The neuropeptides GRP and PACAP and the function of the endocrine pancreas - A study on receptor deficient mice

University dissertation from Kristin Persson, Tullg 9, S-22354 Lund, Sweden

Abstract: The parasympathetic nerves are important for the regulation of insulin secretion, in particular after meal intake. Apart from acetylcholine, several neuropeptides can be found in the parasympathetic nerves innervating the islets of Langerhans, including gastrin-releasing peptide (GRP) and pituitary adenylate cyclase activating polypeptide (PACAP). Exogenous administration of either GRP or PACAP has been shown to increase insulin secretion in a glucose dependant manner. To establish the importance of GRP and PACAP for the function of the endocrine pancreas, we studied mice lacking either the GRP receptor (GRPR-/Y) or the PACAP-specific receptor PAC1 (PAC1-/-), with regard to insulin secretion, both after metabolic or neural stimuli. GRPR-/Y had an impaired insulin secretion and glucose tolerance after oral administration of glucose, due to a combination of impaired secretion of islet hormones after autonomic neural activation and impaired release of incretin hormones from the gut. However, they did not have an impaired glucose-stimulated insulin secretion after intravenous glucose. Instead, it was exaggerated, possibly as a result of increased cholinergic responsiveness, which might be a result of a long-standing glucose tolerance. PAC1-/- mice had an impaired glucose stimulated insulin secretion. PAC1-/- also had an impaired glucagon secretion after hypoglycemia, supporting the role of PACAP as an important neuropeptide in the parasympathetic nervous system. Hence, GRP and PACAP are important for the parasympathetic regulation of islet function, like after a meal. GRP is also involved in the release of endocrine hormones from the gut, and PACAP seems important for islet function.

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