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Somatostatin (SRIF) receptors (ssts) comprise a family of heptahelical membrane proteins encoded by five related genes that map to separate chromosomes and which, with the exception of sst 1 , are intronless. The ssts 1–4 display weak selectivity for SRIF-14 binding, whereas sst 5 is SRIF-28—selective. Based on structural similarity and reactivity for octapeptide and hexapeptide sst analogs, ssts 2,3 and sst 5 belong to a similar sst subclass; ssts 1–4 react poorly with these analogs and belong to a separate subclass. All five ssts are functionally coupled to inhibition of adenylyl cyclase via pertussis toxin-sensitive guanosine triphosphate (GTP)-binding proteins. mRNA for ssts 1–5 is widely expressed in brain and peripheral organs and displays an overlapping but characteristic pattern that is subtype-selective and tissue- and species-specific. All pituitary cell subsets express sst 2 and sst 5 , with sst 5 being more abundant. Individual pituitary cells coexpress multiple sst subtypes. The binding pocket for SRIF-14 ligand lies deep within the membrane in transmembrane domains (TMDs) 3 to 7. Except for extracellular loop 2, it does not involve the other exofacial structures. Human (h)sst 2 A and hsst 5 undergo agonist-mediated desensitization, associated with receptor internalization. The C-tail segment of hsst 5 displays positive molecular internalization signals. The ssts inhibit the growth of tumor cells directly, through blockade of mitogenic signaling leading to growth arrest and through induction of apoptosis. This process is associated with translocation of phosphotyrosine phosphatase (PTP) 1C from the cytosol to the membrane.

In the present study we have attempted to assess the functional status of somatostatin cells in relation to the function of the other islet cell types (B, A, and PP cells) in the BB Wistar rat. Somatostatin-like immunoreactivity (SLI), glucagon, and insulin were measured in extracted plasma obtained from the hepatic portal vein (PV) and inferior vena cava (IVC) of acutely diabetic untreated rats, insulin-treated diabetic rats and nondiabetic controls. Extracts of the pancreas were assayed for SLI, glucagon, and insulin, and the pancreatic populations of A, B, D, and PP cells were evaluated by morphometry. Extrapancreatic somatostatin changes were assessed by measurement of SLI in extracts of the whole gut, hypothalamus, and retina. Direct studies of SLI, glucagon, and insulin secretion in response to glucose, arginine, and theophylline were carried out using the isolated perfused pancreases of two separate groups of untreated diabetic and nondiabetic rats. Our results showed that in the severely insulin deficient BB Wistar rat (1) pancreatic concentrations of SLI, glucagon, and insulin were reduced; (2) the B cells are virtually eliminated and the D cells severely reduced early in diabetes; A and PP cells are resistant initially but eventually sustain major losses as observed in terminal islets; (3) retinal SLI is reduced, but SLI in gut and brain appears unchanged; (4) the secretion of SLI, glucagon, and insulin from the perfused pancreas is diminished 60%, 36%, and 99%, respectively; (5) PV and IVC blood levels of SLI and glucagon are elevated despite decreased pancreatic secretion; (6) The trans-hepatic gradient of SLI is reduced; and (7) Insulin treatment normalizes the elevated PV and IVC levels of SLI and glucagon. It is concluded that the elevated PV and IVC levels of SLI are secondary to insulin deficiency and result from increased SLI secretion most probably from the gut and from diminished hepatic metabolism. The origin of the hyperglucagonemia is less certain, but as in the case of SLI, important contributions from extra-pancreatic secretion appears likely.

Within the central nervous system, immunoreactive somatostatin (SRIF) has been localized to fibers in the external zone of the median eminence, neuronal cell bodies in the anterior hypothalamus, axons in the posterior pituitary lobe, and spinal ganglia and fibers in the spinal cord.1 This extensive brain distribution, the synaptosomal localization, and the effects of SRIF on behavior and on the spontaneous electrical activity of single neuron units in many parts of the brain suggest that the peptide may serve as a central neurotransmitter or a modulator of neuronal function.2 Although these observations imply an important role for SRIF in brain function, little is currently known about the factors controlling the secretion of SRIF from nerve cells. Since the neurohypophysis and stalk median eminence (SME) region of the hypothalamus contain a high concentration of SRIF and can be readily isolated, we have used them as models for studying the release of the peptide from nerve terminals in vitro.3