The concentration of thyrotropin-releasing hormone (TRH, thyroliberin) in rat islets of Langerhans is 30-fold higher than in whole rat pancreas, indicating that the islets are the main source of pancreatic TRH. The TRH extracted from islets is indistinguishable from synthetic TRH in its immunological and biological properties and in its inactivation by human serum. The physiologic function of islet TRH is unknown. However, because TRH is antagonistic to somatostatin in other systems, and somatostatin also is concentrated in islets in high concentrations, it is possible that islet TRH may serve a similar antagonistic function in the regulation of islet cell secretory activity. A rather ubiquitous distribution of thyrotropin-releasing hormone (TRH, thyroliberin) has been demonstrated through the use of a sensitive and specific radioimmunoassay. Significant amounts of TRH have been found in extra hypothalamic areas of the human brain (1-3) as well as in the central nervous system of several mammalian and submammalian species (4-6). The presence of TRH has also been reported in human placenta (7), rat retina (8), and frog skin (9). For this reason, it has been postulated that TRH may not only play a role in the regulation of pituitary thyrotropin and prolactin secretion but may also act as a neurotransmitter or modulator of synaptic function (5, 10). Recently Morley et al. (11) reported that TRH is present throughout the rat gastrointestinal tract as well as in the pancreas. This report confirms the latter finding and localizes TRH to the islets of Langerhans.MATERIALS AND METHODS Preparation of Animals. All rats were males weighing 200-250 g. Strains used were CD (Charles River Breeding Laboratories, Waltham, MA), Lewis (Microbiological Associates, Bethesda, MD), and Sprague-Dawley (Laboratory Supply, Indianapolis, IN). Purina rat chow was continuously available except during 48-hr fast. The animals were housed in screen-floor cages and were given tap water ad lib. Hypothyroid rats were prepared by surgical thyroidectomy, followed by intraperitoneal injection of 80 uCi of 13'I per rat and maintained on low-iodine diet (Teklad Mills, Madison, WI). They were used two months after the induction of hypothyroidism. Thyroid hormone-replaced rats were hypothyroid rats treated with 15 ,gg of triiodothyronine intraperitoneally 24 hr before the tissues were obtained. Rats of the Lewis and Sprague-Dawley strains were made diabetic by a single intravenous injection of streptozotocin (65 mg/kg of body weight) and used 7 and 10 days later.Isolation of Whole Pancreas and Islets. Rats were killed by decapitation and the pancreases were immediately excised.Fat and lymph nodes were trimmed away, and the residual tissue was weighed and frozen on dry ice. For isolation of pancreatic islets, rats were injected intraperitoneally with 0.25 ml of 4% pilocarpine-HCl 2 hr prior to decapitation. A group of rats was similarly pretreated prior to the isolation of the whole pancreas to check whether pilocarpine had any effect on the c...