J Clin Pathol: first published as 10.1136/jcp.s1-8.1.43 on 1 January 1978. Downloaded from J. clin. Path., 33, Suppl. (Ass. Clin. Path.), 8, 43-50 Pancreatic polypeptide T. E. ADRIAN From the Department of Medicine, Royal Postgraduate Medical School, Du Cane Road, London W12 OHS Pancreatic polypeptide (PP) was discovered fortui- exocrine parenchyma as well as being found in the tously during the purification of insulin from birds periphery of the islets (Adrian et al., 1976; Heitz (Kimmel et al., 1968) and later from mammals et al., 1976; Larsson et al., 1976). The PP cells display (Chance et al., 1976). PP has since been extracted the ultrastructural features of the D,-cell of the and purified from several mammalian species. It revised Wiesbaden classification (Solcia et al., 1973). contains 36 amino-acid residues and is quite distinct It has been suggested that the cell producing PP from other known hormonal peptides (Lin and should now be given the functional label of the PP Chance, 1974). The amino-acid sequence of the cell (Solcia et al., 1978). peptides extracted from man, pig, dog, sheep, and cow differs only in one or two residues in positions 2, Release of PP 6, or 23 (Lin and Chance, 1974). The biological activity of these mammalian peptides has been PP circulates in plasma and levels rise rapidly after found to reside in the C terminal hexapeptide (Lin the ingestion of food, particularly protein and fat, and Chance, 1978). Rodent PP, however, appears to and remain raised for several hours (Fig. 2) (Hazel- copyright. be somewhat different in that it does not cross-react wood et al., 1973; Floyd et al., 1976; Polak et al., with the majority of antisera raised to the bovine 1976; Schwartz et al., 1976). This rise is abolished peptide. by total pancreatectomy indicating that the pancreas is the only significant source of this peptide in the Localisation circulation (Adrian et al., 1977b). Intravenous infusions of amino-acids, glucose, or lipids do not PP is localised almost entirely to the pancreas where significantly alter circulating PP levels, so that http://jcp.bmj.com/ it is produced by discrete, small, granular endocrine an entero-PP axis must exist. A substantial increase cells (Fig. 1) which are scattered throughout the in plasma PP concentration is also observed during on September 25, 2021 by guest. Protected Fig. 1 Electron micrograph showing a PP cell in an islet of Langerhans and also showing a B-cell (B) and a somatostatin cell (D). (Original magnification x 30 000). 43 J Clin Pathol: first published as 10.1136/jcp.s1-8.1.43 on 1 January 1978. Downloaded from 44 T. E. Adrian insulin-induced hypoglycaemia, the peak coinciding very marked release in this preparation and may with the lowest blood gluicose concentrations (Floyd enhance the release evoked by other substances. et al., 1976; Adrian et c71., 1977b; Schwartz et al., Gastrointestinal hormones are potent stimulators 1978). This effect is, however, blocked by truncal of PP release in man (Adrian et al., 1977b). Secretin vagotomy, indicating thtat it is mediated through alone has no effect on PP levels (Adrian et al.,1979b) stimulation of the vaguis (Adrian et al., 1977b). but an infusion of cholecystokinin and secretin Immediately after theraLpeutic vagotomy the PP combined increased the plasma PP concentration response to food is impaiired (Schwartz et al., 1976), from 21 ± 5 pmol/l to 94 ± 11 pmol/l (Fig. 3). Very but several months afteer vagotomy it is normal low doses of caerulein (123 fmol/kg/min) combined (Adrian et al., 1977b; T'aylor et al., 1978a). Thus, with a very low dose of secretin (137 fmol/kg/min) vagal stimulation is not the only mechanism of PP caused an increase in plasma PP of 117 ± 26% release. In the isolated perfused canine pancreas (P<0 005) within 90 minutes. caerulein, a cholecysto)kinin analogue, glucose- The entero-PP axis, therefore, appears to have two dependent insulin-releasiing polypeptide (GIP), vaso- components, the vagus and gastrointestinal hor- active intestinal peptide (VIP), and gastrin, all caused mones. A complex interrelationship between these a significant increase in 1perfusate PP concentration two components is suggested by the effect ofatropine (Adrian et al., 1978b). A,cetyl choline also caused a which, in normal subjects, blocks the PP response to gut hormones and also lowers fasting levels of PP (Adrian et al., 1978a). Some degree of cholinergic 150- T tone seems to be essential both for maintaining basal secretion ofPP and for the response to gut hormones. Protein This may be considered to be analogous to the Fat l?-release of acid from the gastric parietal cell which copyright. is dependent on the interaction of acetyl choline, ^ 100 t~~ F t ~gastrin, and histamine; the removal of any one of these very greatly diminishes acid production after a meal. Gastric distension, either by water (Adrian et al., a- Glucose 1978a) or a balloon (Schwartz et al., 1979), evokes a 50 I a significant release of PP in man, perhaps through a local reflex. A local reflex may also be responsible in http://jcp.bmj.com/ part for the PP response to hypoglycaemia as, in addition to being abolished by truncal vagotomy, 0 this is also reduced by selective vagotomy (Adrian 0 60 120 180 et al., 1978a). Gastric acid secretion does not seem to Time v(min' be important in the postprandial release of PP Fig. 2 Effect ofindividual meal components on plasma which is not affected by the administration of PP (HPP) levels in 6 health.y subjects. cimetidine (Taylor et al., 1978a), and only slightly so on September 25, 2021 by guest. Protected 100- E CL a_ Fig. 3 Effect ofan infusion of cholecystokinin (approx 10% pure CCK 0. 5 50 - a IDU/kgfh) and secretin (pure natural E secretin 137 fmol/kg/min) on plasma PP a concentrations in 4 healthy subjects. CCK Isecretin infusion 0 6 3 * W 6 30 60. Minutes J Clin Pathol: first published as 10.1136/jcp.s1-8.1.43 on 1 January 1978. Downloaded from Pancreatic polypeptide 45 by the instillation of hydrochloric acid into the 6%, respectively (P<0*001) (Adrian et al., 1979b) duodenum (Floyd et al., 1976). (Fig. 4, 5). The bilirubin output also fell significantly In common with insulin, glucagon, and all of the during these experiments (P<0 01). When doses of gastrointestinal hormones so far investigated, the PP which mimicked the postprandial rise were super- release of PP both in the basal and postprandial imposed on an infusion ofsmall doses ofsecretin (137 state is inhibited by somatostatin (Adrian et al., fmol/kg/min) and caerulein (123 fmol/kg/min) 1977a; Floyd et al., 1977; Marco et al., 1977). there was a 60 % reduction of trypsin output and an 80% reduction of bilirubin output (for both, Actions of PP P<0 001) (Greenberg et al., 1978b). In cholecy- stectomised patients, trypsin output was reduced by Following the isolation and purification of bovine this procedure to the same degree as in normal PP, Lin and Chance carried out a systematic study subjects but bilirubin output was unaffected, sug- of the biological actions of the peptide on the canine gesting that PP had two quite separate effects in man, gastrointestinal tract (Lin and Chance, 1974, 1978; inhibition of pancreatic enzyme secretion and relaxa- Lin et al., 1977). The effects of PP included stimula- tion of the gall bladder. tion of gastric acid secretion, but inhibition of that Gastric acid and pepsin secretion were unaffected stimulated by pentagastrin. PP inhibited the secretion by infusion of PP, both in the basal state and during of pancreatic juice, and particularly of pancreatic submaximal stimulation of acid secretion by penta- enzymes, both in the basal state and when stimulated gastrin (Peptavlon 15 pmol/kg/min; Greenberg by an infusion of cholecystokinin and secretin. The et al., 1978a). Its effect on gastric emptying was gall bladder was relaxed and the tone of the chole- studied in five healthy subjects by infusing PP or dochal sphincter was increased. Gastric emptying saline during the ingestion of a small carbohydrate- and intestinal transit were enhanced in the rat. rich solid breakfast chosen because it elicited only a small release of endogenous PP. The half-emptying copyright. Infusion of PP in man time when PP was infused (66 ± 7 min) was not significantly different from that when saline was A vital step in establishing that a possible hormone infused (71 ± 11 min). In addition, the emptying does have a physiological role is to show that a rate during a higher PP dose, giving levels similar to biological response occurs when infusion of the those seen after a large mixed lunch, was not substance produces a circulating concentration significantly changed (60 + 12 min). All infusions similar to that seen after natural stimuli. Therefore, http://jcp.bmj.com/ in order to elucidate whether any of the actions of PP mentioned above could be considered to be Secretin Secretin physiological in man, bovine PP was infused at 1 rb several doses from 1 to 5 pmol/kg/min in a total of I PP 48 healthy subjects. Plasma levels rose to above those seen postprandially and reached a plateau by 30 Bicarbonate . minutes. The mean half life was 6.9 minutes (SEM 100 - on September 25, 2021 by guest. Protected ± 0.3; n = 23), the metabolic clearance rate was 5.1 ± 0'2 ml/kg/min, and the apparent space of distribution was 51 ± 3 ml/kg, which approximates to the plasma volume (Adrian et al., 1978c).