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Role of Circulating Somatostatin in Regulation of Gastric Acid

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Role of Circulating Somatostatin in Regulation of Gastric Acid Role of Circulating Somatostatin in Regulation of Gastric Acid Secretion, Gastrin Release, and Islet Cell Function Studies in Healthy Subjects and Duodenal Ulcer Patients Thomas J. Colturi, RFgger H. Unger, and Mark Feldman Department ofInternq(Medicine, Dallas Veterans Administration Medical Center and University of Texas Health Science Center, Dallas, Texas 75235 " As bstract. Studies were designed (a) to deter- to the same extent in ulcer patients and controls. These mine whether somatostatin is released into the circulation studies suggest that duodenal ulcer patients release normal after meals in sufficient amounts to regulate gastric or amounts of somatostatin into the circulation and that pancreatic islet function in humans and (b) to investigate target cells controlling acid secretion and gastrin release the possible role of somatostatin in the pathogenesis of are normally sensitive to somatostatin in these patients. duodenal ulcer disease. Mean plasma somatostatin-like immunoreactivity (SLI) increased from 6.2±1.5 pg/ml to Introduction a peak level of 13.8±1.3 pg/ml in eight healthy subjects after a 1,440-cal steak meal (P < 0.005). When so- Somatostatin is a peptide that has potent inhibitory actions on matostatin-14 was infused intravenously, basal and food- several target tissues (1). Because large amounts ofsomatostatin are present in the stomach and endocrine pancreas, it is possible stimulated gastric acid secretion and also basal and food- that somatostatin normally regulates gastric and islet function. simulated plasma insulin and glucagon concentrations Possible modes of action of endogenous somatostatin on target were reduced significantly at mean plasma SLI concen- cells within the stomach and islets are endocrine (via the systemic trations within the range seen after a meal. Thus, the circulation), neurocrine (from somatostatin-containing nerves), amount ofsomatostatin reaching the systemic circulation and/or paracrine (via local diffusion) (1, 2). after a steak meal was sufficient to inhibit gastric acid Sensitive radioimmunoassays have documented increases in secretion and islet cell function. On the other hand, basal circulating somatostatin-like immunoreactivity (SLI)' after meals and food-stimulated plasma gastrin concentrations were in humans (3-8). Although high intravenous doses of soma- reduced by intravenous somatostatin only at plasma SLI tostatin can inhibit gastric acid secretion and gastrin release (9- concentrations that were several-fold greater than post- 12), it is unknown whether the amount ofsomatostatin released prandial SLI concentrations. into the circulation after a meal is of sufficient magnitude to affect gastric acid secretion or gastrin release. Therefore, studies Although duodenal ulcer patients had significantly were designed to determine whether enough somatostatin is higher basal, food-stimulated, and peak pentagastrin- released into the circulation after a meal to reduce gastric acid stimulated gastric acid secretion rates than healthy con- secretion or plasma gastrin concentrations. In addition, the effect trols, duodenal ulcer patients and controls had nearly ofsomatostatin on -the pancreatic islets, another potential target identical basal and food-stimulated SLI concentrations. of circulating somatostatin, was assessed by simultaneous mea- Moreover, food-stimulated gastric acid secretion and gas- surements of plasma insulin and glucagon concentrations. trin release were inhibited by intravenous somatostatin Patients with duodenal ulcer (DU) often demonstrate gastric acid hypersecretion and hypergastrinemia (13). Two studies have suggested that these patients may have reduced amounts of Receivedforpublication 2 November 1983 and in revisedform 29 March 1984. somatostatin in the gastric antrum (14, 15). If somatostatin normally plays a physiologic role in suppressing gastric acid J. Clin. Invest. © The American Society for Clinical Investigation, Inc. 1. Abbreviations used in this paper: BAO, basal acid output; DU, duodenal 0021-9738/84/08/0417/07 $ 1.00 ulcer; S-14, somatostatin-14; S-28, somatostatin-28; SLI, somatostatin- Volume 74, August 1984, 417-423 like immunoreactivity. 417 Role ofSomatosAtin in Gastric and Islet Function secretion and gastrin release, somatostatin deficiency could con- S-14 and control studies were done on separate days in random order. tribute to acid hypersecretion and hypergastrinemia in some S-14 doses of 1, 2.5, 5, 10, 50, and 100 Ag/h were evaluated (see DU patients. It is also possible that insensitivity to inhibitory Results). Blood samples were obtained from a similar catheter in the op- effects ofsomatostatin on the stomach could be present in some posite arm. study was Gastric acid secretion. The effect of somatostatin on basal gastric DU patients. Thus, another purpose of the present acid output was measured by aspiration by using standard methods to compare in DU patients and normal subjects (a) basal and described previously (17). Hydrogen ion concentration was measured food-stimulated circulating SLI; and (b) inhibitory effects of by pH electrode ( 18). Food-stimulated gastric acid secretion in response exogenous somatostatin on gastric acid secretion and gastrin to the homogenized hamburger meal was measured by in vivo intragastric release. titration to pH 5.5 with 0.3 N sodium bicarbonate (19). Gastrin, insulin, and glucagon. Coded plasma samples were assayed Methods for gastrin, insulin, and glucagon concentrations by using previously described methods (20-22). Subjects and patients. 23 fasting healthy subjects (12 male) with no Statistical analysis. Statistical significance of differences between history ofgastrointestinal or endocrine disorder were studied; their mean mean values was determined with t test for paired values or groups. P age was 31 yr (range 20-52). Their weights averaged 66.3 kg (range values of <0.05 were considered significant. During somatostatin infusion 47.6-81.7 kg). Mean (±SEM) basal acid output (BAO) and peak acid studies, blood hormone concentrations at 30 and 45 min ofeach infusion output in response to 6 ag/kg pentagastrin were 2.7±0.5 and 29.9±1.6 period were averaged and the mean value for each S- 14 infusion period mmol/h, respectively. 10 fasting patients (9 male) with chronic DU were was compared with that during the corresponding NaCl infusion period. also studied. Their mean age was 49 yr (range 21-60). Their weights averaged 79.8 kg (range 63.5-89.8 kg). BAO and peak acid output av- Results eraged 8.5±2.6 and 42.2±3.6 mmol/h, respectively (P < 0.01 vs. healthy subjects). No subject or patient was taking any medication and all gave Basal plasma SLL Basal SLI ranged from 3 to 11 pg/ml in 23 written, informed consent. Studies were approved by a Human Research normal subjects and averaged 7.4±0.4 pg/ml. In the 10 DU Review Committee. patients, basal SLI ranged from 4 to 15 pg/ml and averaged Meals. Two different meals were used in these studies. One consisted 8.7±1.2 pg/ml (P > 0.05 vs. healthy subjects). of 227 g sirloin steak, 150 g french-fried potatoes, 28 g bread with 5 g Plasma SLI response to eaten meals. In response to the steak butter, 8 oz. milk and an ice cream sandwich. This steak meal contained meal, plasma SLI increased above basal concentrations in all 83 g protein, 105 g carbohydrate, and 75 g fat (1,440 cal). A second normal Mean SLI increased from 6.2±1.5 to meal consisted of 143 g ground, lean, cooked hamburger, 28 g bread subjects studied. with 5 g butter, and 8 oz. water (546 cal with 39 g protein, 30 g car- 13.8±1.3 pg/ml after 180 min (P < 0.005, Fig. 1). bohydrate, and 30 g fat). As will be described in Results, the hamburger Somatostatin responses to the eaten hamburger meal were meal was either eaten intact or homogenized in a blender and infused measured in 16 normal subjects and 8 DU patients (Fig. 2). into the stomach. The homogenized meal was diluted to 600 ml with Mean plasma SLI increased significantly above basal concen- distilled water, adjusted to pH 5.5 with 0.1 N HCI, and then infused trations in both groups, with mean SLI increases of -3 pg/ml by gravity into the stomach through a nasogastric tube (AN10, Anderson in each. In contrast, mean plasma SLI in normal subjects did Products, Inc., Oyster Bay, NY). not increase when no meal was eaten. Peak SLI concentrations Somatostatin. Plasma SLI was measured as previously described (16) after either meal ranged from 9 to 26 pg/ml in normal subjects by radioimmunoassay with antibody 80 C at a dilution of 1:80,000. and from 11 to 25 pg/ml in DU patients. Although the mean This antibody appears to be directed against the central portion of so- integrated SLI response to the steak meal was larger than the matostatin because immunoreactivity is completely lost when the the L-tryptophan on the 8-position of somatostatin- 14 (S-14) is replaced integrated SLI response to the hamburger meal, difference with D-tryptophan. On the other hand, immunoreactivity is maintained was not significant (P > 0.3). when the phenylalanine on the 11-position is replaced by tyrosine (Tyr) or when des-Ala' S-14 or des-Ala'-Gly2 S-14 are used instead of native 16'MEALSTEAK S-14. Therefore, 1251-labeled Tyr-l 1 S-14 was used as the tracer in these experiments (16). Half-maximal displacement of tracer occurred at an 12 _ l ___i* S-14 concentration of 20 pg/ml and a somatostatin-28 (S-28) concen- tration of 120 pg/ml. Thus, antibody 80 C detected S-14 more readily Tho- than S-28 by approximately threefold on a molar basis. The sensitivity 68- of this assay (i.e., the minimal change in SLI concentration detectable 5 pg/ml. Intraassay variation was 6.1% and < 2- with 95% confidence) is 2 _ interassay variation 13.9%.
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