S. Lindkaer Jensen

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.

PANCREATIC SOMATOSTATINOMA: Clinical Features and Physiological Implications

The first case of a tumour producing somatostatin-like immunoreactivity and bioactivity is presented. The pancreatic tumour was composed of cells indistinguishable from islet D cells. Radioimmunoassay of blood-samples obtained by tumour-vein catheterisation revealed very high levels of somatostatin immunoreactivity. On gel chromatography tumour extracts were found to contain at least 4 different immunoreactive components, one of which eluted in the position of synthetic somatostatin. Extracts from the tumour were potent in inhibiting insulin and glucagon secretion from isolated perfused porcine pancreas. Clinical abnormalities included hypochlorhydria, steatorrhoea, and diabetic glucose tolerance. Conceivably some of these abnormalities may be related to somatostatin hypersecretion from the pancreatic tumour.

The molecular nature of vascularly released cholecystokinin from the isolated perfused porcine duodenum

Using sequence-specific radioimmunoassays, the quantities and molecular nature of cholecystokinin (CCK) have been determined in extracts of porcine duodenal mucosa and in the vascular perfusate from the isolated porcine duodenum. The basal concentration of CCK in the perfusate was 84 pM equiv. CCK-8 (mean; range: 32-173 pM, n = 5). After intraluminal stimulation with amino acids, acidified fat emulsions and hydrochloric acid, the concentrations increased 2--5-fold. Both in the basal and stimulated state the concentrations of the related hormone, gastrin, were below 5 pM equiv. gastrin-17. CCK in the perfusate was concentrated by affinity-chromatography using antibodies directed against the bioactive C-terminus. Subsequent gel chromatography revealed a form with a size like or slightly larger than the C-terminal dodecapeptide (CCK-12), a predominant form resembling the C-terminal octapeptide (CCK-8), and a form resembling the C terminal tetrapeptide (CCK-4). The duodenal mucosa contained in addition CCK-33, -39 and CCK-peptides with further N-terminal extensions. The results suggest that small CCK peptides are the principal circulating forms, while CCK-33 and larger forms are biosynthetic precursors.

Adenocarcinoma of the anal ducts

The records of 21 patients treated for adenocarcinoma of the anal ducts between 1943 and 1982 were reviewed. The patients were followed until death or current status in April 1987. The median follow-up period was eight months (range, 3 to 144 months). Fifteen patients had an erroneous diagnosis made at first physician visit resulting in a media doctors delay of 14 months (range, 3 to 24 months) before correct treatment was carried out. Nine of the tumors were localized perianally (ischiorectal space), seven anally, and five in a fistula-in-ano. Tumors localized anally were significantly smaller and had a significantly shorter history than perianally or fistula-in-ano localized tumors (P<.05 for each localization). Three patients with anal tumors had their diagnosis made accidentally by routine histologic examination of an excised hemorrhoid. First examination revealed distant metastases in 13 patients and follow-up examination revealed regional or distant metastases in seven patients. Modes of treatment were wide local excision (N=3), abdominoperineal resection (N=3), colostomy (N=9), and radiotherapy (N=2). Twenty of the 21 patients died within 18 months due to the cancer. One long-term survivor was observed; the patient was alive 12 years after local excision of the tumor without evidence of recurrent disease. The crude five- and 10-year survival was only 4.8 percent.

Long-term prognosis after radical treatment for squamous-cell carcinoma of the anal canal and anal margin

Sixty-seven of 100 (67 percent) and 24 of 58 (41 percent) apparently radically treated patients with squamous-cell carcinoma of the anal canal (AC) and the anal margin (AM) developed recurrent disease during a median observation time of ten years (range, 0 to 38 years). A significantly higher number of patients treated for AC tumors with local excision had recurrent disease compared with patients treated with abdominoperineal resection (P<.05). Twenty patients with AC tumors had local recurrence, 21 regional recurrence, and 26 visceral metastases. Eighteen patients with AM tumors had local recurrence, five regional, and one brain metastases. The latest recurrences among AC and AM tumor patients were diagnosed 11 and nine years after primary treatment, respectively. The estimated cure rate by the actuarial method after 15 years was 26 percent and 53 percent for AC and AM tumors, respectively. Thus, if recurrent carcinomas of the anus are to be detected early, frequent life-long control examinations are necessary. It is obvious from this study that, in order to reduce recurrent disease of carcinoma of the anus, new treatment regimens must be tried under controlled circumstances. Surgical therapies alone are clearly insufficient in the treatment of carcinoma of the anus.

The Enteral Insulin-Stimulation after Pancreas Transplantation in the Pig

SummaryThe insulin responses to an oral glucose tolerance test (OGTT) and in intravenous glucose infusion (IVGI), designed to copy the changes in serum glucose concentrations found during OGTT, were measured in four pigs before and after heterotopic pancreatico-duodenal allotransplantation and total pancreatectomy. After transplantation and total pancreatectomy a remarkable hyperinsulinaemia occurred during OGTT and IVGI, reflected by an almost two-fold increment in the insulinogenic index after transplantation. This finding might be explained by drainage of the transplanted pancreas into the systemic circulation instead of the portal vein. The magnitude of the enteral stimulus, i. e. the incretin effect on insulin secretion during OGTT was unchanged after transplantation, suggesting that the incretin effect is not mediated by neural influences upon the endocrine pancreas.

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 ∼ 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 < 0.01). Likewise, hepatic and peripheral venous blood insulin levels were enhanced (p < 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 < 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.

Bacterial Flora of the Small Intestine and Bile Acid Metabolism in Patients with Hepatico-Jejunostomy Roux-en-Y

Duodenal and jejunal bacterial flora and bile acid metabolism were investigated in 14 patients with hepatico-jejunostomy Roux-en-Y. Anaerobic culture procedures were based on the use of a glove-box with an oxygen-free atmosphere and pre-reduced, anaerobically sterilized media. Anaerobic transport was based on evacuation of atmospheric air from transport-tubes and transport-time less than 30 minutes. Bile acid metabolism was evaluated from concentrations of toal bile acids and deconjugated bile acids, glycine/taurine ratio and breath test. In 92 per cent of the patients an abnormal flora-containing anaerobic and/or aerobic bacteria was found in the most proximal part of the jejunum at the site of the entero-entero anastomosis (cf. Fig. 1 and Table 1). Total bile acid concentrations were low in half of the patients, whereas deconjugated bile acids or elevated glycine/taurine ratio was found in one patient only (cf. Table II). An abnormal breath test was found in 5 patients, but without any clear correlation between the breath test and the bacterial flora.

Release of Gastric Inhibitory Polypeptide and Insulin in Response to Intrajejunal Glucose in Duodenal Ulcer Patients before and after Truncal Vagotomy

Six duodenal ulcer patients were investigated before and 3 months after truncal vagotomy and pyloroplasty. Plasma concentrations of gastric inhibitory polypeptide (GIP), insulin, and glucose were measured during intrajejunal infusion of 50 g of glucose. The GIP response was significantly diminished postoperatively; insulin and glucose concentrations, however, were unchanged. The reduction of GIP release was positively correlated with the reduction of the peak acid output. The results suggest that a reduced vagal innervation of the intestine is accompanied by reduced GIP release after intrajejunal glucose, depending on the degree of completeness of vagotomy.

Effect of intraduodenal and intravenous triglyceride infusions on plasma gastric inhibitory polypeptide and insulin in fetal and neonatal pigs.

SummaryThe responses of gastric inhibitory polypeptide (GIP) and insulin to intraduodenal and IV triglyceride infusions were measured in 11 late fetal and 10 neonatal pigs. Basal plasma glucose, insulin, and GIP concentrations were lower in fetal than in neonatal pigs. In the fetal pigs, plasma glucose increased slightly during intraduodenal and IV triglyceride infusions, whereas plasma insulin remained unchanged during the tests. No significant changes were observed in plasma GIP concentration following intraduodenal triglyceride infusion in the fetal pigs, but plasma GIP fell during the IV infusion of triglyceride in these pigs (p<0.01). In the neonatal pigs, plasma glucose and insulin remained unaffected by intraduodenal and triglyceride infusions. Plasma GIP did not change during the IV triglyceride infusion, but exhibited a paradoxical decline after the intraduodenal triglyceride infusion (p<0.05). It is concluded that the GIP-cell response to an oral triglyceride load is suppressed in late fetal and neonatal pigs. The abolished GIP response to oral triglycerides could play a causal role in the inactivity of the enteroinsular axis which is seen in both human and animal neonates.