How potential treatments for Alzheimer’s disease also work for type 2 diabetes

Of the 38 million Americans with diabetes, at least 90% have type 2 diabetes, according to the Centers for Disease Control and Prevention. Type 2 diabetes develops over time and is characterized by the loss of cells in the pancreas that make insulin, a hormone that helps the body manage sugar levels.

These cells produce another protein called islet amyloid polypeptide (IAPP). It is found to clump together in many people with type 2 diabetes. The formation of IAPP clusters is similar to how proteins in the brains of Alzheimer’s patients stick together and eventually form the characteristic plaques associated with the disease.

Researchers at the University of Washington demonstrated further similarities between the IAPP cluster and the Alzheimer’s disease cluster. The research team previously showed that a synthetic peptide could block the formation of small toxic Alzheimer’s disease protein clusters. Now, recently published papers in protein science, The researchers used a similar peptide to block the formation of IAPP clusters.

UW News spoke with co-senior author Valerie Daggett, UW professor of bioengineering and faculty member in the UW Institute for Molecular Engineering Sciences, to discuss protein aggregation and how these synthetic peptides work. I asked for details.

Alzheimer’s disease and type 2 diabetes are types of amyloid diseases characterized by clusters of proteins. what’s happening?

There are more than 50 of these amyloid diseases, and each begins in a benign state where the protein is biologically active. But then the proteins begin to change structure and start clumping together. These aggregates can be of various sizes. They have different underlying structures and may have different effects on surrounding cells.

Early in the process, small toxic clusters develop that cause all sorts of problems. This leads to a very complex disease because many other things go wrong in response to these toxic clusters. Over time, these clusters combine to form nontoxic structures, or longer chains, and eventually large deposits, such as Alzheimer’s disease plaques.

Many people know that protein aggregation is involved in neurodegenerative diseases such as Alzheimer’s disease. Could you please explain what’s going on here?

In Alzheimer’s disease, these small clusters of toxic proteins run around the brain and attack neurons, and over time enough damage is done that symptoms begin to appear. By the time these clusters combine to form a nontoxic plaque, much damage has already occurred. It would be the same as trying to treat stage 4 cancer. That’s why I want to participate early.

What happens in type 2 diabetes?

It’s similar, except it happens in the pancreas instead of the brain. In healthy people, cells in the pancreas called beta cells secrete IAPP along with insulin. The normally active form of IAPP helps maintain metabolism. But when IAPP changes shape, it starts forming these toxic clusters, which then start attacking beta cells. And these clusters are equal opportunity toxins. We and many others have shown that applying them to different types of cells can kill them.

In this paper, we show that IAPP clusters go through an “alpha sheet” phase. What does this mean and why is it important?

We’ve been studying these amyloid systems for a long time, and we’re starting to see this strange protein structure. It’s like all the building blocks of proteins called amino acids move a crankshaft. Half of them are spinning in the wrong direction.

At first, we thought, “This must be an artifact. No one will discover new structures.” But then we showed that this “alpha sheet” structure is real. And the proteins in all the amyloid systems that we’ve studied (currently 14 types, including type 2 diabetes) form these alpha-sheet structures when they’re in these small toxic clusters. No one had seen this for IAPP until this paper was published.

The paper also showed that a synthetic peptide can bind to and neutralize toxic IAPP clusters, keeping beta cells alive. What’s special about this peptide and how does it work?

Previously, we designed a synthetic peptide that binds to the toxic protein cluster in Alzheimer’s disease. The idea here is to shut down these clusters before these peptides wreak havoc on cells. The peptide we created also forms an alpha-sheet structure, but it is not toxic to cells. This bonds very tightly to the cluster. We are currently studying what happens to the clusters after merging.

In this paper, we showed that our synthetic peptide also acts against the toxic IAPP cluster. This means this could be a potential treatment in the future.

Type 2 diabetes is the most prevalent amyloid disease, affecting 500 million people worldwide. Many people think of lifestyle changes when treating type 2 diabetes, but that doesn’t work for everyone. Medications that help minimize the damage that IAPP does to the pancreas could be very helpful.