Study summary
- Skin cells from a person carrying a risk gene for type 2 diabetes were “reprogrammed” into so-called pluripotent stem cells
- Some of these stem cells were corrected using CRISPR gene-editing
- The stem cells were then differentiated into insulin-producing beta cells – some carrying the risk variant and some without it
- Although the main purpose of the study was method development, the researchers also found that cells with the risk variant showed altered signaling pathways controlling how beta cells respond to melatonin
Melatonin is the hormone that helps us fall asleep. At night-time, melatonin levels rise in the body, signaling that it is time to wind down. At the same time, the body’s ability to release insulin decreases – which makes sense, since we normally do not eat at night.
For most people, this system works smoothly. But some individuals carry a genetic variant in the melatonin receptor gene, known as MTNR1B, which makes insulin release more strongly suppressed than normal. Previous studies have shown that people with this variant have an increased risk of developing type 2 diabetes.
A missing piece of the genetic puzzle
Although the link between this gene variant and type 2 diabetes has been known for some time, it has been difficult to understand exactly how the variant affects the insulin-secreting beta cells. Researchers in Lund have now addressed this using a technique that received the Nobel Prize in 2012 – the ability to create stem cells from “ordinary” cells, such as skin cells.
Many diseases arise when a particular cell type in the body fails to function properly. To investigate what goes wrong, researchers can now create new versions of that specific cell type – and all that is needed is a small skin sample. The skin cells are first turned into stem cells, which then can be guided to develop into the desired cell type by providing exactly the right cellular cues at the right time-point. These lab-grown cells carry the same genes and possible mutations or variants as the cells in the original tissue.
Recreating cells with and without the risk gene
In this study, skin cells donated by a person carrying the risk variant were used. These cells were reprogrammed into stem cells, serving as a kind of restart and foundation for generating the cell type of interest – beta cells.
The researchers developed a “recipe” for which growth factors the stem cells needed to mature into insulin-producing beta cells. Using the gene-editing tool CRISPR, they then modified a small section of DNA in some of the stem cells, removing the risk variant.
“In this way, we created two cell lines from the same individual – one carrying the risk variant and one in which the variant had been corrected. We could then study the differences between them side by side,” says Malin Fex, diabetes researcher at Lund University.
“Like science fiction”
This approach could become a powerful tool for understanding disease mechanisms at the molecular level.
“The method feels like science fiction, and it’s incredibly exciting that we’ve now applied it within diabetes research. Thanks to the skilled stem cell researchers at Lund University, we’ve been able to reprogram patient skin cells into stem cells,” says Malin Fex.
Paving the way for new knowledge
The researchers also found that beta cells carrying the risk variant showed differences in their response to melatonin – which in turn affects insulin secretion, as compared to beta cells that did not carry the risk variant .
“One major goal for us was to successfully convert skin-derived stem cells into insulin-producing beta cells. Another key goal was to optimize the CRISPR technique to change a single building block in the DNA sequence, thereby correcting the risk gene,” explains Malin Fex.
By combining stem cell technology and gene editing in this way, the researchers can now continue mapping the molecular mechanisms linking the melatonin receptor to type 2 diabetes – knowledge that may ultimately open up new avenues for treatment.