A 7 6 4 AGA ABSTRACTS GASTROENTEROLOGY, VoI. IO8 , No. 4

• THE EFFECT OF SEVERE MALNUTRITION ON PANCREATIC ENZYME SYNTHESIS IN HUMAN SUBJECTS. TA Winter, SJD O'Keefe, JM Ogden, M Callanan, SA Bridger; NA Tigler-Wybrandi. Gastrointestinal Clinic, Department o f Medicine, University of Cape Town and Groote Schuur Hospital, South Africa.

INTRODUCTION: W e have previously shown that' severe malnutrition is associated with significant impairment in the secretion of pancreatic enzymes. In order to investigate whether this reduction is a consequence of impaired protein synthesis, isotope labelled aminoacid incorporation studies were performed on 5 severely malnourished aPdatients (body mass < 70% ideal). [14C]L-leuelne tracer w a s

ministered as a primed/continuous infusion (20/~Ci + 0.15/~Ci/kg/h) . . . . for a period of 4 hours. Pancreatic secretion was stimulated by continuous infusion of cholecystokinin (CCK-8) 40 ng/kg/h, and duodenal secretions aliquotted into 30 minute collections. Amylase and trypsin were isolated from the duodenal juice by means of affinity chromatography, enabling measurement o f the rate of isotope incorporation into these pancreatic enzymes. Enzyme protein synthesis time, zymogen pool size and turnover rates were then calculated. Results were evaluated in comparison to 5 healthy volunteers (Controls). RESULTS: Controls Patients Body mass (kg) 70.2' (5.i) 40.8 (2.2)* Amylase:

output (U/h) 2209 (605) 476 (170)* synthesis time (minutes) 65.8 (8.6) 77.0 (10.2) zymogeu pool turnover rate (%/h) 27.5 (4.8) 28.0 (10.4) zymogen pool size (U) 9722 (2543) 2087 (1075)#

Trypsin: output (U/h) . 389 (59.9) 106 (52.0)* synthesis time (minutes) 61,2 (4.9) 97.8 (15.5)# zymogen pool turnover rate (%/h) 27,0 (3.6) 43.3 (10.6) zymogen pool size (U) 1625 (592) 173 (74.5)#

Results = mean (SEM) *p < 0.01 # p < 0.05 .... CONCLUSION: Our results indicate that decreased secretion " o~f pancreatic enzymes in severely malnourished hospitalized patients is a consequence of reduced zymogen stores, suggesting pancreatic atrophy. In addition, the synthesis,of trypsin was impaired, whereas .that of : amylase appeared preserved. The explanation for this non-parallel effect on pancreatic enzyme synthesis is unclear and requires further investigation. This research was funded !n.part by PharmaciaSouth Africa.

eENHANCED TROPHIC PROPERTIES OF ENDOGENOUS GASTRIN IN AGED RATS. M.M. Wolfe, C-C. Tseng, D. Gelrud, and L.A Jarboe. Gastroenterology Division, Brigham and Women's Hospital, Boston, M&

In addition to its recognized role in the regulation of acid secretion, another biological property attril:~ted to gastrin is its trophic effect on gastrointestinal mucosa. The incidence of atrophic gastritis and secondary hypergastrinemia is increased in the elderly; however, the effects of the aging process on gastrin's trophic properties have not been determined. To examine these relationships, male Fischer rats (6, 15, and 24 months- old) were rendered achlorhydric by the oral administration of omeprazole (25 mg/kg bid)) for 0 (basal), 2, 5, 10, or 15 days. At that time,~ antral mucosal and serum gastrin levels were determined, and DNA and protein content and ornithine decarboxylase (ODC) mRNA levels were measured in fundic and colonic rnucosal extracts. Both antral and serum gastrin levels increased significantly (p<0,05) and progressively in rats of all ages, and peak concentrations were significantly greater in 24-month rats (p<0.05). Peak antral gastrin levels in 5-, 15-, and 24-month rats were (mean+SE) 75.7~. 0, 69.1 +34.8, and 149.6~30.7 ng/mg protein, respective- ly, and corresponding peak serum gastrin concentrations were 177.3i-63.3, 107.2_+51.2, and 440.5+148.1 pg/ml, respectively. ODE; mRNA levels, undetectable in extracts of gastric fundus and colon in the basal state, increased significantly in response to omeprazole; although increments were similar in each group of rats. Significant increases in both total DNA (p<0.01) and protein (p<0.001) content were detected in the fundus and colon, with the greatest peak increment occurring in 24-month rats:

Peak Increment (expressed as percent of basal + SE-') ~ _ ~ Fundus Protein Fundus DNA Colon Protein Colon DNA

6 701+37 357+18 1034~81 276i-45 15 1002¢78 260640 1160~79 879~147 24 3481+149 1413.+.245 3279~,_231 1336~18

The concomitant IP administration of L740,093 (25 pg/kg tid), a specific gastrin receptor antagonist, to omaprazole-treated rats significantly inhibited secondary trophic effects. These results indicate that both enhanced gastrin expression occurring as a result of ach!orhydria and secondary trophic effects are more pronounced in aged rats, Although the clinical implications of these observations are unknown, hypergastrinemia due to associated achlorhydria could potentially contribute to the higher incidence of gastrointestinal neoplasm observed in the elderly.

INFLUENCE OF ACARBOSE ON CONCENTRATIONS OF STARCH-HYDROLYZING BACTERIA IN HUMAN FECES: M._~. Wolin, T. Miller, S, Yerry, K. Langguth, J. Krause, C. Tangel, P. Jenkins, M. Parfitt and G. Weaver. Wadsworth Center, NYS . . . . Dept. of Health, Albany, NY 12201 and Dept. of Medicine and Research, Bassett Hospital, Cooperstown, NY 13326

The a-glucosidase inhibitor, Acarbose (Aca}, inhibits starch digestion in the small intestine. We hypothesized that =Aca would increase the amount of starch-hydrolyzing bacteria (SB) in the colon because of the increase in starch available for growth of SB. Results of experiments with human volunteers support the hypothesis. Volunteers (17) were fed increasing doses of Ace (up to 200 milligrams in three weeks) or a placebo three times daily in a double-blind experiment. We measured concentrations of SB and total bacteria (TA) in fecal samples obtained before and after periods of feeding Aca or the placebo. Anaerobic procedures were used to prepare fecal suspensions and for • bacteriological analyses; Concentrations of SB were determined using an agar medium with 2.0% corn starch and incubating at 37 ° C. Starch hydrolysis yielded clear zones around colonies of SB. TA were enumerated in a medium without starch. The mean concentrations per gram dry matter (sd)) of TA were 2.04 X 1011 (1.67 X 1011) without and 2.14 X 1011 (3.16 X 1011) with Aca. The mean concentrations of SB were 6.03 X 10 TM (2.34 X 10 TM) without and 9.33 X 1010 (3.45 X 101°) with Ace. Absolute concentrations of TA and SB were not significantly different with or without Aca. However, the ratio (sd) of SB to TA was significantly higher with Aca; 0.49 (.26); and 0.31 (0.14) without Aca (p for paired t test = 0.025). If the SB to TA ratio is indicative of the ratio of starch to total substrate used by colonic bacteria for growth, about 1.6 times more starch reached the colon during the period when Aca was ingested . . . .

D E V E L O P M E N T A L EXPRESSION OF GASTRIN AND S O M A T O S T A T I N IN THE FETAL RABBIT S T O M A C H Laurence F. Yee, Helen C. Wong, Edna Q. Calaustro, and Sean J. Mulvihill. Gastrointestinal Research Laboratory, Department of Surgery, University of California, San Francisco, San Francisco CA. Purpose: A marked increase in acid secretion has been observed between days 24 and 26 of gestation in the fetal rabbit. In adult gastric epithelium, gastrin and somatostatin regulate parietal cell acid secretion, however, their. roles and expression in the fetus are largely unknown. The purpose of this study was to determine the developmental expression of gastrin and somatostatin in the fetal rabbit stomach. Methods: A total of 24 fetal rabbits from 12 time-mated New Zealand white rabbit does were sacrificed at successive intervals during the third trimester of gestation (term is 31 days). Gastric peptides were extracted from fetal stomachs by boiling in water and then in acetic acid. Amidated gastrin and somatostatin contents from tissue extracts were measured by radioimmunoassay using antisera 1296 for gastrin and 8402 for somatostatin. Results: n = 4 fetuses for each gestational day. Data is expressed as mean :1: SEM. Statistics were performed using A_NOVA and the Student-Newman-Keuls test.

180 160 140

120

T i s s u e 100 C o n t e n t 80 - ( p m o l / g160 -

40 2 20 :

[ ] Gastrin [ ] Somatost~ttin ~

= 22 = 24 =

\

2 " Ge statiorml Day

2 3 )

*p~O.05 vS. days 20, 22. ~p<O.05 VS. days 20, 22, 24. Summary: 1) A 12-fold increase in gastrin expression and a 3-fold increase in somatostatin expression was observed between days 20 and 30 of gestation. 2) The molar ratio of somatostatin to gastrin changes from 4.5 to 1.3 between days 24 and 26 of gestation. We conclude that, in the fetal rabbit stomach, the relative expression of gastrin and somatostatin may regulate the onset of parietal cell acid secretion during the third trimester.