By Deborah Roby
The Cell and Developmental Biology labs of Irina Kaverina and collaborators Guoqiang Gu and Chris Wright recently published work in Current Biology that presents a newly discovered means by which the pancreas maintains glucose homeostasis. This work illuminates the crucial steps pancreatic β cells take to package insulin and ready it for release into the body.
Pancreatic β cells are specifically programmed to secrete insulin when glucose levels are high. However, the exact secretion mechanism is still a relative mystery. The Golgi apparatus, the organelle responsible for packaging proteins for secretion, is the sole site of microtubule formation under conditions of high glucose in the pancreatic β cell. Microtubules are hollow tubes that provide structure to cells and are essential for multiple cell survival functions.
“This study is the first evidence for a specific metabolic pathway regulating microtubule dynamics in pancreatic β cells,” said Dr. Kaverina.
The work in this paper showed that Golgi-derived microtubules (GDMTs) balance the production and storage of insulin in structures called insulin granules. The authors also determined which signals told β cells to form GDMTs in high-glucose conditions.
Cells communicate using a complex molecular signaling system. Among these signaling molecules are cyclic-AMP (cAMP), a derivative of the energy molecule ATP, and EPAC2, which amplifies messages and activates a specific cell response when signaled by cAMP. The researchers compared the responses of cells with both low- and high-glucose levels and determined that during high-glucose conditions, GDMTs in the pancreatic β cells formed specifically when cAMP passed a signal to EPAC2, but not to other signaling molecules. Chemically blocking EPAC2 resulted in no GDMTs, indicating that the cells need a cAMP-to-EPAC2 signal to form these microtubules. Once they determined this, the researchers aimed to understand how this process affects insulin secretion.
Pancreatic β cells need a high quantity of pre-packaged insulin granules to be able to respond quickly to high blood glucose levels, but the granules must leave the Golgi first before they are ready for secretion. The researchers mutated pancreatic β cell lines to stop GDMT formation and blocked EPAC2 signaling, preventing the Golgi from releasing insulin granules into the cell even in high-glucose conditions and interfering with the β cells’ ability to regulate glucose. The work suggests that GDMTs serve as a scaffold to help release new insulin granules into the cell.
According to Kaverina, this is, “The first evidence that Golgi-derived microtubules play an essential long-term role in insulin secretion.”
This work gives basic science researchers a better grasp on the intricate pathways that are important to metabolic disease control and sheds light on insulin production balance that is crucial to understanding diabetes mellitus.