Study Reveals Single Enzyme Orchestrating Insulin Release

The growing rates of type 2 diabetes (T2D) has been associated with increasing rates of obesity, and the fitness of pancreatic beta cells is crucial to maintaining metabolic health in obesity through insulin. Recent research by Emilyn Alejandro, PhD, published in the journal, Cell Reports, “O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through SERCA2,” has identified the critical role that O-GlcNAc transferase (OGT) plays in the ability and capacity of pancreatic beta cells to sense obesity and produce and release insulin appropriately.

During early obesity, pancreatic beta cells meet the increased demands of the body to metabolize glucose through overproduction and secretion of insulin, which allows the body to regulate blood glucose levels, and thus slows the progression of diabetes. The process of hypersecretion is evident for an initial phase of obesity and then diminishes over time. A better understanding of the triggering factors for this change in insulin secretion rates and the specific proteins involved in the beta cell process is needed to develop relevant therapies for T2D.

“We believed there were nutrient cues involved in the mechanism for sensing and responding to the body’s need for more insulin,” said Dr. Alejandro, an assistant professor in the Department of Integrative Biology and Physiology. “The primary goal of this preclinical study was to identify the particular enzyme orchestrating the process.” 

The research, which was the thesis focus of the Alejandro Lab’s graduate student Amber Lockridge, shows, for the first time, that the enzyme O-GlcNAc transferase (OGT) plays an essential role in increasing the secretion of insulin in pancreatic beta cells during the pre-diabetic phase of obesity, as well as maintaining the health and identity of these beta cells in general. Beta cell O-GlcNAcylation, the process by which OGT modifies the activity of the pancreatic beta cells proteins, is critical as these cells adapt to higher stress and higher insulin demand during the pre-diabetic phase. The study finds a correlation between beta cell OGT activity levels and elevated insulin secretion during early obesity and a decrease in both beta cell OGT and insulin release as obesity progresses. 

Glucose triggers insulin release and other nutrients, such as lipids, and amino acids too can play a role on insulin secretion. Since OGT is also sensitive to the amount of lipids present, this may be a determinant of increased insulin production and release processes seen in beta cells in early obesity. This is the first time researchers have evidence of lipids acting on OGT in beta cells to facilitate the release of more insulin in the state of obesity.

In a paper published earlier this year in the journal, Development, Dr. Alejandro and her team observed that when OGT was removed from pancreatic progenitor cells, a pancreas did not develop, further demonstrating the importance of OGT in the role of pancreatic function.

“Identifying OGT as the single enzyme orchestrating insulin production and maintaining the integrity of pancreatic beta cells is the first step in a long-term goal to design a drug to fight diabetes,” Dr. Alejandro said.

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