Neuroimmune interactions control glucagon secretion and glucose balance

Abstract

SCIENTIFIC BACKGROUND

Maintenance of stable blood glucose levels is essential for organismal sur- vival, particularly to sustain brain and muscle function during periods of limited nutrient availability. This balance, known as glucose homeostasis, is achieved through coordinated interactions between endocrine organs, metabolic tissues, the nervous system, and the immune system. Central to this process is the pan- creas, which regulates blood glucose through the secretion of hormones from the islets of Langerhans.

Insulin and glucagon are the main hormones from the pancreas that reg- ulate blood glucose. Insulin, made by beta cells, helps the body absorb and store glucose after eating. On the other hand, glucagon is released by alpha cells dur- ing periods of fasting, physical activity, or low blood sugar, raising glucose levels by prompting the liver to break down glycogen (glycogenolysis) and make new glucose from non-carbohydrate sources (gluconeogenesis). Although insulin re- sistance and poor insulin secretion are well-known causes of metabolic diseases, problems with glucagon regulation are also becoming recognized as significant yet less understood factors in these disorders.

Glucagon release has been attributed to intrinsic pancreatic mechanisms and direct neural control, particularly through sympathetic innervation of the pancreas. However, recent research has broadened this view by demonstrating that immune cells contribute actively to metabolic regulation. Both adaptive and innate immune cells influence glucose metabolism by shaping inflammation, insulin sensitivity, nutrient absorption, and energy expenditure. Among these, innate lymphoid cells (ILCs) have emerged as important regulators of tissue homeostasis and lipid metabolism.

ILCs are tissue-resident immune cells that re- spond rapidly to environmental and physiological sig- nals. Type 2 innate lymphoid cells (ILC2) are best known for their roles in barrier tissues, where they contribute to host defense, tissue repair, and type 2 immune re- sponses through the secretion of cytokines such as interleukin-5 (IL-5) and interleukin-13 (IL-13). Beyond immunity, ILC2 have been implicated in metabolic pro- cesses, including adipose tissue regulation and insulin sensitivity, suggesting that they may link immune re- sponses to systemic metabolism.