In this review, we focus on the paracrine regulatory role of δ-cells from four different perspectives: (1) the structural basis of δ-cells; (2) the intracellular signaling of δ-cells in response to nutritional stimuli; (3) the bidirectional signals involved the paracrine crosstalks between δ- and β-cells, δ- and α-cells, and how they coordinate insulin and glucagon secretion; (4) how these interactions are affected in the pathophysiology of diabetes and potential pharmacological implication for glycemic management. Here, INS is linked to diabetes mellitus.