The pancreatic islets are key micro-organs of the endocrine system that allow the maintenance of glycemic control through hormone secretion, mainly beta cell-derived insulin. Increasing evidence suggests a role of the immune system to finely tune metabolic homeostasis. As such, macrophages residing inside pancreatic islets have recently emerged as an important component that may support islet integrity and regulate insulin secretion. Islet macrophages have a surprising activated phenotype even at steady-state and a certain level of islet inflammation seems required for homeostasis. Our preliminary data suggest that macrophage activation may be primed by a specific metabolic reprogramming orchestrated by cystine flux, while being tightly controlled by the TGFb pathway. I propose that this cystine-TGFb balance may shape islet macrophage phenotype and subsequently, impact on beta cell function. My project aims at deciphering the metabolic demands and molecular mechanisms underlying such activation in islets in both females and males at steady-state and in the pathological context of obesity and type 2 diabetes. Learning from islet macrophage endogenous and intrinsic signaling pathways may benefit to the understanding of endocrine pathologies.