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The effect of the type of venous drainage of the graft on its endocrine function was studied in two groups of pigs after segmental pancrease autotransplantation. Group 1 comprised 10 pigs with portal venous drainage (PVD) and group 2 comprised 10 pigs with systemic venous drainage (SVD). The graft consisted of body and tail of the pancreas. The pigs were totally pancreatectomized. The pancreatic duct was occluded by neoprene injected into the duct. One week before and 1 and 3 months after transplantation, intravenous glucose tolerance (IVGTT) and meal stimulation tests (MST) were performed. Plasma glucose (PG), insulin (INS), C-peptide, glucagon (GLU),and pancreatic polypeptide (PP) were measured during the tests. All pigs had normal fasting PG, 1 and 3 months after PanTx, although MST disclosed significantly higher PG (P<0.05) during the test after transplantation. In the PVD group, a decrease in INS level during both test was recorded after PanTx (P<0.05), while in the SVD group a nonsignificant rise in INS level was recorded compared with before transplant. A significant difference (P<0.05) in INS levels were present both 1 and 3 mon. after PanTx between the two groups. Pigs with PVD showed a higher (P<0.05) C-peptide level than pigs with SVD during IVGTT. The initial significant rise in PP during MST and the initial fall in PP during IVGTT recorded in all pigs before transplantation were totally lost after transplantation in both groups. During the tests, PP remained steady and significantly lower than the pretransplantation levels in both groups. A significantly higher GLU level during both IVGTT and MST was observed in SVD compared with PVD 1 month after PanTx (P<0.05), being more pronounced during MST. This accentuated GLU concentration decreased by 3 months after transplantation, although it was still significantly greater than pretransplantation levels. We concluded that the unnatural mode of delivery of pancreas endocrine secretion to systemic rather than to portal circulation leads to derangements in pancreatic endocrine function in order to maintain glucose homeostasis. This may cause earlier exhaustion of islet cells. Segmental rather than whole organ and duct occlusion rather than exocrine drainage may further contribute to this, shortening the effective life of the graft.

The neuropeptide galanin is known to inhibit insulin secretion in a variety of species. However, controversies exist regarding its action on insulin secretion in the perfused pig pancreas, since both inhibitory and stimulatory effects have been described. We therefore perfused the isolated porcine pancreatico-duodenal block with galanin (100 nmol/l) in the presence of 5 or 15 mmol/l glucose or with 5 mmol/l glucose and 10 mumol/l tolbutamide. We found that at this dose level, galanin did not affect insulin secretion stimulated by glucose alone. In contrast, galanin clearly suppressed tolbutamide-stimulated insulin secretion. Hence, we conclude that galanin has a weak influence on insulin secretion in the pig pancreas, being unable to inhibit glucose-stimulated insulin secretion at the dose level of 100 nmol/l. However, when active, galanin clearly inhibits insulin secretion also in the pig pancreas.

The alpha-adrenoceptor subtype mediating inhibition of insulin secretion in the pig was examined in an isolated pancreas preparation perfused with 5 mM glucose. It was found that noradrenaline and the alpha 1-adrenoceptor agonist phenylephrine, but not the alpha 2-adrenoceptor agonist UK 14,304, inhibited insulin secretion. The effect of noradrenaline was abolished by the alpha 1-adrenoceptor antagonist prazosin but was not affected by the alpha 2-adrenoceptor antagonist idazoxan. The inhibitory effect of phenylephrine was also inhibited by prazosin. Thus, in the pig, the alpha-adrenoceptor subtype inhibiting insulin secretion is of the alpha 1-type, which is different from the subtype involved in other species.

The 27-amino acid peptide gastrin releasing peptide (GRP-(1-27] was infused at 4 dose levels (0.01, 0.1, 1.0, and 10 nM) into the arterial line of the isolated perfused porcine pancreas. Infusions were performed at 3 different perfusate glucose levels (3.5, 5.0, and 8.0 mM) and at two levels of amino acids (5 and 15 mM). GRP-(1-27) stimulated insulin and pancreatic polypeptide secretion and inhibited somatostatin secretion in a dose-dependent manner. Glucagon secretion was unaffected by infusion of GRP under all circumstances. The effect of GRP-(1-27) on insulin secretion was enhanced with increasing perfusate glucose levels, whereas the effects upon somatostatin and pancreatic polypeptide secretion were independent of perfusate glucose levels. The responses to GRP were unaffected by elevation of the concentration of amino acids in the perfusate. The effects of GRP were unaffected by atropine at 10(-6) M. The localization of GRP within the porcine pancreas, its release during electrical stimulation of the vagus nerve, and its potent effects upon pancreatic endocrine secretion make it conceivable that the peptide participates in parasympathetic regulation of pancreatic endocrine secretion.

The effects of the four main forms of gastrin (component I, gastrin-34, gastrin-17, and gastrin-14) on insulin, glucagon, and exocrine secretion were measured on the isolated perfused porcine pancreas. All gastrins were studied in concentrations ranging from 10(-11) to 10(-8) M. Depending on the glucose concentration in the perfusate, all four gastrins increased insulin or glucagon secretion in a dose-dependent manner in concentrations above 10(-10) M. These concentrations are slightly above the arterial concentrations in normal pig and man, but they correspond to gastrin concentrations measured in patients with achlorhydria and gastrinomas. The exocrine secretion was stimulated by all gastrins in a dose-dependent manner. The lowest concentrations that stimulated flow rate significantly were within the physiologic range, 10(-11) and 10(-10) M. All gastrins induced maximal flow rate at a concentration of 10(-9) M. The sulfated form of gastrin-17 had the greatest efficacy. The results indicate that all gastrins may influence the exocrine secretion under normal conditions and the endocrine secretion in diseases with endogenous hypergastrinemia.

The responses of gastric inhibitory polypeptide (GIP) and insulin to intraduodenal (OGTT) and iv (IVGI) glucose infusions were measured in 14 late fetal and 9 neonatal pigs. Basal plasma glucose (P < 0.01) and GIP (P < 0.001) concentrations were lower in the fetal than in the neonatal pigs, while basal plasma insulin was not significantly different in the two groups. In the fetal pigs, almost identical plasma glucose curves were obtained during the OGTT and the IVGI, but plasma insulin did not change during either test. In these pigs, plasma GIP increased 3-fold (P < 0.01) during the OGTT, whereas no significant changes in plasma GIP were observed during the IVGI. In the neonatal pigs, plasma glucose increased more during the OGTT than during the IVGI, but plasma insulin exhibited similar increments during both tests. Thus, the insulinogenic index of the IVGI was almost 3 times higher than that of the OGTT (P < 0.05). In contrast to the normal increment in plasma GIP observed in fetal pigs, plasma GIP decreased significantly during both tests in the neonatal pigs. It is concluded that beta-cells of fetal pigs are unresponsive to acute elevations of plasma glucose with or without a concomitant increase in plasma GIP. Conversely, beta-cells of neonatal pigs exhibit a significant response to hyperglycemia, but the enteroinsular axis is defective, since more insulin is released after iv than during intraduodenal glucose administration. The defective enteroinsular axis in neonatal pigs might be due to the observed fall in plasma GIP during the OGTT.

We have previously isolated from porcine small intestine a peptide known as glicentin. The C-terminal portion of glicentin consists of the sequence of glucagon extended at its C terminus by an octapeptide, and differs slightly from the sequence of a proposed fragment of proglucagon. Glicentin-like material has been demonstrated in the pancreatic A cell, wherein it is located in the periphery of the secretory granules, whereas glucagon is located in the centre of the granules. To study the relationship of glicentin to the biosynthesis of glucagon, we have now investigated the glucagon-like and glicentin-like peptides in extracts and perfusates of the porcine pancreas. Our findings that a peptide with glicentin-like immunoreactivity, and intermediate in size between glicentin and glucagon, is secreted synchronously with glucagon suggest that this glicentin-related peptide is a major cleavage product of proglucagon.

The effect of electrical stimulation of the splanchnic and the vagus nerve supply to isolated, perfused pig pancreas on the secretion of insulin, glucagon and pancreatic polypeptide (PP) was investigated. Functional integrity of the autonomic nerve supply was assessed by the effect of nerve stimulation on vascular resistance and exocrine secretion. Splanchnic nerve stimulation increased glucagon and PP output (2 to 3-fold) and inhibited insulin output (by 42%). Propranolol abolished the effect on PP and glucagon secretion, but did not affect the inhibition of insulin secretion. Phenoxybenzamine abolished the inhibition of insulin secretion, reduced the effect on glucagon secretion and enhanced the effect on pancreatic polypeptide secretion. Combined alpha- and beta-adrenergic blockade abolished all effects of splanchnic nerve stimulation. Vagus nerve stimulation increased the secretion of all 3 hormones (PP: up to 30-fold, insulin and glucagon: 3 to 5-fold). The effect on insulin and PP-secretion was mimicked by acetylcholine at 10(-7)-10(-6) M, whereas glucagon secretion was inhibited. The effect of vagus nerve stimulation on insulin and PP secretion was augmented by physostigmine, and inhibited (but not abolished) by atropine at 10(-7)-10(-6) M. The effect on glucagon secretion was inhibited by physostigmine and unaffected by atropine. It is concluded that all of the effects of splanchnic nerve stimulation on insulin and PP secretion can be explained by interactions of norepinephrine with excitatory beta-receptors on PP-cells and inhibitory receptors on the insulin cells. Both cell types are also stimulated via muscarinic cholinoceptors, but the partial atropine resistance suggests that other transmitters participate in vagal activation. The nervous regulation of glucagon secretion is complex and may involve the peptidergic innervation of the pancreatic islets.

In pancreatic islets a peptide corresponding to the C-terminal tetrapeptide amide of cholecystokinin and gastrin, Trp-Met-Asp-Phe-NH2, is present in nerve terminals. This tetrapeptide amide is uniquely potent as a releaser of insulin and the other islet hormones, whereas larger cholecystokinins and gastrins as well as tetrapeptide analogues are considerably less potent. We suggest that neural release of the tetrapeptide amide is implicated in regulation of pancreatic hormone secretion.