Pancreatic islets have a central role in blood glucose homeostasis. In addition to insulin-producing β-cells and glucagon-secreting α-cells, the islets contain somatostatin-releasing δ-cells. Somatostatin is a powerful inhibitor of insulin and glucagon secretion. It is normally secreted in response to glucose and there is evidence suggesting its release becomes perturbed in diabetes. Little is known about the control of somatostatin release. Closure of ATP-regulated K⁺-channels (K_ATP-channels) and a depolarization-evoked increase in cytoplasmic free Ca²⁺ concentration ([Ca²⁺]_i)^,, have been proposed to be essential. Here, we report that somatostatin release evoked by high glucose (≥10 mM) is unaffected by the K_ATP-channel activator diazoxide and proceeds normally in K_ATP-channel-deficient islets. Glucose-induced somatostatin secretion is instead primarily dependent on Ca²⁺-induced Ca²⁺-release (CICR). This constitutes a novel mechanism for K_ATP-channel-independent metabolic control of pancreatic hormone secretion.