Defect in pancreas alpha cells linked to diabetes, Stanford Medicine study shows

Pancreatic alpha cells from people with diabetes release excess amounts of glucagon, a hormone important in blood sugar control, in a new Stanford-developed mouse model of transplanted human islets.

In response to low blood sugar levels, pancreatic islet cells from people with diabetes release significantly more of a hormone called glucagon than do islet cells from healthy people, according to a new study by researchers at the Stanford University School of Medicine.

The discovery was made using a new mouse model of diabetes engineered by Stanford

scientists that for the first time permits functional studies of transplanted human alpha cells.

Glucagon is produced by alpha cells in pancreatic islets while insulin is produced by beta cells. Defects of insulin output and beta cells have been thought to be the main drivers of diabetes. The current study, however, supports the growing realization that diabetes is likely due to defects in multiple cell types and highlights the importance of the mouse model to more accurately simulate the complexities of the disease.

“Our investigations support the idea that diabetes results not just from a defect in pancreatic beta cells, but also in the alpha cells that produce glucagon,” said Seung Kim, MD, PhD, professor of developmental biology and director of the Stanford Diabetes Research Center. “This had been suspected, but our study with human islets provides new, unprecedented evidence to support this idea.”

Kim is the senior author of the study, which was published June 8 in Nature Metabolism. Graduate student Krissie Téllez and research scientist Yan Hang, PhD, share lead authorship of the study.

In healthy people, glucagon works in tandem with insulin to tightly control blood sugar levels. Immediately after a meal, insulin triggers the removal of glucose from the blood and promotes its storage in organs like the liver. Conversely, when blood sugar levels become low, glucagon stimulates the release of stored glucose into the bloodstream.

Identical glucagon structures

Previous research into the relationship between insulin and glucagon has been hampered by the fact that mouse and human glucagon are identical in structure. They are impossible to distinguish from one another after human islets have been transplanted into laboratory mice. As a result, researchers could only study human glucagon production by alpha cells in test tubes or culture dishes, which does not accurately mimic what happens in the body.

Hang, Téllez and their colleagues set out to engineer a mouse strain unable to make its own glucagon. They used a genetic editing process called CRISPR to remove a small piece of the animal’s DNA that encodes for the glucagon protein. The process was laborious and time-consuming, taking more than two years to complete.

Eventually they produced mice with a combination of six specific mutations, including those necessary to allow the animals’ immune systems to accept transplantation of human pancreatic islets, and those enabling the study of human glucagon production in the animals.

“It was quite a testimony to the power of modern genetics and molecular biology,” Kim said. But the results were worth the effort, he added.

“When we compared islet cells from healthy and diabetic donors in test tubes, we saw some differences in glucagon secretion, but the results were not statistically compelling,” Kim said. “It really wasn’t clear what was going on. But once the human islets were engrafted into the mice, we could very clearly see a significant and sustained excessive output of glucagon from human islets when blood sugar levels drop. As a result, the blood glucose levels of these mice were higher than in mice transplanted with normal human islets.”

‘A game-changing moment’

Interestingly, the insulin production by the diabetic islets remained unchanged, indicating an additional defect in the beta cells’ response to the increased blood sugar levels. Kim and his colleagues are eager to find out why.

“The potential role of glucagon output and high blood sugar levels in diabetes has long been debated in diabetes research,” Kim said. “Now we can finally assess the interplay of islet cell types in people with and without diabetes and measure the role of multiple hormones involved in blood sugar control. These mice open up many new avenues of study, including the genetics and pharmacology of the disease and possible treatments. It really is a game-changing moment in diabetes research.”

Other Stanford co-authors are research associate Xueying Gu and postdoctoral scholar Charles Chang, PhD. A researcher from Vanderbilt University also contributed to the study.

The research was supported by the National Science Foundation, the National Institutes of Health (grants DK107507, DK108817, CA21192701, DK120447, DK106755, DK050203, DK090570 and DK116074), the HL Snyder Foundation, the Mulberry Foundation, S. and M. Kirsch, and the Stanford Diabetes Research Center.



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