Failure to secrete sufficient quantities of insulin is a pathological feature of type-1 and type-2 diabetes, and also reduces the success of islet cell transplantation. Here we demonstrate in a number of models that Y1 receptor signaling inhibits insulin release in b-cells, and show that this can be pharmacologically manipulated to boost insulin secretion. Importantly, transplanting islets with Y1 receptor deficiency accelerates the normalization of hyperglycemia in chemically induced diabetic recipient mice, which can also be achieved by short-term pharmacological blockade of Y1 receptors in transplanted mouse and human islets. Furthermore, treatment of NOD mice with a Y1 receptor antagonist delays the onset of diabetes. Mechanistically, Y1 receptor signaling in islets inhibits the production of cAMP, which via CREB mediated pathways results in the down-regulation of several key enzymes in glycolysis and ATP production. Thus, manipulating Y1 receptor signaling in β-cells offers a unique therapeutic opportunity for correcting insulin deficiency as it occurs in the pathological state of type-1 diabetes as well as during islet transplantation.