Expression and Regulation of Neuropeptide Y (NPY) in the Islets of Langerhans

Sammanfattning: This thesis deals with the expression, localization and regulation of neuropeptide Y (NPY) in the pancreatic islets of Langerhans under normal and experimental conditions. NPY is widely distributed in the mammalian nervous system and belongs to a family of closely related petides also comprising peptide YY (PYY) and pancreatic polypeptide (PP). NPY exerts a variety of biological effects, such as stimulation of food intake, vasoconstriction, regulation of endocrine functions, and in the pancreas inhibition of insulin secretion. All three peptides occur in the mammalian pancreas; NPY in neuronal elements adrenergic as well as nonadrenergic, and PP and PYY in endocrine cells. Reinnervation of xenografts consisting of purified rat ß-cells and nonß-cells, respectively, transplanted beneath the kidney capsule of nude mouse revealed ingrowth of numerous sympathetic NPY-containing nerves into the ß-cell grafts while reinnervation of nonß-cell grafts was scarce, suggesting a neurotrophic action of the ß-cells. The islet expression and localization of NPY differed between species and was related to the developmental stage in rat. In islets of the hamster, NPY was detected in numerous nerve fibers as well as in somatostatin producing cells, while NPY was confined to nerve fibers within islets of the adult rat. During rat embryogenesis expression of NPY was detected in islet cells and co-localized with insulin. The expression of NPY in fetal rat ß-cells coincides with the known prepartal glucocorticoid surge, which rapidly declines after birth. At the same time the expression of NPY in the ß-cells disappears. Following treatment with the potent glucocorticoid dexamethasone of adult rats, a model for type 2 diabetes, NPY expression was re-induced in the ß-cells. The NPY expression in rat ß-cells rapidly declined after cessation of dexamethasone treatment, indicating that expression of NPY in rat ß-cells is dependent on continuous excessive levels of glucocorticoids. The glucocorticoid-induced expression of NPY in rat ß-cells was found to be markedly reduced by concomitant treatment with insulin or by sympathectomy. Culture of the insulin-producing cell line RINm5F with dexamethasone also induced expression of NPY. Stimulation of RINm5F cells with D-glyceraldehyde and depolarization with KCl increased the release of insulin Ca2+-dependently. However, the release of NPY was not affected by stimulation or removal of extracellular Ca2+, reflecting a constitutive release of NPY in contrast to the regulated release of insulin. Glucocorticoids induce peripheral insulin resistance with increased demands on the functional capacity of the ß-cells to produce and secrete insulin, as in type 2 diabetes. Our findings suggest that the expression of NPY in ß-cells could be part of the ß-cell activation upon the increased secretory demands induced by dexamethasone. Possibly, NPY, being a potent inhibitor of insulin secretion, could act by paracrine or autocrine mechanisms to prevent overwork of the ß-cells.