Reversing insulin resistance with tailor-made cells

This article was originally published in Swedish by Vetenskap och hälsa (vetenskaphalsa.se)

“Actually, there are no ‘errors’, it can be a deviation in one of the genetic predispositions, which leads to the gene working in a different way”, says Hindrik Mulder, physician at Skåne University Hospital and professor of metabolism at Lund University. 

He wants to solve this by taking skin cells from the patient, reprogramming the skin cells into stem cells and then developing them into a desired cell type, such as beta cells. The stem cells can also be genetically modified before they develop into mature cells that are transplanted back into the patient. It may seem like science fiction and it will probably take a long time until it becomes a reality for ordinary patients, but research has already come a long way. 

“We know today how to reprogram skin cells or blood cells into stem cells and how to then make them develop into other types of cells. What we need is more knowledge about which mechanisms we should select as targets for these techniques, i.e. what and in which genes we should change.” 

400 gene variations linked to type 2 diabetes 

Thanks to new technology, researchers have in the last decade been able to identify about 400 variations of genes that are linked to type 2 diabetes. It is known that they affect the metabolism, but not exactly how. 

“We do not know which mechanisms are the most important or in which combinations they occur, that research must be finalised before you have some kind of ‘recipe’ for which genes to change.” 

However, Hindrik Mulder believes that in the near future we will see new drugs based on the knowledge that exists today. 

“If you know that there is a mechanism that has an effect on a disease, the pharmaceutical companies can develop drugs that affect the mechanism that the genes control.” 

The “hormone of darkness” lowers insulin release 

In his previous research, Hindrik Mulder has found a link between melatonin and type 2 diabetes that seems to be controlled by a variation of a single gene. Melatonin is often called the “hormone of darkness” as levels increase during the dark hours of the night and make us sleepy. In the morning the level decreases due to the light. The insulin-producing beta cells have receptors, receptor cells, for melatonin. 

“We believe that the normal function of melatonin is to lower insulin release at night, so that the brain gets the sugar it needs.” 

A special gene variant of the melatonin receptor makes the insulin-producing beta cells in the pancreas more sensitive to melatonin, which slows down insulin release even more and leads to higher blood sugar levels than the brain needs. 

Using CRISPR to strengthen insulin release 

Now Hindrik Mulder will study whether it is possible to take cells from patients with the current gene variation, correct it in reprogrammed stem cells using CRISPR and then investigate whether this leads to enhanced insulin release after the cells have matured into insulin cells. 

“This will be tested in the laboratory, but in the future it is conceivable to transplant them back to the patient so that the modified insulin cells can contribute to better insulin release. But before we get that far, we have the opportunity to examine the modified insulin cells to better understand how type 2 diabetes arises. These cells can also be used to test new drugs for type 2 diabetes.” 

However, type 2 diabetes is a complex disease and rarely depends on a single factor. 

“The ideal scenario would be to be able to find out which genetic factors lead to insufficient insulin release in each patient with type 2 diabetes. In that way, we could tailor cells and optimise the treatment for each individual”, Hindrik Mulder says. 

Text: Sara Liedholm