Thrittene is a recently described peptide with a sequence homologous with somatostatin-28 ((1-13)) but is produced independent of the preprosomatostatin gene. It is localized in epithelial cells in stomach and gut mucosal crypts and in neuronal cell bodies in the myenteric plexus and enteric axons. It is also present in human plasma. The aim of this study was to determine whether the release of thrittene into the circulation was affected by the ingestion of nutrients and, if so, whether the pattern of release was distinct from the closely related peptide somatostatin-28 (S-28). Thrittene was indirectly measured in human plasma by an RIA using antiserum F4. F4 interacts with the Asn(5)-Pro(6) region shared by S-28 and thrittene. The contribution of S-28 to F4 immunoreactivity (F4-IR) was determined using a specific two-site assay, and this measure was subtracted from the total F4-IR to give an estimate of thrittene levels. Plasma for assay was taken from healthy men on 4 separate days before and after intake of: a mixed meal (715 kcal), and meals containing primarily fat (25 g; 225 kcal), carbohydrate (100 g; 454 kcal), and protein (22 g; 100 kcal). After the mixed meal, both S-28 and thrittene rose by 50-100% within 30 min and gradually declined by 4 h. These increments were mimicked after ingestion of fat. By contrast, thrittene levels increased after carbohydrate but not protein intake, whereas S-28 concentrations rose after protein but not carbohydrate ingestion. These findings indicate that thrittene is secreted into the mammalian circulation during food intake and raise the possibility that thrittene may play a role in nutrient disposition. The dichotomy in responses of thrittene and S-28 to ingestion of the major macronutrients suggests that they are secreted from different gastrointestinal cells.