Weill Cornell Medicine.