Mitochondrial protein misfolding found to kill pancreatic cells in type 2 diabetes

Aging-related diseases, including cancer, cardiovascular disorders and type 2 diabetes, are associated with defects in protein synthesis and folding.

Previous studies have shown that protein misfolding occurs in insulin-producing β-cells of patients with type 2 diabetes. These cells are found in pancreatic islets.

The resulting stress was believed to mainly occur within the endoplasmic reticulum, which is responsible for producing and distributing proteins to the cell.

Ultimately, the stress results in cell death.

In a study published in Nature Metabolism, researchers at the University of Michigan found that mitochondria also accumulate misfolded proteins, which kills β-cells.

Reversing this process could help treat type 2 diabetes.

Previously, scientists had observed that two proteins-insulin and amylin-were frequently misfolded in patients with type 2 diabetes.

Both are produced by the β-cells in the pancreas.

Amylin promotes the feeling of fullness after a meal, while insulin helps lower blood glucose levels by helping cells bring in sugar. 

Amylin can form amyloid aggregates in diabetic β-cells that are similar to the amyloid plaques found in the brain in Alzheimer's disease.

These two proteins were the sole focus in diabetic islet cells. We wanted to take an unbiased approach and find all the misfolded proteins in these cells."

Scott Soleimanpour, M.D., Larry Soderquist Professor of Diabetes Research and director of the Michigan Diabetes Research Center

The team compared islet cells from donors with type 2 diabetes to healthy donor cells and found that misfolded proteins build up in the mitochondria at higher levels than elsewhere in the islet cells.

The group had previously discovered that mitochondrial damage affects β-cells, but the underlying mechanisms were unclear.

By sequencing the genes and proteins in healthy and diabetic β-cells, the researchers found that the defense systems that respond to misfolded mitochondrial proteins do not turn on during type 2 diabetes.

Specifically, LONP1, a protein responsible for getting rid of damaged or misfolded proteins, was lower in cells from donors with diabetes.

"Although LONP1 has some associations with rare mitochondrial diseases, this is the first study to show that it has a role in type 2 diabetes," Soleimanpour said.

The team confirmed their findings by comparing mice that had the LONP1 system with those that did not.

Mice lacking LONP1 had higher glucose levels and fewer β-cells.

These defects were reversed when LONP1 was reintroduced into the mice, suggesting that targeting this system could be a new avenue for therapy.

"It is clear that people with type 2 diabetes have problems with eliminating misfolded proteins," Soleimanpour said.

"The next step is to find drugs that can help refold or eliminate these proteins."

The group is also interested in understanding the timeline of how type 2 diabetes develops.

The condition is often found in adults and Soleimanpour hypothesizes that the misfolded proteins might accumulate over time and eventually overwhelm the β-cells, leading to disease.

Early intervention, therefore, could be key.