Ola Hansson

Ola Hansson

Hjelt grant holder 2013, Lund university

Mechanisms whereby genetic variation in the TCF7L2 gene causes diabetes: novel targets for anti-diabetic therapy?

Mechanisms whereby genetic variation in the TCF7L2 gene causes diabetes: novel targets for anti-diabetic therapy?

In recent years, researchers have discovered around 70 genetic risk variants for diabetes, but still TCF7L2, known as the diabetes gene, is the gene that carries with it the largest risk of developing type 2 diabetes. Using a new method called exon skipping, Ola Hansson at Lund University Diabetes Centre (LUDC) wants to learn more about TCF7L2 by studying new ways of delaying the onset of type 2 diabetes in animal trials.

Ola Hansson at LUDC is one of four researchers that have been awarded a grant of half a million Swedish kronor from the Hjelt Foundation. “It’s confirmation that we’re doing good work and that we’re on the right track. It’s a prestigious grant and I’m happy to have been awarded it in competition with other good projects”, he says.

Exon skipping is a process that restores the production of a certain protein using short RNA strings, almost like a ’molecular plaster’. The method was developed to treat muscle dystrophy, which is caused by a fault in a gene that carries the instructions for the muscular protein dystrophin. In the same way, Ola Hansson now wants to examine if it is possible to repair, or restore, damaged or mutated functions within TCF7L2.

TCF7L2 is a so-called transcription factor. This means that the protein governs the activity of several other genes. “If you manipulate TCF7L2, which other genes are regulated?” Ola Hansson asks. As with many risk genes for type 2 diabetes, TCF7L2 is linked to decreased beta cell function. The pancreatic beta cells secrete insulin, which helps the body’s cells to absorb glucose from the blood. If the pancreas stops producing insulin or if the number of beta cells decreases, the person develops type 2 diabetes over time.

When beta cell function decreases, but before too many of the cells have died, it is possible to change lifestyle behaviours and thereby delay or prevent the onset of type 2 diabetes. “With better diet and improved exercise habits, combined with other treatment, it’s possible to change this to increased insulin secretion. We would also like to find out why the beta cells die. If we can find out why, perhaps we can find a way to delay the onset or even reverse the process”, says Ola Hansson.

Ola Hansson is a biologist. His research group consists of Yuedan Zhou from China, who has a biomedical degree, Nikolay Oskolkov from Russia, who is a theoretical physicist, and Peter Osmark from Denmark, who is a protein chemist. In previous studies, they have studied the gene in different human tissues: in fat, muscles, the islets of Langerhans (where insulin is produced), and in blood, and described which variants of the gene there is and how they are expressed. The group deduced that there are four different variants of the TCF7L2 gene that dominate in the islets of Langerhans. What the group is now looking for are the molecular mechanisms behind the altered expression and what this leads to, and if you can correct it by using exon skipping. The group is now testing their hypothesis on animal models in collaboration with a research group based in Chicago. “We will inject mice with exon skipping RNA in order to correct the imbalance of the different variants of TCF7L2,” explains Ola Hansson.

Owing to the fact that researchers at LUDC have access to insulin producing cells from deceased donors, he believes they are on the right track. “We know that what we’re examining in the cell systems is relevant to humans. It will be exciting to see what the trials on the animal models show, as they are more similar to the human situation,” he concludes.

Sara Liedholm

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