What is it about?

We previously discovered that the protein CD59 is necessary for insulin secretion from beta-cells. CD59 is otherwise most well-known for its role in defending cells from damage caused by the immune system. We now found that the two variants that are responsible for this function of CD59, named by us CD59-IRIS-1 and IRIS-2, are decreased in diabetes. This made us very interested as it could mean that the lack of CD59-IRIS may contribute to the insufficient insulin secretion seen in some diabetic patients. Compared to the well known variant of CD59, which remains at the cell surface and protects the cell from immune attack, CD59-IRIS-1 and -2 remain inside the cell. There they have another function and affect beta-cells' ability to secrete insulin. With help from the gene scissors CRISPR/Cas9, we “silenced” the gene encoding CD59-IRIS-1 and -2, in beta-cells from mice, rats, and humans. This stopped the cells from secreting insulin. But when we introduced the newly discovered CD59-IRIS variants back into the beta-cells, they started to secrete insulin again.

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Why is it important?

Insulin affects many functions of our bodies, and is required for survival. It causes cells to take up glucose from the blood, which can then be used as energy source in tissues, or stored. To better understand how insulin is secreted and which proteins are involved in this process can give valuable clues to future treatments for diabetes. In common type of diabetes, type 2, the body needs to produce more insulin than usual to control blood glucose, due to a lack of responsiveness in target tissues. This leads to exhaustion and death of beta-cells, the cells in the pancreas which produce insulin. When this happens, blood glucose levels get dangerously high, which can lead to serious complications in whole body.


The next step in the research will now be to investigate whether the amount of these specific CD59 variants can be altered in patients with diabetes. The hope is that this could improve insulin secretion. Its exciting that the body uses the same gene to produce different variants of one protein that have such different functions, from protecting against the immune system, to insulin secretion. It was a big surprise and shows how it is possible that only 20 000 genes in the human genome are enough to achieve all the complicated functions in our bodies. Presumably the IRIS proteins also contribute to secretion of other substances than insulin, for example in the brain, which we now plan to investigate.

Anna Blom
Lunds Universitet

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This page is a summary of: Alternative splicing encodes functional intracellular CD59 isoforms that mediate insulin secretion and are down-regulated in diabetic islets, Proceedings of the National Academy of Sciences, June 2022, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2120083119.
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