A rare mutation of three Libyan brothers opens the door to diabetes treatment



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Spanish and Swedish scientists have discovered that genetic mutation is behind a pathology that in the world only presents three younger brothers of Libyan origin, an investigation that also served to advance the understanding of a totally different and more common disease, diabetes.

Although this is a basic research done in the laboratory, it raises a possible new way to attack diabetes and opens the door to develop in future therapies against this disease in which blood glucose-sugar levels are very high.

The children, who live 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 presented 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.

Treatment is fundamentally reduce levels of lactic acid, which occurs primarily in muscle cells and red blood cells, to prevent 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 he got in touch with the Spanish scientist Alfredo Giménez-Cassina, Center of Molecular Biology Severo Ochoa (CBMSO) – center of the Autonomous University of Madrid and the Superior Center of Scientific Research -.

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.

For this, they were skin and muscle biopsy; From Stockholm, they sent skin cells (fibroblasts) and muscles (myoblasts) to Madrid.

The researchers identified a genetic mutation never described before which 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.

What does this have to do with diabetes?

The TXNIP protein, in turn, is related to problems in the regulation of blood sugar levels: previous studies have found that Diabetic people 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 insulin hormone that sends a signal to all tissues – Muscles, liver – to incorporate this 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 precisely one possible way to stop this excess of glucose in the blood 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 sugar in blood. "

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.

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