Substitutes for the endocrine pancreas

Since it is generally accepted that a tight metabolic control might prevent the chronic complications of diabetes mellitus, several systems have been developed in which insulin is administered in a manner that mimicks the characteristics of insulin secretion. 1) In the so-called closed-loop systems, insulin delivery is regulated by the concomitant plasma glucose level. These systems, which involve continuous measurement of plasma glucose concentration are not to date implantable and have been used so far only for short-term studies. 2) By contrast, in the "open-loop systems", no glucose sensor is needed and insulin delivery is pre-programmed to achieve a constant basal infusion with peaks of insulin delivery during the meal periods. These systems have been used in man for several months. The present achievement and limitations of both kinds of systems are discussed in this review.     

Galanin and the endocrine pancreas

Galanin is a 29 amino acid peptide, initially isolated from the porcine small intestine. The peptide has been shown to occur in intrapancreatic nerves in close association to the islets. Its effects on islet hormone secretion and its possible mechanisms behind these effects are reviewed. Galanin has been shown to inhibit basal and stimulated insulin secretion both in vivo and in vitro under a variety of experimental conditions. The peptide has also been shown to inhibit somatostatin secretion and the secretion of pancreatic polypeptide (PP). With regard to glucagon secretion, however, results in the literature are not consistent since both stimulatory and inhibitory effects have been reported. A direct interaction with the pancreatic beta-cells has been proposed behind its inhibitory action on insulin secretion, since galanin inhibits insulin secretion from isolated beta-cells from obese, hyperglycaemic, mice. Galanin has thereby also been shown to induce repolarization and to reduce the free Ca2+ concentration, [Ca2+]i. The reduction in [Ca2+]i is probably not due to a direct interference with the voltage-activated Ca2+ channels, since there is no effect of galanin when these channels are opened by depolarization induced by high concentrations of K+. Instead, preliminary studies indicate that galanin activates the K+ channels that are regulated by ATP, in turn inducing a repolarization-induced reduction in [Ca2+]i resulting in reduced insulin secretion. However, the possibility that galanin inhibits the insulin secretory mechanism at a step distal to the regulation of cytoplasmic free Ca2+ concentration should not be overlooked.     

Pathology of the endocrine pancreas.

An immunocytochemical analysis of 94 pancreatic endocrine tumors revealed that 73 tumors were multicellular. Significant amounts of somatostatin and human pancreatic polypeptide were found by radioimmunoassay in extracts of 19 and 17 tumors resp., in addition to the hormone causing the clinical syndrome. Numerous tumors contained ductular structures. In the surrounding pancreatic parenchyma a proliferation of small ducts and budding-off from the ductular epithelium of endocrine cells was often observed. These features are hallmarks of nesidioblastosis of the endocrine pancreas which is a hyperplasia. In multiple endocrine neoplasia I hyperplasia of the endocrine pancreas is combined with larger nodules, currently labeled tumors. On the basis of these findings it is conceivable that pancreatic endocrine tumors are not primarily neoplastic and autonomous but that they are rather of hyperplastic origin.     

Formation and regeneration of the endocrine pancreas

The elaboration of the pancreas from epithelial buds to the intricate organ requires complex patterning information that controls fundamental cellular processes such as differentiation and proliferation of pancreatic progenitor cells. During pancreatic organogenesis, endocrine cells are generated from a population of pancreatic progenitor cells. The progenitor cells during the early development simultaneously receive multiple signals, some mitogenic and some inducing differentiation. These extrinsic signals are interpreted through an intrinsic mechanism that either commits the progenitor cell to the mitotic cell cycle or leads to exit from the cell cycle in order to differentiate. The endocrine cells that differentiate from progenitor cells are postmitotic, and direct lineage tracing analyses indicate that a population of progenitor cells persists throughout embryogenesis to allow the differentiation of new endocrine cells. At the end of embryogenesis an early postnatal period is characterized by high rates of beta cell proliferation leading to massive increases in beta cell mass. The beta cell mass expansion considerably slows down in adult animals, though variations in insulin demand due to physiological and pathological states such as pregnancy and obesity can lead to adaptive changes in the beta cells that include hyperplasia, hypertrophy, and increased insulin synthesis and secretion. Deciphering the mechanisms that regulate the plasticity of beta cell mass can be an important step in developing effective strategies to treat diabetes.     

Ontogeny of endocrine responses to methadone in rats

The effects of methadone (METH) on serum levels of prolactin (PRL), growth hormone (GH), corticosterone (CS) and TSH were determined in developing rats. METH increased PRL, GH and CS and decreased TSH at all ages tested, but the time course and magnitude of these effects changed during ontogeny. METH effects on day 10 were lower in magnitude than those observed in adults. In 20 day old pups, METH effects on GH and CS were comparable to those of adults, but TSH effects were still blunted. METH effects on hormone secretion in both 10 and 20 day old pups lasted longer than those observed in adults. Naloxone blocked all hormonal responses in adults, but did not completely block METH effects on CS secretion in 10 day old pups.     

Synaptophysin immunoreactivity in the mammalian endocrine pancreas

Summary Synaptophysin, a major membrane glycoprotein of small presynaptic vesicles in neurons, has also been found in microvesicles of endocrine cells, e.g., of the endocrine pancreas. In the present study, the endocrine pancreas in 9 mammalian species (man, dog, mink, bovine, rabbit, guinea pig, rat, mouse, gerbil) has been investigated immunohistochemically for synaptophysin immunoreactivity. Synaptophysin-positive cells have been identified and localized on semithin plastic sections. Our study demonstrates that, in all species examined, all pancreatic endocrine cell types are consistently synaptophysin-positive independent of their location within the tissue, or the conditions of tissue processing. In addition, a few cells that cannot be hormonally identified show synaptophysin immunoreactivity. Hence, synaptophysin appears to be a regular constituent of all pancreatic endocrine cells in mammals. In several species, a subpopulation of endocrine cells, consisting of glucagon-containing and/or pancreatic-polypeptide-containing cells, exhibits a significantly higher degree of synaptophysin immunoreactivity. In the gerbil, this heterogeneity can readily be detected from the day of birth onwards. Our findings indicate that closely related endocrine cell types may differ with respect to the content of synaptophysin.     

Surgical treatment of endocrine tumors of the pancreas

Surgeons have a key role in the management of most endocrine tumors of the pancreas. The objective of surgery is either curative or palliative, according to the resectability of the tumor. The preoperative management includes the assertion of the tumoral syndrome, the localization of the tumor by imaging techniques and the preparation of the patient to surgery. Emergency indications to operate have become exceptional since the temporary control of inappropriate secretions by pharmacologic agents is available. Intraoperative ultrasonography is useful both for detection of the tumors and selection of the best procedure for resection. A careful postoperative follow-up is advocated for patients with malignant tumors and MEN-1, since iterative resections can be undertaken in case of limited tumoral recurrence or liver metastases. The place of hepatic transplantation for diffuse metastases is still under evaluation.     

Cx36 and the function of endocrine pancreas

The secretory, duct, connective and vascular cells of pancreas are connected by gap junctions, made of different connexins. The insulin-producing beta-cells, which form the bulk of endocrine pancreatic islets, express predominantly Cx36. To assess the function of this connexin, we have first studied its expression in rats, during sequential changes of pancreatic function which were induced by the implantation of a secreting insulinoma. We observed that changes in beta-cell function were paralleled by changes in Cx36 expression. We have also begun to investigate mutant mice lacking Cx36. The absence of this protein did not affect the development and differentiation of beta-cells but appeared to alter their secretion. We have studied this effect in MIN6 cells which spontaneously express Cx36. After stable transfection of a construct that markedly reduced the expression of this connexin, we observed that MIN6 cells were no more able to secrete insulin, in contrast to wild type controls, and differentially displayed a series of still unknown genes. The data provide evidence that Cx36-dependent signaling contributes to regulate the function of native and tumoral insulin-producing cells.     

Ontogeny of peptide-producing nerves and endocrine cells of the gastro-duodeno-pancreatic region

Summary The ontogeny of different types of endocrine cells and nerves producing different hormonal peptides was studied by immunocytochemistry. The data indicate that several endocrine cell types are more frequent in the foetal than in the adult gastro-duodeno-pancreatic region. Some cell types were found to show an over-lapping distribution. Such distributional over-laps were more frequent in foetuses and neonates than in adults. Both parallel and non-parallel patterns of development of endocrine cells and peptide-producing nerves were detected. Together with available information on the trophic effects of the gastrointestinal hormonal peptides these findings indicate that foetal and neonatal endocrine cells may participate in the regulation of growth and morphogenesis in the gastrointestinal tract.     

The endocrine pancreas of Alligator mississippiensis

Summary Immunocytochemical methods for light and electron microscopy were used to demonstrate the regulatory peptides present in the endocrine pancreas of thealligator, Alligator mississippiensis.The peptides studied included insulin, glucagon (pancreatic and enteric), somatostatin, pancreatic polypeptide (avian, bovine and human), vasoactive intestinal polypeptide, substance P, metenkephalin, -endorphin, C-terminal gastrin/CCK and gastric inhibitory polypeptide. Endocrine cells were detected using antisera to insulin, pancreatic glucagon, somatostatin and avian pancreatic polypeptide, whereas peptidergic nerves were stained with antisera to vasoactive intestinal polypeptide. All other antisera were unreactive in the alligator pancreas. The peptide-containing structures were identified ultrastructurally by both the semithin/thin and immuno-gold methods. The results showed that five of the regulatory peptides commonly detected in the mammalian pancreas were immunologically recognisable in the alligator. In addition, the ultrastructural appearance of the peptide-containing cells was clearly distinct from that reported in mammals.     

Ontogeny of endocrine cells in the gut of the insect Periplaneta americana

Summary The ontogeny of the endocrine cells of the gut of the cockroach Periplaneta americana was studied by immunohistochemistry. During embryogenesis, the midgut begins to be formed as an outgrowth of the foregut and hindgut invaginations. Gut endocrine cells with pancreatic polypeptide (PP)-like immunoreactivity begin to appear at the anterior and posterior ends of the forming midgut. These cells are restricted to the midgut epithelium, and no mitotic cells with PP-like immunoreactivity are observed. These results strongly suggest that the gut endocrine cells, at least those with PP-like immunoreactivity, are derived from precursor cells they have in common with other epithelial cells of the midgut.     

Purinergic receptors in the endocrine and exocrine pancreas

The pancreas is a complex gland performing both endocrine and exocrine functions. In recent years there has been increasing evidence that both endocrine and exocrine cells possess purinergic receptors, which influence processes such as insulin secretion and epithelial ion transport. Most commonly, these processes have been viewed separately. In beta cells, stimulation of P2Y(1) receptors amplifies secretion of insulin in the presence of glucose. Nucleotides released from secretory granules could also contribute to autocrine/paracrine regulation in pancreatic islets. In addition to P2Y(1) receptors, there is also evidence for other P2 and adenosine receptors in beta cells (P2Y(2), P2Y(4), P2Y(6), P2X subtypes and A(1) receptors) and in glucagon-secreting alpha cells (P2X(7), A(2) receptors). In the exocrine pancreas, acini release ATP and ATP-hydrolysing and ATP-generating enzymes. P2 receptors are prominent in pancreatic ducts, and several studies indicate that P2Y(2), P2Y(4), P2Y(11), P2X(4) and P2X(7) receptors could regulate secretion, primarily by affecting Cl(-) and K(+) channels and intracellular Ca(2+) signalling. In order to understand the physiology of the whole organ, it is necessary to consider the full complement of purinergic receptors on different cells as well as the structural and functional relation between various cells within the whole organ. In addition to the possible physiological function of purinergic receptors, this review analyses whether the receptors could be potential therapeutic targets for drug design aimed at treatment of pancreatic diseases.