Beta cells produce and secrete insulin in the pancreas. Since beta cells were first discovered in the late 19th century and later linked to diabetes in the early 20th, researchers have been trying to trace their origins. Understanding where the cells come from is critical for developing new treatments for diabetes, as it can help regenerate or replace beta cells that are lost or damaged.
A longstanding theory – dating back to the year 1906 – is that beta cells arise from cells in the lining of pancreatic ducts, the branched tubes that deliver enzymes into the gut. Since then, researchers have shown that this only occurs during embryonic development and not after birth, and that in adulthood beta cells are generally replaced by other beta cells.
In 2021, a research paper in the journal Cell Stem Cell challenged this view, finding evidence that adult mice are able to form new beta cells and that these arise from pancreatic duct cells. The study was one of the latest examples of a centuries-long controversy on the origins of beta cells, especially as several independent research groups had used a similar methodology to explore the same question for more than two decades.
The study used two genetic tools to label insulin-producing beta cells in eight-week-old mice. After a six-month period, the researchers found a dilution of the marked beta cells every week, suggesting another source of beta cells aside from other beta cells. The results were exciting because newly formed beta cells would account for a 30% increase in overall beta cell number over a year, a process which could be harnessed for new strategies to treat diabetes.
However, an international group of diabetes experts, including experts who had developed the genetic tools used in the study in the first place, were sceptical. Today, these experts have published a follow-up on the paper, also in the journal Cell Stem Cell, challenging the findings made in the 2021 paper. The experts show that the tools used to mark beta cells accidentally marked delta cells instead – another type of pancreatic islet cell – resulting in a case of mistaken identity.
“Delta cells are very thin and are easily camouflaged if not labelled correctly because they get squished between beta cells,” explains Dr. Jorge Ferrer, co-corresponding author of the paper and researcher at the Centre for Genomic Regulation (CRG) and the Centro de Investigación Biomédica en Red enfocado a Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM). “Given the shortcomings in the original study, the evidence is still overwhelming that in the adult pancreas most, if not all, beta cells arise from pre-existing beta cells.”
“It is critically important to get this right. An incorrect interpretation could, for example, result in years of wasted work trying to stimulate a physiological regenerative process that does not exist,” says Professor Yuval Dor, co-corresponding author of the study and researcher at the Hebrew University-Hadassah Medical School.
The researchers acknowledge that although the weight of evidence shows beta cells make other beta cells in adulthood, there could be untested scenarios not yet found in which the processes that occur during embryonic development are recapitulated in adulthood. All the research carried out so far has been in mice, which can be genetically manipulated. Future studies are needed to show if there are differences in humans, although according to the researchers so far there are no indications that this is fundamentally different or needs to be addressed with new tools.
The research published today is a collaboration led by the Hebrew University of Jerusalem, the Centre for Genomic Regulation in Barcelona and the Centro de Investigación Biomédica en Red enfocado a Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM). Co-authors include co-key researchers from Harvard University, Vanderbilt University, the University of Utah, University College San Diego, the Israel Institute of Technology Technion, University of British Columbia and the University of Geneva.
Image: Image of mouse pancreatic islets, where beta cells are located. Credit: Jonas Juan Mateu
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