S.R. Bloom

HUMAN PANCREATIC GROWTH-HORMONE-RELEASING FACTOR SELECTIVELY STIMULATES GROWTH-HORMONE SECRETION IN MAN

A growth-hormone-releasing factor has been characterised and sequenced from a pancreatic tumour removed from a patient with acromegaly. It is a 40-residue linear peptide. Synthetic human pancreatic growth-hormone-releasing factor (hpGRF-40), 1 microgram/kg bodyweight, was administered as an intravenous bolus to six healthy men. hpGRF-40 selectively stimulated growth-hormone secretion. Serum growth-hormone concentrations were increased within 5 min, reaching a peak between 30 and 60 min (20 . 4 +/- 6 . 5 ng/ml compared with 2 . 1 +/- 0 . 1 ng/ml after placebo). Serum levels of prolactin, thyrotropin, luteinising hormone, and corticotropin (measured indirectly through plasma cortisol) were not increased after administration of hpGRF-40. Similarly, the concentrations of blood glucose, plasma insulin, glucagon, pancreatic polypeptide, cholecystokinin, gastrin, gastric inhibitory peptide, motilin, and somatostatin were unaffected by hpGRF-40. There were no changes in blood pressure, pulse rate, or body temperature, and no side-effects were noted. The characteristics of this peptide fulfil many of the criteria required of the hypophysiotropic growth-hormone-releasing hormone. hpGRF holds promise for a new approach to the diagnosis and treatment of various disorders of growth-hormone secretion.

Neuromedin U--a study of its distribution in the rat.

The distribution of neuromedin U, a novel peptide originally isolated from porcine spinal cord, was investigated in the rat using a recently developed radioimmunoassay. High concentrations of neuromedin U-like immunoreactivity were found in the pituitary gland and gastrointestinal tract. Significant concentrations of immunoreactivity were also found in several regions of the rat brain, spinal cord and both male and female genitourinary tracts. In the small intestine, neuromedin U-like immunoreactivity was restricted to the submucosal muscular layers, suggesting localization in neurones rather than in epithelial cells. Chromatographic analysis of pituitary, spinal cord and gut revealed a single peak of immunoreactivity which did not co-elute with either synthetic porcine neuromedin U-25 nor neuromedin U-8, indicating inter-species molecular heterogeneity.

Occurrence and developmental pattern of neuromedin U-immunoreactive nerves in the gastrointestinal tract and brain of the rat

Neuromedin U is a newly described regulatory peptide, found by radioimmunoassay in significant concentrations in both the brain and gut of the rat. The aim of the present study was to localize this peptide immunoreactivity to discrete structures of the gut and brain and to map its distribution using immunocytochemistry. In the gut, neuromedin U was confined to nerve fibres mainly in the myenteric and submucous plexuses and the mucosa of all areas except stomach. Immunoreactive ganglion cells were seen in both ganglionated plexuses and their number did not increase following colchicine administration. This observation and the finding that the population of neuromedin U-immunoreactive nerves in the ileum was not affected by complete extrinsic denervation indicated that the nerves are mostly intrinsic in origin. Colocalization studies revealed neuromedin U and calcitonin gene-related peptide were present in the same myenteric and submucosal ganglion cells. Transection experiments showed that, like calcitonin gene-related peptide-immunoreactive nerves, fibres containing neuromedin U project for very short distances in both an oral and anal direction. At the electron microscopic level, neuromedin U immunoreactivity, demonstrated using the immunogold technique, was localized to large granular vesicles. In the central nervous system, neuromedin U immunoreactivity was localized to fibres which were widespread throughout the brain, except in the cerebellum. The presence of neuromedin U-immunoreactive cell bodies was restricted to the rostrocaudal part of the arcuate nucleus. Colocalization studies showed that a proportion of the neuromedin U-immunoreactive cell bodies in the arcuate nucleus also contained pro-opiomelanocortin. Neuromedin U-immunoreactive fibres were first detected in the rat intestinal mucosa at day 1 after birth. In the brain, the arcuate nucleus showed neuromedin U-immunoreactive neuronal cell bodies at E16 but not at E14. In conclusion, neuromedin U is a new member of the group of molecules known as brain-gut peptides.

Saturation of fat and cholecystokinin release: implications for pancreatic carcinogenesis

In a study to determine the effect of saturation of fats on their ability to stimulate cholecystokinin (CCK) release six normal volunteers ate five test meals containing different fats with intervals of 1 week. Plasma CCK levels were measured by a specific radioimmunoassay and the gallbladder volume was calculated from ultrasound measurements. The sodium salt of the monounsaturated fatty acid oleic acid (3.5 g) produced a significantly greater integrated CCK response than that of the saturated fatty acid stearic acid (mean [SEM] 103 [41] vs 8[41] pmol.l-1.min). The gallbladder contracted to 42 (3)% of its initial volume after oleate but remained at 89 (8)% of its initial volume after stearate. Integrated CCK responses to dietary triglycerides (30 g) also differed significantly according to the degree of saturation--277 (58) pmol.l-1.min after corn oil (predominantly diunsaturated), 143 (14) pmol.l-1.min after olive oil (predominantly monounsaturated), and 44 (12) pmol.l-1.min after suet (predominantly saturated). The finding that unsaturated fats are stronger stimulants of CCK release than saturated fats may explain the promotion of pancreatic carcinogenesis in rats by unsaturated but not saturated fats and may support the role of CCK in this effect.

c-fos expression in the paraventricular nucleus of the hypothalamus following intracerebroventricular infusions of neuropeptide Y.

Intracerebroventricular (i.c.v.) infusions of neuropeptide Y (NPY) (2500 pmol) induced c-fos protein in the paraventricular nucleus (PVN) of intact male rats 60 min later. The greatest expression was observed in the dorsal (parvicellular) region of the PVN; there were intermediate levels in the lateral (magnocellular) and lowest ones in the medial (parvicellular) regions. Allowing rats to eat during the post-infusion interval did not modify this pattern of c-fos expression. Depriving rats of food for either 24 or 48 h did not induce recognisable expression of c-fos in the PVN, and allowing 24 h-deprived rats to eat also had no effect on PVN c-fos. Plasma insulin was increased by i.c.v. NPY, and raised still further in rats that were allowed to eat following NPY infusions. However, plasma glucose was not altered by either treatment. Food-deprived rats had low levels of insulin, but unaltered blood glucose, compared to controls. These results show that NPY can induce c-fos expression in both parvicellular and magnocellular areas of the PVN. The pattern of expression within the PVN seems to differ from that induced by other peptides, such as angiotensin II, vasopressin and corticotropin-releasing factor, suggesting that distinct populations of neurons are activated by different peptides within the complex structure of the PVN. Food deprivation does not induce c-fos expression within the PVN, though other studies have shown that NPY levels and release are both increased, so there is no simple relation between current energy state, blood levels of either glucose or insulin and c-fos expression within the PVN.

Vasoactive intestinal peptide, the major mediator of the WDHA (pancreatic cholera) syndrome: Value of measurement in diagnosis and treatment

8. Chears WC, Jr, Thompson JE, Hutcheson JB, Patterson CO: Pancreatic islet cell tumor with severe diarrhea. Am J Med 29:529-533, 1960 9. Hindle W, McBrien DJ, Creamer B: Watery diarrhea and islet cell tumor. Gut 5:359-362, 1964 10. Marks IN, Bank S, Louw JH: Islet cell tumor of the pancreas with reversible watery diarrhea and achlorhydria. Gastroenterology 52:695-708, 1967 11. Kahn CR, Levy AG, Gardner JD, Miller JV, Gorden P, Schein PS: Pancreatic cholera: Beneficial effects of treatment with streptozotocin. N Engl J Med 292:941-945, 1975 12. Verner JV, Morrison AB: Endocrine pancreatic islet disease with diarrhea. Arch Intern Med 133:492-500, 1974

COMBINED USE OF GUAR AND ACARBOSE IN REDUCTION OF POSTPRANDIAL GLYCÆMIA

Symptoms associated with carbohydrate malabsorption limit the usefulness to diabetics of a powerful glycoside-hydrolase inhibitor (acarbose) which reduces postprandial glycaemia. Addition of a low dose (50 mg) of a acarbose together with 14.5 g guar gum to a breakfast test meal taken by 8 healthy volunteers reduced the mean peak rise in blood-glucose at 30 min by 70%. Areas under the insulin and gastrointestinal-polypeptide response curves were also greatly reduced. No evidence of carbohydrate malabsorption, as assessed by measurement of breath hydrogen, was found during any of the test periods. When acarbose was taken alone, 3 of the 8 subjects had troublesome symptoms and the 30 min rise in blood-glucose was reduced by only 28%. Thus, combination of these two agents effectively reduces the rate of carbohydrate absorption without increasing side-effects and may make combined acarbose and guar acceptable in the management of some diabetics.

Regional differences in concentrations of regulatory peptides in human colon mucosal biopsy

The study was undertaken to examine regional differences in the concentrations of five regulatory peptides in the human colonic mucosa. Biopsies were obtained during routine colonoscopy from 33 patients whose colonic mucosa was macroscopically and histologically normal. Regulatory peptides were extracted, and measured by specific radioimmunoassays. Concentrations of three peptides that are present predominantly in endocrine cells within colonic mucosa increased significantly towards the rectum: Mean concentrations of peptide YY, enteroglucagon, and somatostatin were about three times greater in the rectum than in the cecum. However, concentrations of two peptides that are present in mucosal nerve fibers diminished significantly towards the rectum: Mean rectal concentrations of vasoactive intestinal peptide and peptide histidine methionine were both about 0.6 of mean cecal concentrations. Concentrations of all five peptides were lower in biopsies taken from colonic polyps than in normal colonic mucosa. Regional differences in colonic mucosal concentrations of regulatory peptides probably reflect differences in the physiological functions of different parts of the colon.

D cell pathology in duodenal ulcers and a chlorhydria

Abstract Somatostatin is a unique peptide as most of its actions appear to be inhibitory. These include the inhibition of release of thyroid-stimulating hormone, insulin, glucagon, and pancreatic juice enzyme. 1–3 In the stomach, somatostatin is a powerful inhibitor of gastrin release 4 and gastric acid secretion. 5 This inhibitory action in the stomach suggests that somatostatin may play a role in diseases in which there is abnormal gastric secretion. The mode of secretion of gastrin and gastric acid is probably regulated by a delicate balance of agonist and antagonist hormonal mechanisms. The part played by somatostatin and gastrin in this delicate balance was therefore investigated by quantitative immunocytochemical studies into the ratio of somatostatin D cells to gastrin G cells in the antra of three groups of patients with an abnormal acid production.

The effect of central blockade of kappa-opioid receptors on neuropeptide Y-induced feeding in the rat

Neuropeptide Y (NPY) and the endogenous kappa-opioid receptor ligand, dynorphin (dyn), stimulate feeding when injected centrally in the rat. Norbinaltorphimine (norBNI, 25 nmol) reduced the feeding response to NPY (2.4 nmol) by 67% (P < 0.02). An additive effect of dynorphin and NPY was seen on food intake (saline 0.8 +/- 0.1, dyn 1.9 +/- 0.4, NPY 6.1 +/- 1.4, dyn and NPY 9.7 +/- 2.2). A component of NPY-induced feeding may be mediated by kappa-opioid neuronal systems.