Multiple types of beta cells produce insulin in the pancreas, which helps balance blood sugar levels. Loss of a particularly productive type of beta cell may contribute to the development of diabetes, according to a new study by Weill Cornell Medicine investigators.
In the study published March 16 in the nature cell biology, Dr. James Lu, assistant professor of medicine at Weill Cornell University, and colleagues measured gene expression in individual beta cells collected from mice to determine how many different types of beta cells are present in the pancreas. The team discovered four distinct types of beta cells, including one distinct type. The first group of beta cells produced more insulin than the other beta cells and seemed to be better able to metabolize sugar. The study also showed that the loss of this type of beta cell may contribute to type 2 diabetes.
said Dr. Lo, who is also a member of the Weill Center for Metabolic Health and the Cardiovascular Research Institute at Weill Cornell Medicine, a cardiologist at NewYork-Presbyterian/Weill Cornell Medical Center. “But this study tells us that it may be important to subtype the beta cells and that we need to study the role of these particular cluster 1 beta cells in diabetes.”
Dr.. Doron Bittle, Jingli Cao, Jeffrey Pitt, and Xuebing Chen at Weill Cornell Medical College collaborated with Dr. Lu to conduct the study.
The researchers used a technique called single-cell transcription to measure all the genes expressed in mouse beta cells, and then used that information to group them into four types. Cluster beta1 cells possess a unique gene expression signature that includes high expression of genes that help cellular powerhouses called mitochondria break down sugar and enable them to release more insulin. In addition, they could distinguish staphylococcal beta1 cells from other beta cell types by their higher expression of the CD63 gene, which enabled them to use the CD63 protein as a marker for this specific type of beta cell.
“Expression of CD63 provided us with a way to recognize cells without destroying them and allowed us to study living cells,” he said.
When the team looked at human and mouse beta cells, they found that cluster 1 beta cells with higher CD63 gene expression produced more insulin in response to sugar than the other three types of beta cells with low expression of CD63.
“They are high-functioning beta cells,” said Dr. Lu. “We think they may take on the bulk of the workload of insulin production, so their loss could have profound implications.”
In mice fed an obesity-inducing high-fat diet and mice with type 2 diabetes, the number of insulin-producing beta cells decreased.
“Because you have a lower mass 1/high CD63 cell count, you may have less insulin production, which may play a major role in the development of diabetes,” he said.
Transplantation of high-producing CD63-producing beta cells into mice with type 2 diabetes returned blood sugar levels to normal. But removing the transplanted cells caused the high blood sugar levels to return. Transplanting beta cells with low CD63 production into mice did not return blood sugar to normal levels. Instead, the transplanted low CD63 beta cells appeared dysfunctional.
Dr Lu said the discovery could have important implications for the use of beta cell transplants to treat diabetes. For example, it may be preferable to transplant only high CD63 beta cells. It might also be possible, he noted, to transplant fewer of these high-yielding cells. Dr. Lu’s team also found that humans with type 2 diabetes had lower levels of high CD63 beta cells than people without diabetes.
Next, Dr. Lo and his colleagues want to find out what happens to the high-producing CD63 beta cells in diabetic mice and how to prevent them from disappearing.
“If we can figure out how to keep them alive longer, surviving and functioning, that could lead to better ways to treat or prevent type 2 diabetes,” he said.
They also want to study how current diabetes treatments affect all types of beta cells. GLP-1 agonists, which help increase insulin secretion in diabetic patients, interact with high and low CD63-producing beta cells.
“Our study also shows that GLP-1 agonists may also be a way to make low-CD63-producing beta cells work better,” said Dr. Lu.