Clinical and Translational Report Paracrine Interactions within the Pancreatic Islet Determine the Glycemic Set Point Graphical Abstract Highlights d Species-specific glycemic set points are transferred with islet transplantation d The pancreatic islet thus carries the information to impose the glycemic set point d The glycemic set point does not depend on islet graft mass d Control of glycemia by insulin secretion relies on paracrine input from alpha cells Authors Rayner Rodriguez-Diaz, R. Damaris Molano, Jonathan R. Weitz, ..., Antonello Pileggi, Alejandro Caicedo, Per-Olof Berggren Correspondence r.diaz4@med.miami.edu (R.R.-D.), acaicedo@med.miami.edu (A.C.), per-olof.berggren@ki.se (P.-O.B.) In Brief It is not known if there is a leading organ that maintains blood glucose levels within the narrow physiological range. Rodriguez-Diaz and colleagues show that the pancreatic islet serves as the systemic glucostat and that paracrine glucagon input from alpha cells is essential for setting the glycemic set point. Therapeutic strategies using glucagon receptor antagonists to lower glycemia should thus be reassessed. Rodriguez-Diaz et al., 2018, Cell Metabolism 27, 549–558 March 6, 2018 ª 2018 Elsevier Inc. https://doi.org/10.1016/j.cmet.2018.01.015