IIT Kanpur discover how immune cells silence insulin, a new clue in the fight against diabetes

In a breakthrough that changes our understanding of how diabetes develops, researchers at the Indian Institute of Technology Kanpur (IIT Kanpur) have found that immune cells inside the pancreas can switch off insulin release within minutes and have identified the molecular switch that allows them to do it. The study published in the Journal of Clinical Investigation, one of the leading biomedical journals in the world, was jointly led by Simran Singh and Ashish Kumar, who are the co-first authors of the research, under the supervision of Dr. Sai Prasad Pydi at the Department of Biological Sciences and Bioengineering, IIT Kanpur.

The team has also confirmed that the same pathway is present and active in human pancreatic tissue, which makes it a target for drugs meant to protect insulin production in people with obesity and type 2 diabetes.

The human  pancreas contains several types of cells, including insulin-producing beta cells and immune cells called macrophages. While beta cells regulate blood glucose by secreting insulin, macrophages help maintain tissue health and immune balance. This study reveals how macrophages directly communicate with neighbouring beta cells to regulate insulin secretion.

The understanding till now was that obesity triggers low grade inflammation which damages beta cells slowly, over months and years. Now, the IIT Kanpur research has revealed a much faster and more direct exchange of signals.

Dr Sai Prasad Pydi, Assistant Professor in the Department of Biological Sciences and Bioengineering at IIT Kanpur said,”We discovered that immune cells that are present next to beta cells can switch off insulin release within minutes,” said  who led the study. “And they do it without giving any of the classical inflammation signals we have been studying for decades. The findings change our fundamental understanding of how immune cells influence insulin production. The effect is not slow damage from inflammation but instruction that is delivered in minutes. The fact that this works the same way in human tissue is what makes it exciting, It is not just a finding in tissues of laboratory mice, but a real biological circuit that could be targeted with a drug “

The team used a precision genetic technique that allowed them to switch a single signalling pathway on or off inside immune cells. Activating this pathway in macrophages caused a sharp reduction in insulin release in mouse models. Conversely, switching the same pathway off had the opposite effect, with insulin secretion improving.

The messengers were fats, a class of lipids called sphingolipids, and not inflammatory proteins. Once activated, the macrophages rapidly released these fats that the neighbouring beta cells took up through a transporter on their surface. These then interfered with the internal insulin machinery of the beta cells.

The team traced the trigger to GPR18, a receptor on macrophages that sits at the top of the chain. Blocking GPR18, or any of the steps below it, restored normal insulin release. The pathway therefore has three points at which a potential drug could act: the receptor, the lipid signal and the uptake step.

The part of the work with the most consequence for patients was carried out on human tissue. Working with the Indiana Biosciences Research Institute in the United States, the IIT Kanpur team confirmed that GPR18 is heavily concentrated in the immune cells of human pancreatic islets. When the researchers activated the pathway in donated human pancreatic tissue, insulin secretion was blocked there as well.

While the study does not offer a treatment for diabetes, the validation establishes a foundation for further research into how disrupting the pathway can help preserve insulin secretion in people with obesity and type 2 diabetes.

The paper, “Acute activation of Gq-signaling in pancreatic islet macrophages inhibits insulin secretion through AMPK-sphingolipid axis,” is published in the Journal of Clinical Investigation.