O. Vagn Nielsen

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.

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.

Gastrin-Releasing Peptide in the Porcine Pancreas

The presence of gastrin-releasing peptide (GRP) was studied in extracts of porcine pancreata. Gel filtration and high-pressure liquid chromatographic profiles of these extracts as monitored with both C-terminally and N-terminally directed radioimmunoassays against GRP showed pancreatic GRP to consist of one main form, namely the 27-amino acid peptide originally extracted from porcine stomach, and small amounts of a C-terminal fragment identical with the C-terminal 10-amino acid peptide. Gastrin-releasing peptide-like immunoreactivity released from the isolated perfused porcine pancreas during electrical vagal stimulation was shown by gel filtration to consist of the same two forms. By use of immunocytochemical techniques employing an antiserum directed against its N terminus, GRP was localized to varicose nerve fibers in close association with the exocrine tissue of the porcine pancreas in particular. Some fibers were found penetrating into pancreatic islets also. Immunoreactive nerve cell bodies as well as fibers were found within intrapancreatic ganglia. The potency of GRP in stimulating exocrine as well as endocrine secretion from the porcine pancreas, its presence in close contact with both acini and islets, and its release during vagal stimulation indicate that GRP may have a role in the parasympathetic regulation of endocrine and exocrine secretion from the pig pancreas.

Autonomic nervous control of the endocrine secretion from the isolated, perfused pig pancreas

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.

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.

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.

Routine measurements of liver and bone alkaline phosphatase in human serum: Differential inhibition by l-phenylalanine and carbamide (urea) on the LKB 8600 reaction rate analyzer

Abstract A method suitable for routine determination of liver and bone alkaline phosphatase (EC 3.1.3.1) on the LKB 8600 is described. Experimental data on differential inhibition by l -phenylalanine, 10 mmoles/1 and carbamide, 3.81 moles/1 under strictly controlled conditions on the LKB 8600 are given. Data on the stability of the tissue alkaline phosphatase extracts and on the precision of the analytical system are provided. The method permits the determination of 15 samples per h.

Role of gastrin-releasing peptide in the neural control of pepsinogen secretion from the pig stomach

A new experimental model, the isolated perfused antrectomized pig stomach with intact vagal innervation, was shown to produce pepsinogen and gastric acid upon electrical stimulation of the vagus nerves and by intravascular administration of carbachol (from a basal value of 111 +/- 24 units of pepsin per minute and 0.044 +/- 0.012 mEq H+/min to 393 +/- 75 units of pepsin per minute and 0.102 +/- 0.022 mEq H+/min upon vagal stimulation). Vagal stimulation also increased the release of the neuropeptide gastrin-releasing peptide to the venous effluent from 0.42 +/- 0.12 to 3.1 +/- 0.95 pmol/min. Intravascular infusions of gastrin-releasing peptide at a concentration of 10(-8) mol/L resulted in a threefold increase in pepsinogen secretion and a small increase in acid output. Because gastrin-mediated effects of gastrin-releasing peptide are excluded with this preparation, our results show that gastrin-releasing peptide acts either directly or through another unknown local mediator on the pepsinogen-secreting cells. Gastrin-releasing peptide may thus participate in the vagal control of pepsinogen secretion.