How the Immune System Regulars Blood Sugar Level: Regulating Pancreatic Glucagon and Glucose Homeostasis Through Neuronal-ILC2 Interactions

“For decades, immunology has been dominated by a focus on immunity and infection,” said study coauthor H. Veiga-Fernandes, who also heads the Immunophysiology Lab at the Champalimaud Foundation. “But we are starting to realize the immune system does a lot more than that.”

Moreover, while insulin and glucagon, both produced in the pancreas, are considered the primary regulators of blood sugar, Veiga-Fernandes and his team suspected there was more to this process. Note that insulin lowers blood glucose by promoting its uptake into cells. Glucagon raises it by signaling the liver to release glucose from stored sources.

Glucose regulation involves multiple systems but the interaction among these systems remains unclear. Evidence also suggests the nervous system and immune system interact to regulate energy levels and endocrine functions. This prompted a hypothesis about the role of the two.

“Some immune cells regulate how the body absorbs fat from food, and we have recently shown that brain-immune interactions help control fat metabolism and obesity,” Veiga-Fernandes explained. “This got us thinking—could the nervous and immune systems collaborate to regulate other key processes, like blood sugar levels?”

Findings

The researchers carried out five experiments on genetically engineered mice that were selectively lacking certain immune cells. These specific cells are the group 2 innate lymphoid cells or ILC2s. These cells produce cytokines that play a role in allergic and inflammatory diseases. The experiments on the genetically engineered mice allowed the researchers to understand further the role of ILC2s and the specific effects on glucose levels in their absence. Below are further details of the experiments and their results:

• Experiment 1: ILC2 Deficiency and Blood Sugar Regulation: The team found that mice deficient in ILC2s could not produce enough glucagon. Their glucose levels dropped to dangerously low levels as a result. The team transplanted ILC2s into these deficient mice to confirm the role of these cells in glucose regulation. Findings showed that the process restored normal blood sugar levels and that these cells are essential for maintaining glucose stability when energy is scarce.

• Experiment 2: Identifying the Mechanism of ILC2 Function: The team further sought to understand the biological mechanisms behind the impact of ILC2s on glucagon production. They initially assumed that regulation was occurring primarily in the liver since this is where glucagon typically acts. However, based on the data, the critical events were happening between the intestine and the pancreas.

• Experiment 3: Cell Tagging to Track ILC2 Movement: The team used advanced cell-tagging methods to mark ILC2s with a glow-in-the-dark marker. This enabled them to track the movement of these immune cells. Their tracking showed that ILC2s had migrated from the intestine to the pancreas after fasting. This showed that these immune cells were not just involved in defense but also in regulating glucose by stimulating glucagon production in distant organs.

• Experiment 4: Cytokine Release and Glucagon Production: The ILC2s also released cytokines upon arriving at the pancreas. This instructed the organ to produce glucagon. The increase in glucagon levels then triggered the liver to release glucose. However, when the researchers blocked these cytokines, glucagon levels dropped significantly. This showed that cytokines are essential for regulating blood sugar.

• Experiment 5: The Role of the Nervous System in ILC2 Migration: The team found that the migration of ILC2s from the intestine to the pancreas was orchestrated by the nervous system. Gut neurons, which are also connected to the brain, released chemical signals that bind to immune cells during fasting. These signals instructed ILC2s to leave the intestine and migrate to the pancreas. The study showed that these neural signals caused changes in the immune cells.

Implications

This study uncovers a sophisticated communication network linking the nervous, immune, and hormonal systems to regulate glucose levels. The immune system was specifically revealed to also play a role in regulating blood sugar or blood glucose levels. This was more pronounced during energy deprivation due to fasting or exercise.

In addition, while insulin and glucagon have long been considered the primary regulators of blood sugar, this study identifies a critical role for innate lymphoid cells or ILC2s. These immune cells help stabilize blood glucose by prompting the pancreas to produce glucagon. Glucagon then signals the liver to release glucose.

Neural signals drive the migration of ILC2s from the intestine to the pancreas during fasting. These immune cells then release cytokines in the pancreas to stimulate glucagon production and ensure adequate blood glucose levels during energy scarcity. The nervous system through the gut neurons orchestrates this migration via neural signals.

The researchers underscored the practical implications of their findings. These include shedding light on how fasting and exercise trigger inter-organ communication to maintain energy balance. The findings also explain the evolutionary role of the immune system in sustaining energy supplies during periods of limited food availability.

Furthermore, considering medical applications, understanding how ILC2s regulate glucagon could to innovative treatments for managing blood sugar in diabetic patients and preventing obesity. The insights from the findings can also help counteract how tumors exploit glucagon-driven glucose production to fuel their growth.

FURTHER READING AND REFERENCE

• Šestan, M., Raposo, B., Rendas, M., Brea, D., Pirzgalska, R., Rasteiro, A., Aliseychik, M., Godinho, I., Ribeiro, H., Carvalho, T., Wueest, S., Konrad, D., and Veiga-Fernandes, H. 2025. “Neuronal-ILC2 Interactions Regulate Pancreatic Glucagon and Glucose Homeostasis. In Science. 376(6731). American Association for the Advancement of Science. DOI: 1126/science.adi3624