Metabolism regulates exposure of pancreatic islets to circulating molecules in vivo

Pancreatic beta cells modulate insulin secretion through rapid sensing of blood glucose and integration of gut-derived signals. Increased insulin demand during pregnancy and obesity alters islet function and mass, and leads to gestational and type 2 diabetes in predisposed individuals. However, it is unclear how blood-borne factors dynamically access the islets of Langerhans. Thus, understanding the changes in circulating molecule distribution that accompany compensatory beta cell expansion may be key to developing novel anti-diabetic therapies. Here, using 2-photon microscopy in vivo in mice, we demonstrate that islets are almost instantly exposed to peaks of circulating molecules, which rapidly pervade the tissue before clearance. In addition, both gestation and short-term high fat diet-feeding decrease molecule extravasation and uptake rates in vivo in islets, independently of beta cell expansion or islet blood flow velocity. Together, these data support a role for islet vascular permeability in shaping beta cell adaptive responses to metabolic demand by modulating the access and sensing of circulating molecules.