Spread of misfolded proteins could trigger type 2 diabetes

New research in mice raises the question of whether the disease is transmissible

deformed mouse pancreas proteins

GREEN GLOB-LINS Spurred by a dose of misfolded proteins, a 20-week-old mouse developed clumps of deformed proteins (green) in a cluster of cells called an islet (red) in its pancreas.

A. Mukherjee et al/J. Exper. Medicine 2017

Type 2 diabetes and prion disease seem like an odd couple, but they have something in common: clumps of misfolded, damaging proteins.

Now new research finds that a dose of corrupted pancreas proteins induces normal ones to misfold and clump. This raises the possibility that, like prion disease, type 2 diabetes could be triggered by these deformed proteins spreading between cells or even individuals, the researchers say.

When the deformed pancreas proteins were injected into mice without type 2 diabetes, the animals developed symptoms of the disease, including overly high blood sugar levels, the researchers report online August 1 in the Journal of Experimental Medicine.

“It is interesting, albeit not super-surprising” that the deformed proteins could jump-start the process in other mice, says Bruce Verchere, a diabetes researcher at the University of British Columbia in Vancouver. But “before you could say anything about transmissibility of type 2 diabetes, there’s a lot more that needs to be done.”

Beta cells in the pancreas make the glucose-regulating hormone insulin. The cells also produce a hormone called islet amyloid polypeptide, or IAPP. This protein can clump together and damage cells, although how it first goes bad is not clear. The vast majority of people with type 2 diabetes accumulate deposits of misfolded IAPP in the pancreas, and the clumps are implicated in the death of beta cells.

Deposits of misfolded proteins are a hallmark of such neurodegenerative diseases as Alzheimer’s and Parkinson’s as well as prion disorders like Creutzfeldt-Jakob disease (SN: 10/17/15, p. 12).

Since IAPP misfolds like a prion protein, neurologist Claudio Soto of the University of Texas Health Science Center at Houston and his colleagues wondered if type 2 diabetes could be transmitted between cells, or even between individuals. With this paper, his group “just wanted to put on the table” this possibility.

The mouse version of the IAPP protein cannot clump — and mice don’t develop type 2 diabetes, a sign that the accumulation of IAPP is important in the development of the disease, says Soto. To study the disease in mice, the animals need to be engineered to produce a human version of IAPP. When pancreas cells containing clumps of misfolded IAPP, taken from an engineered diabetic mouse, were mixed in a dish of healthy human pancreas cells, it triggered the clumping of IAPP in the human cells.

The same was true when non-diabetic mice got a shot made with the diabetic mouse pancreas cells. The non-diabetic mice developed deposits of clumped IAPP that grew over time, and the majority of beta cells died. When the mice were alive, more than 70 percent of the animals had blood sugar levels beyond the healthy range.

Soto’s group plans to study if IAPP could be transmitted in a real world scenario, such as through a blood transfusion. They’ve already begun work on transfusing blood from mice with diabetes to healthy mice, to see if they can induce the disease. “More work needs to be done to see if this ever operates in real life,” Soto says.

Even if transmission of the misfolded protein occurs only within an individual, “this opens up a lot of opportunities for intervention,” Soto says, “because now you can target the IAPP.”

Verchere also believes IAPP is “a big player” in the progression of type 2 diabetes, and that therapies that prevent the clumps of proteins from forming are needed. Whether or not future research supports the idea that the disease is transmissible, the study is “good for appreciating the potential role of IAPP in diabetes.”

Aimee Cunningham is the biomedical writer. She has a master’s degree in science journalism from New York University.

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