Immune System the Missing Link in Blood Glucose Control?

Immune cells native to the intestines travel to the pancreas to stimulate glucagon production in pancreatic alpha cells, thereby contributing to the regulation of blood glucose levels, suggests a Portuguese mouse study that has sparked debate in some quarters.

“For decades, immunology has been dominated by a focus on immunity and infection,” said senior author Henrique Veiga-Fernandes, PhD, head of the Immunophysiology Lab at the Champalimaud Foundation, Champalimaud Centre for the Unknown, Lisbon, Portugal, in an accompanying news release. “But we’re starting to realize the immune system does a lot more than that.”

“This is the first evidence of a complex neuroimmune-hormonal circuit,” Veiga-Fernandes added. “It shows how the nervous, immune, and hormonal systems work together to enable one of the body’s most essential processes — producing glucose when energy is scarce.”

The research was published in the journal Science.

A Surprising Discovery

The discovery was almost accidental, Veiga-Fernandes told Medscape Medical News.

Initially, the researchers hypothesized that immune-related energy balance would occur in the liver. However, mouse model tests showed no impact on glucose control, disappointing the lead researcher who had invested substantial time and effort into the work. Yet upon reviewing the data together, Veiga-Fernandes and his colleague quickly observed an unexpected pattern.

“Then there were 4 years of work to pinpoint exactly what was happening,” Veiga-Fernandes said.

They found that mice lacking adaptive and innate lymphocytes exhibited reduced blood glucagon levels, impaired gluconeogenesis, and low fasting blood glucose levels. Transplantation and conditional cell-specific deletion experiments revealed that group 2 innate lymphoid cells (ILC2s) were both sufficient and necessary for preserving physiological blood glucose levels, inducing pancreatic glucagon secretion, and promoting hepatic gluconeogenesis.

“When we transplanted ILC2s into these deficient mice, their blood sugar returned to normal, confirming the role of these immune cells in stabilizing glucose when energy is scarce,” explained Veiga-Fernandes.

Further experiments revealed that fasting induced intestinal ILC2s to migrate to the pancreas.

“We’re seeing mass migration of immune cells between the intestine and pancreas, even in the absence of infection,” Veiga-Fernandes said. “Immune cells aren’t just battle-hardened soldiers fighting off threats — they also act like emergency responders, stepping in to deliver critical energy supplies and maintain stability in times of need.”

Debating the Data

The idea that such a crucial and time-sensitive process as glucose control depends on immune cell migration has drawn skepticism.

Bart Roep, MD, PhD, professor of diabetology, immunopathology and intervention and director of the National Diabetes Center of Excellence at Leiden University Medical Center, Leiden, the Netherlands, cautioned that the mouse model used is “notoriously misleading” and prone to other diseases.

“That makes it a little bit troublesome, but it doesn’t mean we should dismiss [the study] immediately,” Roep said.

He also noted that ILC2 cells “have never been seen in a human pancreas,” although this simply could be due to limited research.

But Roep’s primary concern is the distance between the gut and pancreas in humans — several inches compared with just 1 mm in mice — potentially making the migration too slow to regulate blood sugar levels.

However, Roep said that ILC2 cells have been shown to play “a very important role” in the gut microbiome, and he “would not be surprised if there are signals from the gut microbiome that can travel to the pancreas, and the ILC2s are interesting couriers of that message.”

“But that would be indirect regulation through metabolites,” he added.

Remaining Questions

Paul Kubes, PhD, of the Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada, was less skeptical.

He told Medscape Medical News that cell homing between organs using homing receptors is well-established. However, he noted that the ILC2 cells were not observed leaving the pancreas once the need for them subsided.

“The homing receptors are to get in, not to leave,” he said, and the apparent lack of a means for the cells to go back to the intestine “was a little bit funky for me.”

“I’m not sure why it’s such a complicated system — I would put the ILCs right in the pancreas — but I guess it makes sense if you eat, then you get alerted: ‘Hey, we need these ILCs now in the pancreas,’ and they then leave” the intestines and head to the pancreas.

“That process will take minutes,” Kubes noted. “So I don’t think that that’s a big issue at all.”

Veiga-Fernandes agreed that it’s a fast mechanism.

“Whether then it goes through the lymphatics or through the bloodstream, we don’t know, but it’s not like they have to cross tissues,” he said. “They use ‘professional routes’ that not only immune cells but other components of the body use.”

He added that gluconeogenesis begins approximately 3-4 hours after fasting and ramps up “very slowly, very steadily,” leaving ample time for ILC2 cells to “migrate and exert their function in the human pancreas.”

Kubes noted that the study raises several questions including whether ILC2 cells could be targeted to treat type 2 diabetes and how immunosuppressive drugs might affect glucose metabolism. Kubes speculated that dysfunction in this system could contribute to type 1 diabetes, whereby immune cells attack islet cells instead of regulating glucose.

“This study reveals a level of communication between body systems that we’re only beginning to grasp”, Veiga-Fernandes concluded. “We want to understand how this inter-organ communication works — or doesn’t — in people with cancer, chronic inflammation, high stress, or obesity. Ultimately, we aim to harness these results to improve therapies for hormonal and metabolic disorders.”

This study was funded by the Champalimaud Foundation.

The authors were supported individually by the European Molecular Biology Organization, Acteria, Fundação para a Ciência e Tecnologia, a European Crohn’s and Colitis Organisation Grant, the European Foundation for the Study of Diabetes, the Swiss National Science Foundation, ERC, the Paul G. Allen Frontiers Group, Chan Zuckerberg Initiative, La Caixa, and the EU Chan Zuckerberg Initiative, La Caixa HORIZON-MISS-2src21-CANCER-src2-src3.