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Alonso Lab Demonstrates the Accuracy of BrdU Labeling to Measure Beta Cell Replication

Rohit Sharma, PhD (left) led a study published by the laboratory of Laura C. Alonso, MD, which confirms the fidelity of a widely used technique to measure beta cell replication, despite doubt by some in the field.  The Alonso Lab is investigating which pathways guide proliferation in insulin producing pancreatic beta cells. The ultimate goal is to determine approaches to make more beta cells, so as to prevent or treat diabetes. 

Loss of beta cells and beta cell function in people with diabetes results in less insulin being secreted by the pancreas. This may eventually lead to chronic hyperglycemia (high blood sugar). By creating additional beta cells in a person with type 2 diabetes, researchers at the UMass Medical Diabetes Center of Excellence could potentially devise a way to therapeutically reverse the disease.

One scientific method used to label replicating cells is the use of an nucleotide analog, called BrdU.  It’s an accepted technique in all other fields of developmental and cell biology. Some doubt has been cast on this technique within the diabetes research community due to the slow rate of proliferation of beta cells. BrdU is a chemical that is specifically incorporated into DNA during S phase, the DNA synthesis phase that marks entry into the cell division process. However, BrdU-labeled beta cells were occasionally observed to also label with a DNA damage marker called gH2Ax, raising a question as to whether BrdU always labeled proliferating beta cells, or could sometimes instead label cells with damaged DNA. 

“It was important for us to put to rest the controversy of questioning whether BrdU is an accurate measure of DNA replication,“ said Sharma. “Not only was the method being questioned by some, but it was doubted if beta cells can divide or not. This resulted in slow progress in the field due to repeating experiments and measuring proliferation of beta cell by every possible measure.”

Sharma performed experiments in both mouse and human beta cells, to test the accuracy of BrdU as a method to label replicating cells. The data, as published in the March 2019 issue of the American Diabetes Association journal Diabetes, proved that directly causing DNA damage does not cause BrdU labeling in both mouse and human beta cells, rather BrdU labeling was drastically decreased. However, under stimulatory conditions which cause many cells to divide, only a very small percentage of cells had markers of DNA damage in mouse beta cells, and even fewer in human beta cells. Additionally, some cells which were labeled with BrdU during S-phase, entered mitosis (the process of one cell becoming two). Therefore, our data suggests that BrdU labeling is an accurate method which can be used for quantifying beta cell replication towards the overall goal of beta cell regeneration as a therapy for diabetes.

“This is also important in the field because people can trust BrdU and EdU incorporation as a measure of cell’s entry into the cell cycle for high throughput chemical screens to find new drug targets resulting in increased beta cell proliferation to overcome diabetes,” added Sharma.

Learn more about beta cell research in the Alonso Lab 

Read the full article in Diabetes   

More Diabetes Center of Excellence News