Research shows that proteins accumulated in mitochondria in patients with type 2 diabetes

Aging-related diseases such as 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 beta cells in type 2 diabetes patients. These cells are found in the islets.

The resulting stress was thought to occur primarily within the endoplasmic reticulum. This is responsible for the production and distribution of proteins in cells.

Ultimately, stress leads to cell death.

In a study published in Natural Metabolism, researchers at the University of Michigan discovered that mitochondria also accumulate misfolded proteins that kill beta cells.

Reversing this process can help treat type 2 diabetes.

Previously, scientists observed that insulin and amylin proteins frequently misfolded in type 2 diabetes patients.

Both are produced by pancreatic beta cells.

Amylin promotes a sense of fulfillment after a meal, while insulin helps lower blood sugar levels by helping cells bring in sugar.

Amylin is able to form amyloid aggregates in diabetic beta cells similar to the amyloid plaque found in the Alzheimer's brain.

“These two proteins were the sole focus on islet cells in diabetes,” said Scott Soleimanpool, MD, professor of diabetes research and director of the Michigan Diabetes Research Center.

“We wanted to take a fair approach and find all the misfolded proteins in these cells.”

-SCOTT SOLEIMANPOUR, MD

By sequencing genes and proteins for healthy and diabetic beta cells, the researchers found that defense systems that respond to misfolded mitochondrial proteins during type 2 diabetes were not turned on.

Specifically, LONP1, a protein involved in removing damaged or misfolded proteins, was low in cells from diabetic donors.

“LONP1 has a rare association with mitochondrial diseases, which is the first study to demonstrate a role in type 2 diabetes,” says Soleimanpour.

The team confirmed the findings by comparing mice that had and did not have the LONP1 system.

Mice lacking LONP1 had higher glucose levels and fewer beta cells.

These defects are reversed when LONP1 is reintroduced into mice, suggesting that targeting this system could be a new tool for treatment.

“It's clear that people with type 2 diabetes have problems eliminating misfolded proteins,” says Soleimanpour.

“The next step is to find a drug that will help you repeat or eliminate these proteins.”

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

This condition is often seen in adults, and Soleiman pool hypothesizes that folded proteins accumulate over time, ultimately overwhelming beta cells, leading to disease.

Therefore, early intervention is important.

Additional authors: Jinlee, Yammyden, Marie Gusser, Geeziz, Emma C. Rek, Emily M. Walker, Vaibahushidarara, Drell Harbor, Mabel B. Pasmui, Chunsiksin, Kushdeep Bandesh, Eftymiosmotakis, Betakis, siddhi nargund, Roman Alexey I. Nesvizhskii, Michael L. Stitzel, David C. Chan, and Guy A. Rutter.