Type 1 Diabetes not to be blamed on the immune system

27 February 2017• PRESSRELEASE

Type 1 Diabetes can develop when stress causes beta cells to produce nonsense proteins instead of insulin, as Leiden University Medical Center (Netherlands) researchers just reported in Nature Medicine. "This is an entirely new way of looking at this disease", says senior author Bart Roep, Professor of Diabetes.

The immune system of people with type 1 diabetes turns against beta cells in the pancreas that produce insulin, the hormone that controls sugar metabolism. The underlying mechanism has always been assumed to involve the immune system inappropriately considering insulin to be hazardous and attacking the cells producing it. LUMC researchers have now discovered that the immune system often responds to an incorrect protein that beta cells sometimes produce instead of insulin. This means that the beta cells are at fault and not the immune system.

Misread

Arnaud Zaldumbide (Molecular Cell Biology LUMC) discovered the origin of the error. The gene that encodes insulin is first transcribed to messenger RNA, which is then turned into protein by a process called translation. The initiation of this process occurs at a specific triplet letter combination and the identity of each amino acid, incorporated in the protein, is defined by the next triplet letters. Dr Zaldumbide, PhD: "We found an alternative translation initiation site in the insulin messenger RNA that can be used for protein synthesis. This causes a frameshift in the translation process and results in an incorrect amino acids chain, creating a nonsense protein."

Productive factories

It is not entirely strange that beta cells occasionally produce incorrect proteins. Professor Roep: "Beta cells are highly productive factories, which can produce up to one million insulin molecules per minute when the demand is high. Even if the chances of errors are extremely small, one million molecules per minute means that a number of incorrect proteins are likely to be produced." The researchers have shown that beta cells make more errors when they are stressed, e.g. due to an infection, abnormal gut flora or frequent antibiotics in young children.

Experiments have shown that the nonsense protein produced under stress, triggers an immune response that destroys insulin producing cells. Roep says: "This means that there is nothing wrong with the immune system in patients with type 1 Diabetes. In fact, it does exactly what it is supposed to do: attack cells that produce incorrect proteins as normal defence mechanism, as it does against infected cells or cancer cells."

Rescue beta cells

"This new level of understanding has an impact on the treatment", says Dr Zaldumbide. "One option would be to resolve the stress on beta cells so that the beta cells function more effectively and make fewer mistakes. Or we might be able to vaccinate people against diabetes using fragments of the incorrect protein."

"It would be worth investigating whether other autoimmune diseases, i.e. diseases where the immune system inappropriately attacks natural cells, are caused by those cells producing incorrect proteins under stress," Bart Roep adds; "If beta cells can be rescued by allowing them to rest, the risk of complications is considerably smaller, perhaps even negligible! Without even realising it, you can help your body by reducing ‘stress’ and at the same time creating time and opportunity for researchers to find therapies to stop the disease."

This study by Prof. Bart Roep and Dr Arnaud Zaldumbide was funded by the Dutch Diabetes Research Foundation, the Juvenile Diabetes Research Foundation and the DON Foundation (Diabetes Research Netherlands).

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