Physiological synergy between IL-1β and insulin on glucose disposal and macrophage activity

Type 2 diabetes (T2D) is an inflammatory disease associated with infiltration of immune cells into various tissues and increased levels of inflammatory factors including Interleukin-1 β (IL-1β). In pancreatic islets elevated glucose levels stimulate IL-1β production resulting in impaired function and survival of β cells.
Blockade of IL-1β improves T2D, pointing on a major role for IL-1β in the
development and T2D. While the deleterious role of chronic activation of the IL-1 system in T2D is well documented, little is known about its potential physiological role(s).
The aim of the present study is to reveal the physiological role of inflammation
and specifically of IL-1β in metabolism.
In vivo acutely administered IL-1β dose dependently induced insulin secretion even at IL-1β concentrations in the circulation that are below the detection limit.
Together with glucose IL-1β promotes insulin secretion via parasympathetic nerve stimulation. In vitro IL-1β had a dual effect on glucose stimulated insulin secretion: it was beneficial at low doses and deleterious at high doses. The endotoxin lipopolysaccharide (LPS) strongly induced IL-1β, stimulated insulin secretion and improved glucose tolerance. Interestingly, the improvement of glucose tolerance was not only a consequence of increased insulin levels but was also due to direct IL-1β mediated glucose uptake into various tissues. One of the compartments responding to IL-1β with elevated glucose uptake was the cells of the immune system, mainly macrophages. We further show that macrophages significantly contribute to IL-1β mediated glucose disposal from the circulation. In addition, this work provides evidence for a role of insulin in mounting an immune response. Indeed, insulin increased the secretion of IL-1β via the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome preferentially in inflammatory M1 macrophages but not from alternatively activated M2 macrophages. In line with this response, M1 macrophages expressed higher levels of insulin receptors than naïve or M2. Further, insulin had an overall pro inflammatory effect in naïve and inflammatory macrophages, which could be attributed to increased glucose uptake via the GLUT1 glucose transporter.