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New insights into the genetic basis of a rare type of diabetes in babies have uncovered a biological pathway that is fundamental to insulin production by pancreatic β cells, and which could boost research into new treatments for more common forms of diabetes. An international research team led by scientists at the University of Exeter, the Université Libre de Bruxelles, and the University of Helsinki, used genome sequencing to reveal that a group of babies with shared clinical features, including the development of diabetes soon after birth, all had genetic changes in the YIPF5 gene, which is involved in cell trafficking from the endoplasmic reticulum (ER) to the Golgi. The team then combined stem cell research and CRISPR gene editing to show that this gene is essential for the function of the β cells that produce insulin.

The research demonstrated how the genetic changes result in high levels of stress within the cells, causing cell death, and also showed, for the first time, that YIPF5 gene function is essential for neurons and insulin-producing β cells, but appears to be dispensable for the function of other cells.

Co-study lead, Elisa De Franco, PhD, from the University of Exeter, said, “This study highlights the importance of gene discovery to further our understanding of fundamental mechanisms in biology. In this case, our research has resulted in the identification of a gene essential for both insulin-producing cells and neurons, highlighting a biological pathway we previously did not know was so fundamental for insulin-producing cells. This has the potential to open new avenues of research and ultimately result in a better understanding of how other types of diabetes develop.”

De Franco and colleagues reported on their findings in the Journal of Clinical Investigation (JCI), in a paper titled, “YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress.”

Neonatal diabetes develops before the age of six months, and is caused by reduced numbers of insulin-producing pancreatic β cells, or impaired β cell function, the authors explained. Previous research has found that neonatal diabetes is most likely caused by a mutation in a single gene, rather than presenting as an autoimmune type 1 form of the disease. “To date, 30 genetic causes have been described, which account for 82% of cases,” the team noted. Many patients with neonatal diabetes also have neurological symptoms, which is not surprising, the researchers continued, as β cells and neurons have many genes and cellular functions in common. Pathogenic variants in 11 genes are already known to cause neonatal diabetes with neurological features, and one of the pathways known to be crucial for the function of both β cells and brain cells is the endoplasmic reticulum stress response. In fact, “Pathogenic variants in eight genes known to be involved in regulating the ER stress response have been found to caused diabetes (ranging from neonatal to adolescent/adult-onset diabetes), often associated with neurological features,” the scientists pointed out.

To further study which genes are key to the function of insulin-producing cells, in the context of neonatal diabetes, the research team studied the genetics of almost 190 patients from all over the world who developed diabetes soon after birth. “Identifying the genes causing syndromic forms of neonatal diabetes that include neurological features can highlight path­ways important for development and function of β-cells and neurons, giving insights into the pathogenesis of more common diseases,” they noted. The results identified six babies who had neonatal diabetes and other very similar clinical features—including epilepsy and microcephaly—and who all exhibited mutations in the YIPF5 gene.

Researchers at the Université Libre de Bruxelles and the University of Helsinki then carried out a series of studies in insulin-producing cells and in stem cells to try to understand the function of YIPF5 in the insulin-producing cells. “We used three human β cell models (YIPF5 silencing in EndoC-βH1 cells, YIPF5 knockout and mutation knockin in embryonic stem cells, and patient-derived induced pluripotent stem cells) to investigate the mechanism through which YIPF5 loss of function affects β cells,” the investigators explained. Their results showed that when the gene was lacking, or had the same mutations as those found in the neonatal diabetes patients, the insulin-producing β cells couldn’t function normally to produce enough insulin. And an attempt to cope with this malfunction the cells activated stress mechanisms, which ultimately resulted in cell death. “ … YIPF5 deficiency reduces β-cell survival by enhancing the ER stress response and sensitizing human β-cells to ER stress-induced apoptosis,” they commented.

Co-senior study author Timo Otonkoski, from the University of Helsinki, explained, “Using the CRISPR ‘gene scissor’ DNA-editing technology … we could correct the patient mutation in stem cells in order to fully understand its effects. The combination of gene editing with stem cells provides powerful new tools for the study of disease mechanisms.” Colleague and co-senior author, Miriam Cnop, PhD, from the Université Libre de Bruxelles, continued, “The possibility to generate insulin-producing cells from stem cells has given us the possibility to study what goes wrong in β cells from patients with this rare form and also other types of diabetes. It is an extraordinary disease-in-a-dish model to study mechanisms of disease and test treatments.”

The team’s study results offer new insights into which cellular steps are important for making insulin, and for maintaining the function of insulin-producing cells in the pancreas. This insight could help researchers develop better therapies to treat patients with common types of diabetes that affect 460 million people worldwide.

“To the best of our knowledge, this is the first report of mutations in a gene affecting ER-to-Golgi traf­ficking resulting in diabetes by increasing β-cell ER stress, uncov­ering a critical role of YIPF5 in the human β-cell,” the authors reported. “Our findings high­light a biological pathway essential for β-cells.”

“We are very grateful to the patients, their families, and their doctors for their participation in the study,” noted Andrew Hattersley, PhD, one of the senior authors of the study, from the University of Exeter. “Without them, we could not have accomplished this. It is our wish that further research will benefit the patients, to facilitate diagnosis and treatment of their diabetes.”

Anna Morris, assistant director of research strategy and partnerships at Diabetes UK, which provided funding for the studies, said, “These findings provide important new information on how beta cells in the body manufacture insulin and what happens when this process goes wrong. Understanding more about how rarer forms of diabetes develop brings us closer to discovering new ways to cure and prevent all forms of the condition. This is a key part of Diabetes UK’s new strategy, and we are proud to have funded De Franco’s vital research.”

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