Imai discovers protein’s role in insulin secretion

A study led by Yumi Imai, MD, Professor in Endocrinology and Metabolism, has identified a protein that helps pancreatic beta cells respond to glucose and release insulin. The findings, published this month in Diabetes, shed light on a cellular process that may be disrupted in type 2 diabetes.  

Researchers have known for several years that an enzyme called adipose triglyceride lipase (ATGL) does not function properly in pancreatic islets from people with type 2 diabetes. When ATGL activity declines, lipids accumulate within the cells, which can interfere with insulin secretion. Exactly how the enzyme regulates has remained unclear, however.  

To answer this question, the team studied laboratory beta-cell models and human pancreatic islets obtained from organ donors. Their experiments focused on α/β-hydrolase domain-containing 5 (ABHD5), a protein thought to play a role in the pathway that connects glucose sensing to insulin secretion.  

The researchers found that ABHD5 acts as a glucose-responsive regulator of ATGL.  

“Glucose is one of the most important signals that the beta cells receive,” Imai said. “Our study showed that ABHD5 responds to glucose and activates ATGL, which helps drive the lipolysis needed for insulin secretion. We were also surprised by just how important ABHD5 was. When we reduced its activity, the enzyme could no longer function effectively, showing that ABHD5 is a critical regulator in beta cells.” 

The findings may point researchers toward new approaches for treating type 2 diabetes. ABHD5 appears to work through a signaling pathway involving cyclic AMP—a molecule already targeted by GLP-1 receptor agonists and other diabetes medications. Better understanding that pathway could help researchers identify additional ways to improve beta-cell function. According to Imai, understanding how ABHD5 is activated could eventually help researchers identify new ways to restore insulin secretion when beta cells no longer respond appropriately to glucose.  

The study’s findings were made possible by trainee contributions to the project. First author Lucy Kim began working in Imai’s lab as an undergraduate student at the University of Iowa and has since gone on to attend the Carver College of Medicine. She said the most rewarding part of contributing to the project was watching it evolve from its earliest stages to publication.  

“I started working on it as an undergraduate with early molecular experiments and then eventually working with INS-1 cells and human pseudoislets,” Kim said. “I was able to learn and acquire new skills along the way to follow the whole project through. I also love how it builds nicely off of previous work on ATGL in the lab so that, overall, the Imai Lab is uncovering a really solid picture of lipid metabolism’s role in beta cell function.” 

Imai also emphasized the importance of human donor tissue in the study.