Vagal, cholinergic regulation of pancreatic polypeptide secretion.

THE EFFECT OF EFFERENT, PARASYMPATHETIC STIMULATION UPON PANCREATIC POLYPEPTIDE (PP) SECRETION WAS STUDIED IN THREE WAYS: (a) Plasma PP concentrations increased in response to insulin-induced hypoglycemia in both normal subjects, from 11 pM (9.5-12.5) to 136 pM (118-147), n = 8 (median and interquartile range) and in duodenal ulcer patients, from 33 pM (21-52) to 213 pM (157-233), n = 7. The PP response to hypoglycemia was diminished by atropine in normal subjects (P < 0.005) and completely abolished by vagotomy in the duodenal ulcer patients. (b) Electrical stimulation, 8 Hz, of the vagal nerves in anesthetized pigs induced an increase in portal PP concentrations within 30 s from 32 pM (28-39) to 285 pM (248-294), n = 12. Minimal stimulatory frequency was 0.5 Hz and maximal stimulatory frequency 8-12 Hz. Atropine inhibited the PP response to electrical stimulation. Median inhibition with 0.5 mg of atropine/kg body wt was 74%, range 31-90%, n = 6. The response was eliminated by hexamethonium. Adrenergic alpha and beta blockade did not influence the release of PP in response to vagal stimulation. (c) Acetylcholine stimulated, in a dose-dependent manner, the secretion of PP from the isolated perfused porcine pancreas, half-maximal effective dose being 0.19 muM; maximal PP output in response to 5 min stimulation was 228 pmol, range 140-342 pmol, n = 5. Atropine completely abolished this response.The results of the present study together with the previously demonstrated poor PP response to food in vagotomized patients, indicate that vagal, cholinergic stimulation is a major regulator of PP secretion.

Effect of ethanol on the glucose-mediated insulin release in triply catheterized anesthetized pigs.

In order to further elucidate the potentiating effect of ethanol on the glucose-mediated insulin response, triply catheterized anesthetized pigs were submitted to an intravenous glucose infusion test after a four-hour preinfusion with ethanol (11 pigs) or saline (six pigs, control experiment). During the tests portal, hepatic, and peripheral venous blood was drawn simultaneously. Two series of ethanol-preinfusion experiments were carried out: in one series the serum ethanol concentration was maintained at approximately 10 mM and in the other at 19 mM. Compared with saline, 10 mM of serum ethanol induced a more than threefold increment in the insulin secretory response to glucose as estimated in the portal blood (p less than 0.01). Likewise, hepatic and peripheral venous blood insulin levels were enhanced (p less than 0.01). In contrast, 19 mM of serum ethanol did not elevate serum insulin levels above those found in the control experiments. When individual incremental portal insulin areas were plotted against the corresponding average value of serum ethanol in the preinfusion period, a significant inverse relationship was found (p less than 0.02), indicating a decrease in the potentiating effect of ethanol on the glucose-mediated insulin response with increasing levels of serum ethanol. Comparison of portal and hepatic incremental insulin areas revealed that ethanol did not, in the concentration range investigated, influence the hepatic insulin degradation rate. In conclusion, ethanol seems to potentiate, in an inverse concentration-dependent manner, the glucose-mediated insulin response through an action directly on the pancreas.

Porcine gastric insulin.

We recently found that plasma from pancreatectomized pigs contained concentrations of insulin of 5-10 muU/ml up to five days after pancreatectomy. In search of an extrapancreatic source of insulin, acid-ethanol extracts of porcine stomach and small bowel mucosa were investigated for the presence of insulin. The extracts of the stomach contained large amounts of insulin immunoreactivity while insulin was not detectable in extracts of the small bowel. Upon gel filtration, immunoreactive insulin eluted from the gastric mucosa in a major peak corresponding to the elution volume of an insulin standard and a minor peak corresponding to the elution volume of a proinsulin standard.

Effect of truncated glucagon-like peptide-1 [proglucagon-(78-107) amide] on endocrine secretion from pig pancreas, antrum, and nonantral stomach.

We studied the effect of truncated glucagon-like peptide-1 [naturally occurring GLP-1; proglucagon-(78-107) amide], a potent insulinotropic peptide from the pig ileum, on endocrine and exocrine secretion of potential gastrointestinal target organs using isolated perfused preparations of the porcine pancreas, antrum, and nonantral part of the stomach. Truncated GLP-1 significantly increased somatostatin secretion from the pancreas at 10(-10) mol/liter and more than doubled the secretion at 10(-9) mol/liter, but had no effect on either somatostatin or gastrin secretion from the antrum or on somatostatin secretion from the nonantral stomach in concentrations up to 10(-8) mol/liter. Insulin secretion from the pancreas (with 7 mmol/liter glucose in the perfusate) increased 2-fold with truncated GLP-1 at 10(-10) mol/liter and almost 5-fold at 10(-9) mol/liter. Pancreatic glucagon secretion was inhibited by 50% at 10(-10) mol/liter and by 70-80% at 10(-9) mol/liter. Full-length GLP-1 [proglucagon-(72-107)] and GLP-2 [proglucagon-(126-159)] had no effect on hormone secretion from any of the perfused organs. It is concluded that truncated GLP-1 may participate in an entero-insular control of pancreatic endocrine secretion.

Glucagon-like peptides GLP-1 and GLP-2, predicted products of the glucagon gene, are secreted separately from pig small intestine but not pancreas.

We developed specific antibodies and RIAs for glucagon-like peptides 1 and 2 (GLP-1 and GLP-2), two predicted products of the glucagon gene, and studied the occurrence, nature, and secretion of immunoreactive GLP-1 and GLP-2 in pig pancreas and small intestine. Immunoreactive GLP-1 and GLP-2 were identified in glucagon-producing cells of the pancreatic islets, and in glicentin-producing cells of the small intestine. Immunoreactive GLP-1 and 2 in intestinal extracts corresponded in molecular size to peptides synthesized according to the predicted structure. By reverse phase HPLC, intestinal and synthetic GLP-1 behaved similarly, whereas synthetic and intestinal GLP-2 differed. Pancreatic extracts contained a large peptide with both GLP-1 and GLP-2 immunoreactivity. Secretion was studied using isolated perfused pig pancreas during arginine stimulation, and isolated perfused pig ileum during either luminal glucose stimulation or vascular administration of the neuropeptide, gastrin-releasing peptide (GRP). Immunoreactive GLP-1 and GLP-2 were secreted in parallel with pancreatic glucagon and intestinal glicentin. The molecular forms of secreted immunoreactive GLP-1 and 2 corresponded to those identified in the tissue extracts.

Truncated glucagon-like peptide I, an insulin-releasing hormone from the distal gut.

By hydrophobic gel permeation and high pressure liquid chromatography we isolated from pig intestinal mucosa a peptide which corresponds to proglucagon 78-107 as suggested by chromatography and determination of its N-terminal sequence. Natural and synthetic proglucagon 78-107 dose dependently and potently increased insulin secretion from the isolated perfused pig pancreas. Proglucagon 78-107 also secreted by the small intestine may participate in the hormonal control of insulin secretion.

Nervous control of gastro-pancreatic somatostatin secretion in pigs.

The influence of the autonomic nervous system on the secretion of somatostatin from the antral and the fundic parts of the stomach and from the pancreas of the pig was investigated in experiments involving electrical stimulation of the vagal nerves and the splanchnic nerves in (1) intact, anesthetized pigs and (2) isolated perfused preparations of (a) antrum with intact vagal supply, (b) pancreas with intact vagal supply, (c) pancrease with intact sympathetic supply. The results clearly demonstrated that parasympathetic activity inhibits D-cell function in all gastro-pancreatic tissues; antral gastrin secretion was inversely correlated to somatostatin secretion and it is suggest that antral D-cell secretion participates in the control of gastrin secretion; the inhibitory effect of Gastric Inhibitory Polypeptide (GIP) as well as intraluminal HCl on gastrin secretion may be exerted via the stimulatory effect of both on somatostatin secretion. The sympathetic innervation of the pancreas is also clearly inhibitory to the pancreatic somatostatin secretion, whereas sympathetic nervous activity influences little the gastric somatostatin release.

The intestinal mucosa preferentially releases somatostatin-28 in pigs.

We studied the molecular forms of somatostatin-like immunoreactivity (SLI), newly released from isolated perfused preparations of the porcine antrum, stomach, pancreas and upper small intestine: Perfusion effluents were concentrated by Sep-Pak C-18 adsorption, eluted with ethanol, dessicated, and subjected to gel filtration with subsequent radioimmunoassays for somatostatin-14 and N-terminal somatostatin-28 immunoreactivity. All the SLI newly released from the stomach and antrum eluted at the position of somatostatin-14, and such was also the case for more than 95% of the SLI newly released from the pancreas, while 68 -/+ 7% and 75 -/+ 8% of the SLI newly released from the isolated perfused jejunum and ileum, respectively, corresponded to somatostatin-28. By reverse phase HPLC the identity of these peptides with synhetic somatostatin-14 and -28 was established.

The effect of gastrin-releasing peptide on the endocrine pancreas.

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.

Oxyntomodulin (glicentin-(33-69)): pharmacokinetics, binding to liver cell membranes, effects on isolated perfused pig pancreas, and secretion from isolated perfused lower small intestine of pigs.

The pharmacokinetics of purified synthetic oxyntomodulin were studied after infusing it into euglycaemic pigs at two rates. The elimination of the peptide from plasma was characterized by two components, a fast one (t1/2 7.2 +/- 0.6 min) and a slow one (t1/2 20.4 +/- 3.8 min) (mean +/- S.E.M., n = 7). The metabolic clearance rate was independent of infusion rate (6.96 +/- 0.99 vs 7.44 +/- 0.98 ml/kg . min (mean +/- S.E.M., n = 7). The synthetic peptide bound to pig hepatic glucagon receptors, but with approximately 2% of the affinity of glucagon, and showed insulinotropic and somatostatinotropic effects when infused into isolated perfused pig pancreases at concentrations higher than 10(-10) M. A dose-dependent increase was also shown for pancreatic glucagon output. A naturally occurring peptide, identified as oxyntomodulin by gel filtration and HPLC, was released into the circulation from the pig lower small intestinal mucosa upon intraluminal administration of glucose, and represented 25 +/- 3.8% of the secreted glucagon-like immunoreactivity. 11 +/- 2.3% of the secreted glucagon-like immunoreactivity was indistinguishable from glucagon itself upon gel filtration; thus at least 36% of the glucagon-like immunoreactivity secreted from the intestinal mucosa is already in an active form.

Vasoactive intestinal polypeptide (VIP) in the pig pancreas: role of VIPergic nerves in control of fluid and bicarbonate secretion.

Vasoactive intestinal polypeptide (VIP) in the pig pancreas is localized to nerves, many of which travel along the pancreatic ducts. VIP stimulates pancreatic fluid and bicarbonate secretion like secretin. Electrical vagal stimulation in the pig causes an atropine-resistant profuse secretion of bicarbonate-rich pancreatic juice. In an isolated perfused preparation of the pig pancreas with intact vagal nerve supply, electrical vagal stimulation caused an atropine-resistant release of VIP, which accurately parallelled the exocrine secretion of juice and bicarbonate. Perfusion of the pancreas with a potent VIP-antiserum inhibited the effect of vagal stimulation on the exocrine secretion. It is concluded, that VIP is responsible for (at least part of) the neurally controlled fluid and bicarbonate secretion from the pig pancreas.

Role of gastrin-releasing peptide in neural control of pancreatic exocrine secretion.

We studied the effect of electrical stimulation of the vagus nerves on the exocrine secretion of isolated perfused porcine pancreas before and after procedures that almost completely blocked the effects elicited by infusions of gastrin-releasing peptide (GRP): desensitization of the pancreas for GRP (by perfusion with high concentrations of GRP); administration of an antagonist of GRP action [D-Arg1, D-Pro2, D-Trp7,9, Leu11)-substance P]; and perfusion with Fab fragments of antibodies against GRP. Both desensitization and antagonist administration significantly (p less than 0.01) inhibited the effect of vagus stimulation on pancreatic protein secretion (by 42.1 and 33%). The inhibitory effect of anti-GRP perfusion was less pronounced (22% inhibition, 0.05 greater than p less than 0.1). The results support the notion that pancreatic, GRP-producing nerve fibers are involved in the neural control of pancreatic enzyme secretion.

Processing and secretion of prosomatostatin by the pig pancreas.

Antisera and radioimmunoassays against five different regions of prosomatostatin (proSS) were used for chromatographical analysis and for immunohistochemical mapping of the products of proSS in the pig pancreas. Secreted products of proSS were studied by analysis of effluent from isolated perfused pig pancreas obtained during isoproterenol stimulation. All cells that were stained with one antiserum also stained with the other antisera. Immunoreactive nerves were not observed. Isoproterenol increased equally the secretion of proSS 20-36, proSS 65-76, and proSS 79-92 immunoreactivity. The major molecular forms identified in pancreatic extracts and released from the pancreas were proSS 79-92; proSS 65-76; an N-terminally extended form of proSS 65-76; and two larger forms comprising the proSS 20-36 sequence (but not the 1-13 sequence) with and without the proSS 65-76 sequence. ProSS 1-10, 1-32 and 65-92 (somatostatin 28) were not identified.

Basal hyposecretion of gastric inhibitory polypeptide after Roux-Y hepaticojejunostomy in man.

We previously showed that basal and pentagastrin-stimulated gastric acid secretion, gastrin in serum and gastrin in antral mucosa were significantly greater in patients with Roux-Y hepaticojejunostomy than in those with choledochoduodenostomy. These findings prompted investigation of basal secretion of gastric inhibitory polypeptide (a peptide with an enterogastrone as well as an insulinogenic effect), insulin and glucose in the same patients. Basal gastric inhibitory polypeptide was significantly lower in patients with Roux-Y hepaticojejunostomy than in those with choledochoduodensotomy, whereas glucose and insulin did not differ in the two groups. No correlation could be demonstrated between gastric inhibitory polypeptide, gastric acid secretion and gastrin, suggesting that hyposecretion of gastric inhibitory polypeptide is not a pathogenetic factor for the hypersecretion of gastric acid secretion in patients with Roux-Y hepaticojejunostomy. Hyposecretion of gastric inhibitory polypeptide and gastric acid hypersecretion in patients with bile diversion seem to be two independent phenomena.

Results of hepatic lobectomy for primary epithelial cancer in 31 adults.

Hepatic lobectomy for primary epithelial cancer was performed in 31 adults from 1964 through 1977 in the surgical departments of six Scandinavian hospitals. Twenty-three patients were discharged and had a 2 year survival rate of 62 per cent and a 5 year survival rate of 16 per cent. Alternatives to surgery have not yet emerged. Further progress requires centralization.

[Hydatidosis. A survey]. / Hydatidose. En oversigt.

With the increased influx of foreign workers, refugees and immigrants, particularly from endemic areas, we will probably see more patients with hydatid disease, chiefly hydatid disease of the liver caused by E. granulosus. Thus it is important to bring the disease to the attention of the general surgeon. The diagnosis of hydatid disease is primarily made by ultrasound and serological examination. Other tests such as CT, angiography and ERCP are as a rule only important in surgical planning and in complicated cases. Treatment is principally surgical. The choice of surgical procedure should be individualized as much as possible due to the many aspects of the disease. Drainage of residual cavities should be avoided. Preoperative evaluation by ERCP is indicated in cases complicated by biliary communication. Percutaneous drainage can be indicated in cases of recurrence and in cysts of poor accessability. Medical treatment has its place primarily pre- and postoperatively. The preferred drug is albendazole. Mebendazole is now considered obsolete. It is not possible to monitor the effect of treatment with current serological methods.

The effect of experimental heterotopic pancreatic allotransplantation on the insulin response to oral glucose administration.

Oral glucose tolerance tests (OGTT) were performed in 6 healthly, unimmunosuppressed pigs before and after heterotopic pancreatic transplantation and total pancreatectomy. Mean survival time after grafting was 55 days. Mean basal concentrations of glucose and insulin in serum were significantly higher after grafting and total pancreatectomy (p less than 0.01), but the insulin-to-glucose ratio was unaffected. The tolerance to oral glucose decreased after grafting and total pancreatectomy (p less than 0.01), even though the insulin levels in serum during OGTT were higher tp less than 0.01). This finding was also reflected in the insulinogenic index, which was almost twice as large after transplantation (p less than 0.01) as before. The decreased oral glucose tolerance might be explained by drainage of the transplanted pancreas into the systemic circulation instead of the portal vein.

Delay in the diagnosis of insulinomas.

The median diagnostic delay in 32 patients with verified insulinomas was 2 3/4 years (range 1/4--18). The median delay in the 1939--1958 period was shorter (2 years, n = 17) than in the 1959--1978 period (3 years, n = 15). Thus, modern developments with insulin estimations were without noticeable effect upon the diagnostic delay. The findings can probably only be explained by a poor awareness of the insulinoma syndrome in the medical profession.

Influence of basal plasma glucose concentration on the glucagon response to arginine.

Plasma glucose and glucagon concentrations were measured in the portal vein of six healthy, anaesthetized pigs submitted to an intravenous arginine infusion test. A monophasic glucagon response was observed in all pigs, the peak glucagon value being reached within an average of 5 minutes after the beginning of the infusion. The glucagon response, expressed as the incremental area below the hormone concentration curve, correlated inversely with the plasma glucose concentration before the start of arginine infusion (r=0.78) (p less than 0.05) indicating that glucose is a potent inhibitor of arginine-induced glucagon secretion in pigs.

Isolation and perfusion of the porcine pancreas.

The isolation of a porcine pancreas preparation without the attached duodenum is described. The preparation is suitable for study of the secretion of insulin and pancreatic glucagon. The surgical procedure by which the pancreas is removed from tha animal is decribed as well as the perfusion system. The effect of various concentrations of glucose (63, 90, 135 and 180 mg per 100 ml) in the perfusion medium on the secretion of insulin and pancreatic glucagon was investigated in order to observe the performance characteristics of this preparation. Increasing concentrations of glucose caused a significantly greater insulin release, whereas the glucagon response was significantly reduced.