Tripartite cell networks for glucose homeostasis

Controlling the excess and shortage of energy is a fundamental task for living organisms. Diabetes is a representative metabolic disease caused by the malfunction of energy homeostasis. The islets of Langerhans in the pancreas release long-range messengers, hormones, into the blood to regulate the homeostasis of the primary energy fuel, glucose. The hormone and glucose levels in the blood show rhythmic oscillations with a characteristic period of 5-10 min, and the functional roles of the oscillations are not clear. Each islet has [Formula: see text] and [Formula: see text] cells that secrete glucagon and insulin, respectively. These two counter-regulatory hormones appear sufficient to increase and decrease glucose levels. However, pancreatic islets have a third cell type, [Formula: see text] cells, which secrete somatostatin. The three cell populations have a unique spatial organization in islets, and they interact to perturb their hormone secretions. The mini-organs of islets are scattered throughout the exocrine pancreas. Considering that the human pancreas contains approximately a million islets, the coordination of hormone secretion from the multiple sources of islets and cells within the islets should have a significant effect on human physiology. In this review, we introduce the hierarchical organization of tripartite cell networks, and recent biophysical modeling to systematically understand the oscillations and interactions of [Formula: see text], [Formula: see text], and [Formula: see text] cells. Furthermore, we discuss the functional roles and clinical implications of hormonal oscillations and their phase coordination for the diagnosis of type II diabetes.