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Black and white electron microscopy image showing a slice through a cell. Deformed mitochondria are visible.

A study published in Nature Genetics has investigated the impact of thousands of genes on type 2 diabetes, to find genes that are key for insulin production in human beta cells.

The study’s first author is Dr Antje Rottner, who is one of the winners of the 2022 RDM Graduate Prize. She and her colleagues used a genome-wide CRISPR screen to knock out every gene one at a time in insulin-producing pancreatic human beta cells and assessed any effects on the amount of insulin within the cells.  

Beta cells are the central players in regulating glucose levels and understanding how they work is important for decoding how diabetes develops and progresses. Genetic factors are known to be important for type 2 diabetes risk, but most of the genes involved are still unknown.  

So, the research team (led by Professor Anna Gloyn, now at Stanford University), approached these questions in an unbiased and high-throughput manner, by looking at the effects of all human genes, instead of only testing selected genes.

This revealed 20 possible candidate genes, including a gene called CALCOCO2. This gene encodes a protein which breaks down malfunctioning cellular organelles or invading pathogens, but Professor Gloyn’s group have now shown that CALCOCO2 also regulates the level of insulin within the beta cell - crucial in maintaining balanced glucose levels within the body.

Her research team have found that the cells that don’t have a working CALCOCO2 gene had lower levels of insulin. These cells also had distorted mitochondria (seen in main image towards the middle) and fewer transport molecules of insulin precursors. Beta cells from with people with specific CALCOCO2 mutations even had reduced insulin secretion. When the researchers artificially inhibited autophagy (the process by which damaged cell organelles are being disassembled), they found that cells without the CALCOCO gene had a build up of the autophagosomes, meaning that CALCOCO2 regulates the amount of insulin in the cell through autophagy.

Dr Antje Rottner, first author of the study and a former RDM scholar, said “These pancreatic beta cells have been used in many smaller studies, but they are incredibly sensitive and slow growing, which is probably the reason why nobody else had attempted such a large-scale experiment at that point.

We hope that our findings can be applied to design better treatment strategies or develop personalized risk scores which could help to prevent the development of type 2 diabetes or give patients more tailored treatments. - Dr Antje Rottner

This research was not just an incredibly large-scale experiment as it required many hundred million cells grown in the lab but was also an international collaboration involving researchers from the University of Oxford, Stanford University and the University of Alberta, funded by both the Wellcome and the National Institute of Diabetes and Digestive and Kidney Diseases.”

Senior author Professor Anna Gloyn, who was previously at the Oxford Centre for Diabetes Endocrinology & Metabolism and is now Professor of Pediatrics & Genetics at Stanford University said “To accelerate progress in identifying the proteins which are altered by genetic risk factors, we need to work at scale, generating information on how perturbating genes influences the function of cells in our body which are important for regulating blood sugar levels in humans.

"Our study is an important first step in generating and assembling these types of datasets in multiple cell types which are relevant for diabetes”.

The full paper, ‘A genome-wide CRISPR screen identifies CALCOCO2 as a regulator of beta cell function influencing type 2 diabetes risk’, can be read in the journal Nature Genetics.

Read more about the impact of the paper in a linked News and Views article.

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