Researchers at Weill Cornell Medicine report losing a type of beta cell may contribute to the development of diabetes. The researchers measured gene expression in individual beta cells of mice and discovered four distinct beta cell types, including one that stood out and may pave the way for novel therapies for diabetes.

The findings are published in Nature Cell Biology in an article titled, “A beta cell subset with enhanced insulin secretion and glucose metabolism is reduced in type 2 diabetes.”

“The pancreatic islets are composed of discrete hormone-producing cells that orchestrate systemic glucose homeostasis,” wrote the researchers. “Here we identify subsets of beta cells using a single-cell transcriptomic approach. One subset of beta cells marked by high CD63 expression is enriched for the expression of mitochondrial metabolism genes and exhibits higher mitochondrial respiration compared with CD63lo beta cells.”

“Before this, people thought a beta cell was a beta cell, and they just counted total beta cells,” said James Lo, MD, PhD, associate professor of medicine at Weill Cornell Medicine. “But this study tells us it might be important to subtype the beta cells and that we need to study the role of these special cluster 1 beta cells in diabetes.”

The researchers used single-cell transcriptomics to measure all the genes expressed in individual mouse beta cells and then used that information to group them into four types. The cluster 1 beta cells had a unique gene expression signature that included high expression of genes that help mitochondria to break down sugar and power them to secrete more insulin.

“CD63 expression provided us a way to identify the cells without destroying them and allowed us to study the live cells,” he explained.

When the team looked at both human and mouse beta cells, they found that cluster 1 beta cells with high CD63 gene expression produce more insulin in response to sugar than the three other types of beta cells with low CD63 expression.

“They are very high-functioning beta cells,” Lo said. “We think they may carry the bulk of the workload of producing insulin, so their loss might have profound impacts. Because the numbers of cluster 1/high CD63 cells went down, you may have less insulin production, which may play a major role in diabetes development,” he said.

Transplanting beta cells with high CD63 production into mice with type 2 diabetes restored their blood sugar levels to normal. But removing the transplanted cells caused high blood sugar levels to return. Transplanting low CD63 production beta cells into the mice didn’t restore blood sugar to normal levels. The transplanted low CD63 beta cells instead appeared dysfunctional.

The researchers plan to further study high CD63-producing beta cells in mice with diabetes and how to keep them from disappearing.

“If we can figure out how to keep them around longer, surviving and functional, that could lead to better ways to treat or prevent type 2 diabetes,” he said.

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