An international team led by Professor Nikolay Ninov at the Center for Regenerative Therapies Dresden, part of Dresden University of Technology, used optogenetics to analyze transparent fish pancreases to understand how the body controls blood sugar. They found a special group of “first responder” cells in the pancreas that are crucial for triggering blood sugar response. Human bodies need to keep blood sugar levels in check to keep going. This balance is disturbed in diabetes, leading to serious health issues. Beta cells in the pancreas manage this balance by releasing insulin when blood sugar levels rise. Understanding how beta cells work and coordinate the response to rising blood sugar can ultimately help develop better treatments for diabetes. To understand the work of the pancreas, the Ninov-led team turned to zebrafish, a small tropical fish with transparent properties whose pancreas works similarly to a human one. Due to a lack of pigment, the researchers can use the transparent fish and observe the pancreas at work in real-time in a living subject. Beta cells from a zebrafish pancreas. The researchers used the transparent properties of zebrafish cells to track how blood sugar is regulated in a living being. Courtesy of Prateek Chawla. The researchers discovered that a small group of beta cells are more sensitive to sugar levels than the others. These cells respond to glucose quicker than the rest of the cells, so the team referred to them as “first responder” cells. They initiate the glucose response, which is followed by the remaining “follower cells.” The team wanted to test if first responders are necessary for the follower cells to respond to glucose by taking advantage of optogenetics, a modern light-based technology that allows single cells to turn on or off with a beam of light. Turning off the first responder cells lowered the response to the blood sugar of the follower cells. At the same time, when the first responders were selectively activated, the response of the follower cells was enhanced. “The first responders lie at the top of the beta cell hierarchy when it comes to control of the sugar response. Interestingly, only about 10% of the beta-cells act as first responders. It suggests that this small population of cells serves as a control center for regulating the activity of the rest of the beta cells,” explained Ninov." The researchers then compared the gene expression of highly glucose-sensitive beta cells to those that are less sensitive. They found that first responders are involved in vitamin B6 production. The first responder cells express a key enzyme involved in transforming the inactive form of dietary vitamin B6 into the form that is active in the cells. When looking at B6 production in both zebrafish and mouse pancreases, they found that the ability of the beta cells to respond to high blood sugar was dramatically reduced in both species. “This indicates that vitamin B6 plays an evolutionarily conserved role in the response to glucose,” said Ninov. “It is possible that the first responders produce and supply vitamin B6 to the rest of the beta cells to regulate their activity. Checking whether this indeed is the case is one of our next steps.” From the research, along with other studies showing correlations between low levels of vitamin B6 and metabolic disease and type 2 diabetes, the researchers believe that understanding how vitamin B6 regulates the beta cells in the pancreas could lead to new insights into the pathology of diabetes and ultimately to new treatments. The research was published in Science Advances (www.doi.org/10.1126/sciadv.ado4513).