A Strong Stomach for Somatostatin.

Evolution of life from single cell to complex multicellular organisms necessitated sophistication in communication between a myriad of specialized cell types. This communication is enabled by a network of neurocrine, endocrine, paracrine, and juxtracrine (contact-dependent) arrangements. The first 3 forms involve release of chemical messengers that activate receptors expressed on the surface or within the target cell to affect a response. Such an array of communication modes enables rapid (eg, neurocrine) and selective (eg, paracrine) communication, while also ensuring a broader reach of chemical substances to all cells within the system (eg, endocrine). One unique chemical within the organism that functions and is regulated by all of the aforementioned modes is somatostatin. Originally isolated from hypothalamic extracts as an inhibitory signal to GH release from the pituitary gland (1, 2), somatostatin was later found to be synthesized by an extensive network of distinct endocrine cells in the gastrointestinal (GI) tract and pancreas (3). Somatostatin subsequently was discovered to function broadly throughout the body as an inhibitor of multiple secretory processes, including insulin and glucagon from the pancreas, gastrin, secretin, cholecystokinin (CCK), vasoactive intestinal peptide, glucagon-like peptide 1, gastric inhibitory peptide, ghrelin, pepsin, and gastric acid from the digestive tract, T3, T4, and calcitonin from the thyroid gland, aldosterone from the adrenal gland, and monoamines from the brain (4, 5). Clinical therapeutics has taken advantage of some of these functions, resulting in the development of various somatostatin analogues for diagnosis, staging and treatment of certain neuroendocrine tumors and for treatment of acromegaly; they also hold promise to treat inflammatory conditions as well as obesity and diabetic complications (4, 6–8). Further studies on somatostatinsecreting cells, and in particular, the mechanisms regulating somatostatin release, hold similar promise. Gastric D cells serve as a major source for circulating somatostatin and are of particular interest because of their relatively large numbers as compared with other sources and due to their distinctive ability to secrete somatostatin in response to a plethora of neurotransmitters, hormones as well as nutrients. These somatostatin-secreting cells are similar to other gastric endocrine cells, which include ghrelin cells, serotonin-secreting enterochromaffin cells, histamine-secreting enterochromaffin-like cells and gastrin-secreting G cells, in that they are sparsely distributed within the mucosa. Nestled among neighboring endocrine and exocrine cells, the D cells exert inhibitory input onto their neighbors’ secretory capacities via release of somatostatin from characteristic basal cytoplasmic peduncles. Gastric D cells are also major contributors to the picomolar concentrations of somatostatin found in circulation, even though most of the somatostatin produced in the stomach acts locally and is rapidly degraded by proteases. Somatostatin therefore lacks selectivity and precision in its role as a “hormone,” in terms of both site of origin and its target organs (9). The speckled distribution of D cells within the gastric mucosa has hindered the derivation of homogenous populations of D cells thus slowing research on their physiology. Also, lack of selective antibodies to membrane-bound G protein-coupled receptors (GPCRs) and other receptor classes has largely prevented immunohistochemical characterization of the signaling systems that directly regulate somatostatin secretion and other aspects of D-cell function. Instead, insights into somatostatin secretion from D cells so far have been obtained mostly