A rare mutation in three siblings gives new clues to diabetes


Madrid, Apr 21 (EFE) .- Spanish and Swedish scientists have discovered that genetic mutation is behind a pathology that in the world has only three younger brothers of Libyan origin, a research that also served to advance the understanding of a disease totally different and more common, diabetes.

Although this is a basic research done in the laboratory, it raises a possible new way of attacking diabetes and opens the door for the development of future therapies against this disease in which blood glucose levels are very high.

Children born in Sweden were born in 2005, 2009 and 2014 – the parents are familiar with each other – and from the first day of life the three had excessively high levels of lactic acid and very low levels of the amino acid methionine; were treated from the beginning and, although at the beginning could present some muscular problem, now they develop without complications practically.

The treatment is mainly to reduce the levels of lactic acid, which occurs mainly in muscle cells and red blood cells, to avoid damage to the body such as weakness. However, scientists have so far failed to understand why methionine is low and what the consequences this has on the bodies of patients.

To study this case, the researcher at the Karolinska Institute in Sweden, Anna Wedell, contacted the Spanish scientist Alfredo Giménez-Cassina, from the Center for Molecular Biology Severo Ochoa (CBMSO) – the center of the Autonomous University of Madrid and the Superior Center. of scientific investigations.

In both centers, thanks to new techniques of genetic analysis, this family was investigated that presents "abnormal metabolic abnormalities in the blood", explains Efe Giménez-Cassina, one of the leaders of this work.

To do this, they underwent a skin and muscle biopsy; From Stockholm, they sent skin cells (fibroblasts) and muscles (myoblasts) to Madrid.

Researchers have identified a genetic mutation never before described that causes the total disappearance of a protein called TXNIP, which in turn causes high levels of lactic acid.

There are other genetic mutations linked to high levels of lactic acid, but this that causes the "cancellation" of the TXNIP protein is the first time it is described.

But what does this have to do with diabetes? TXNIP protein, in turn, is related to problems in regulating blood sugar levels: Previous studies have found that diabetics have high levels of this protein.

It has been seen that TXNIP slows the incorporation of sugar into different tissues: sugar enters the blood once ingested through different sources and is the hormone insulin that sends a signal to all tissues-liver-to which glucose and remove it from the blood.

When this does not occur and sugar accumulates in excess in the blood, problems appear.

Scientists had already proposed, thanks to experiments with animal models, that a possible way to stop excess blood glucose would be to inhibit TXNIP, but there was a problem: it was not known whether its inhibition in humans could be toxic.

Now, this is solved: the three children who have a genetic mutation that causes high levels of lactic acid, do not have this protein and live, so "the total absence of TXNIP is compatible with life," although it has side effects. .

"Thanks to this disease, we can predict which side effects could have a therapy based on the inhibition of this protein – lactic acid increase -" says the researcher, who points out: "we now have a great advantage: we know that inhibiting it is not lethal ".

Therefore, "we propose that moderate inhibition of this protein could help at least remove excess blood sugar."

However, we must be cautious, warns Gimenez-Cassina, to whom we must continue to investigate and validate these findings, first, in animal models for a future move to the clinic.

The description of the role of this protein and the genetic analysis of the family were published in the journal Diabetes. EFE

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