INFLUENCE OF INTRAJEJUNAL GLUCOSE ON PANCREATIC EXOCRINE FUNCTION IN MAN

Transcription

1 GASTROENTEROLOGY 1971 by The Williams & Wilkins Co. Vol. 60, No.5 Printed in U.S.A. INFLUENCE OF INTRAJEJUNAL GLUCOSE ON PANCREATIC EXOCRINE FUNCTION IN MAN WALTER P, DYCK, M.D. Department of Research, Scott and White Memorial Hospital, and the Veterans Administration Center, Temple, Texas The effect of intrajejunal glucose on pancreatic exocrine function was studied in 5 human subjects during continuous intravenous infusion of secretin and pancreozymin. Intrajejunal glucose markedly depressed volume flow and bicarbonate concentration in the stimulated gland while plasma levels of immunoreactive glucagon and immunoreactive insulin increased simultaneously. The time of onset of the inhibitory effect appears compatible with a glucagon-mediated mechanism. Small amounts of pancreatic glucagon have been shown to suppress hormonally stimulated pancreatic exocrine secretion in the dog l and in man. 2 The demonstration by other investigators of a glucagon-like hormone in the small bowel mucosas" suggested a possible pancreatic inhibitory role for this gut peptide as well. Since intrajejunal glucose promotes the release of this hormone from the gut,3. 4 the influence of intrajejunal glucose on pancreatic exocrine function in man was examined. Methods Five healthy young subjects (3 females, 2 males), varying in age from 20 to 30 years, were studied the morning after an overnight fast. A radio-opaque double lumen duodenal drainage Received October 6, Accepted December 14, This work was presented in part at the Annual Meeting of the American Gastroenterological Association, Research Forum, May 21, 1970 in Boston, Massachusetts. An abstract appeared in Clin Res 18 (1): 37, Address requests for reprints to: Dr. W. P. Dyck, Department of Research, Scott and White Memorial Hospital, Temple, Texas This work was supported by a research grant from the Scott and White Memorial Hospital and Scott, Sherwood, and Brindley Foundation, and by the Veterans Administration Center, Temple, Texas. The author wishes to thank Drs. Morton I. Grossman and Roger H. Unger for their critical review of the manuscript and helpful suggestions. tube was positioned under fluoroscopic control so as to obtain proper separation of gastric and duodenal fluids upon aspiration. Continuous suction at 5 mm Hg with 2 to 4 sec of interruption every 2 min was applied to both tubes by means of a Gomco pump. Continuous intravenous infusion of isotonic sodium chloride solution was given throughout each test at a rate of 100 ml per hr. Observations were carried out during simultaneous intravenous infusion of Jorpes secretin, 3 U per kg per hr, and pancreozymin, 1 Ivy dog U per kg per hr, by a Harvard peristaltic pump. The secretin (lot 16921) and pancreozymin (lot 26861) used in these studies were purchased from the Gastrointestinal Research Unit, Chemistry Department, Karolinska Institutet, Stockholm, Sweden. Pancreatic secretion was collected continuously in 5-min samples. Constant aspiration of gastric contents was designed to prevent entry of acid into the duodenum. At least 60 min of control collections were obtained to determine a plateau of secretion. Fifty grams of glucose dissolved in 100 ml of water were then administered through a polyethylene catheter 3 to 5 inches distal to the ligament of Treitz over a 5- min period and collections of duodenal juice were continued for another hour. This dose of glucose solution was selected after larger amounts were found to produce restlessness, nausea, and diarrhea. No subjective side effects or significant changes in blood pressure and pulse rate were observed with 100 ml of 50% glucose administration. The effects of intrajejunal glucose on pancreatic secretion were evaluated by comparison 864

2 May 1971 GLUCOSE AND PANCREATIC EXOCRINE FUNCTION 865 of the mean of two 5-min periods of maximum suppression following intrajejunal glucose administration with the mean control 5-min response to secretin and pancreozymin alone. The control response was established by determining the mean of 12 to 15 5-min periods immediately preceding the administration of intrajejunal glucose. Five-minute collections of duodenal juice were analyzed individually for volume and for concentrations of bicarbonate, chloride, and total protein-the latter serving as a measure of enzyme secretion. Bicarbonate was measured with a Van Slyke manometer5 and chloride concentration was determined with the Cotlove chloridometer.6 Protein determinations were performed by the method of Lowry et ai.7 Venous blood was obtained 5 min before and at 5-min intervals after intrajejunal glucose administration for measurements of plasma immunoreactive glucagon (ffig), immunoreactive insulin (IRD, and glucose. Plasma glucose was measured by the orthotoluidine method. 8 Immunoreactive insulin was assayed by a double antibody radioimmunoassay,9 and immunoreactive glucagon by a similar method.'o Glucagon and insulin assays were performed through the courtesy of Dr. James E. Vance at the Endocrine Research Laboratory, Veterans Administration Hospital Center, Temple, Texas. Results Secretory data obtained from 5 subjects before and after the intrajejunal administration of glucose are summarized in table 1. Intrajejunal glucose significantly depressed pancreatic secretory flow and bicarbonate concentration in all subjects. Mean secretory volume was inhibited to a proportionately greater degree (52%) than was the maximum bicarbonate concentration (25%). No significant alteration of total protein concentration followed the intrajejunal administration of glucose. The mean output of total protein was therefore decreased in proportion to the mean fall in secretory volume. TABLE 1. Influence of intra jejunal glucose (100 ml of 50% glucose) on mean rate of pancreatic secretion and output of bicarbonate and protein a Subject no Volume Bicarbonate Protein F. Y. ml15 min meqlliter "Eq15 min mglml mgl5 min Control ± 1.50' 89 ± ± ± ± 7.67 Postglucose L. G. Control ± ± ± ± ± 6.72 Postglucose L. D. Control ± ± ± ± ± 5.61 Postglucose C. B. Control ± ± ± ± ± 3.54 Postglucose R. F. Control ± ± ± ± ± 1.58 Postglucose Mean Control ± ± ± ± ± 4.06 Postglucose ± ± ± ± ± 4.09 P <0.01 <0.01 <0.01 >0.5 <0.01 a All studies performed during continuous intravenous infusion of secretin, 3 U per kg per hr, and pancreozymin, 1 U per kg per hr. n, number of 5-min periods in each mean. '±SE.

3 [HC0 3 ].. Eq/L [IRI] ; ~._._.-.- "..._._._.,/ _.-._."., [IRG] [IRI] I'I'Gr/." I'U/.. I 800 loo ~ 700 I7S 600 ISO SOO IlS S loo SO 100 ls los VOLUME 90 mils' 75 SO S lo ~ w ro ~ SO ~ TIME (min.) ro ~ 90 ~ SECRETIN 3u/K./hr. AND PANCREOZYMIN lu/kl/hr. I-J GLUCOSE (SO GRAMS IN 100cc) FIG. 1. Influence of intrajejunal (I-J) glucose on secretin- and pancreozymin-stimulated pancreatic secretion and plasma levels of immunoreactive glucagon (IRG) and immunoreactive insulin (IRI) in a single subject. HC0 3 I'Eq/5' 1600 BOO [IRG) 1'1' Gr Iml [IRI) I' U/ml ISO loo (GLUCOSE] <0' lime MHR 1-) GLUCOSE (min.) lo 100 ms ~ SECRETIN 3u/ka/hr. AND PANCREOZYMIN lu/k./h,. 1-) GLUCOSE (SO GRAMS IN 100cc) FIG. 2. Mean values for pancreatic bicarbonate output and plasma concentrations of immunoreactive glucagon (IRG), immunoreactive insulin (IRI), and glucose 5 min before (0 time) and at 5-min intervals after intrajejunal (l-j) glucose. 866

4 May 1971 GLUCOSE AND PANCREATIC EXOCRINE FUNCTION 867 Figure 1 illustrates the effects of intrajejunal glucose on the pancreatic secretory response and peripheral blood values of immunoreactive glucagon and insulin in a single individual. A significant inhibition of hormonally stimulated volume and bicarbonate concentration occurred within the 1st 10 min and the inhibitory effect persisted for no more than 30 min. The inhibition of pancreatic exocrine secretion was accompanied by a simultaneous rise in the concentrations of plasma IRG and IRI. Figure 2 demonstrates the mean calculated bicarbonate outputs for all subjects during each 5-min period following the administration of intrajejunal glucose. Simultaneous mean measurements of plasma IRG, IRI, and glucose are plotted as well. A marked reduction of mean bicarbonate output within the 1st 5 min following intrajejunal glucose administration was accompanied by a simultaneous increase in plasma glucagon and a less rapid rise in plasma insulin. As mean bicarbonate output values returned toward control levels, mean plasma IRG values showed a reciprocal, although slower, decline while mean plasma IRI continued to rise. Mean plasma glucose showed a slower rise which continued through the periods when pancreatic secretion returned toward normal and plasma IRG values began to decline. Discussion Earlier observations on the effects of small amounts of glucagon on pancreatic exocrine function in dog and man suggested a possible regulatory role for this hormone in the control of pancreatic exocrine secretion. 1, 2 The possibility that this suppression of pancreatic secretion by glucagon is of physiological significance was enhanced by reports from several laboratories of the demonstration of a peptide hormone in the gut mucosa bearing biological and immunological similarities to pancreatic glucagon. 3, 4 That the rise in plasma glucagon -like immunoreactivity following intrajejunal glucose administration in dogs is of extrapancreatic origin has been shown by Unger and associates. 3 While a 50% glucose solution represents an unphysiological preparation, Unger's group observed a similar rise in plasma glucagon-like immunoreactivity following the intrajejunal administration of a 20% glucose solution. More recently, Unger has shown that a 5 % glucose solution will likewise promote the release of glucagon-like immunoreactivity from the intestine (personal communication). Wang and Grossman ll in 1951 reported that the introduction of glucose into the duodenum of dogs had no effect on the release of secretin or pancreozymin. Recent attempts at immunoassay of secretin in human serum suggest, however, that glucose absorption is accompanied by an increase in secretin release. I2 In 1967 Sum and PreshawI3 reported on the pancreatic secretory response to intrajejunal infusion of glucose in human subjects. They observed no change in the basal pancreatic secretion of fluid, bicarbonate, and protein. In a recent report, Go et al. 14 described an increase in basal pancreatic secretory flow following intra duodenal glucose perfusion. The authors attribute this observation to the probable release of secretin from the gut. Lawrence et al. 15 in 1960 reported a marked suppression of pancreatic secretory flow and moderate decrease in bicarbonate concentration in secretin-stimulated dogs following the intraduodenal administration of large volumes of hypertonic glucose solution. Serotonin was suggested as the agent probably responsible for this suppression of pancreatic exocrine secretion. This suggestion was supported by the finding that exogenous serotonin could mimic the pancreatic response to the feeding of hypertonic glucose and that the chronic oral administration of the serotonin antagonist, methyldopa, eliminated the pancreatic inhibitory effects of intraduodenal glucose.i 6 The same authors found, however, that acute intravenous pretreatment with many compounds thought to be serotonin antagonists failed to prevent this inhibitory response. 17 Interpretation of these and similar studies I8 is made somewhat difficult because of the large volumes of hypertonic

5 868 DYCK Vol. 60, No.5 solution which were infused into the gut. A 150- to 200-ml 50% glucose solution was instilled and this was accompanied by restlessness, increased salivation, diarrhea, and vomiting-side effects which were also observed following exogenous serotonin administration. 17 Schapiro and co-workers,19 utilizing much smaller volumes of glucose solution in dogs (20 ml of 50% glucose), demonstrated a similar marked inhibition of secretin-stimulated pancreatic exocrine secretion without associated subjective side effects. These observations were presented as favoring a mechanism of pancreatic secretory inhibition not mediated by serotonin. While both the intravenous administration of pancreatic glucagon and the intrajejunal infusion of glucose suppressed pancreatic secretory flow, pancreatic glucagon produced a marked suppression of enzyme output with little influence on bicarbonate concentration,i'2 whereas in the present study intrajejunal glucose resulted instead in a significant suppression of bicarbonate concentration with little or no influence on enzyme concentration. The output of total protein was decreased in proportion to the fall in secretory volume. This apparent difference in response does not, however, invalidate the concept of a glucagon-mediated suppression of pancreatic secretion following intrajejunal glucose administration. Unger and associates 3 have shown that the glucagon-like immunoreactivity extractable from jejunum is not identical with pancreatic glucagon but is a larger molecule with distinct biological properties, a cross reactant in the radioimmunoassay for glucagon. Pancreatic and gut glucagon might thus each exert an independent suppressive effect on pancreatic exocrine secretion, with the pancreatic hormone exercising a predominant influence on enzyme synthesis or release, and the peptide of gut origin exerting its inhibitory effects on the fluid and electrolyte fraction predominantly. Of considerable interest are reports from several groups that the intravenous administration of pancreozymin causes a dramatic increase in levels of immunoreactive glucagon in the pancreatic venous blood of dogs,20, 21 whereas the continuous intravenous infusion of secretin has no such effect.21 The reported enhancement of pancreatic glucagon secretion during the ingestion of amino acids is also noteworthy, 22 as is the observation that glucagon administration will reduce blood amino acid concentration.23,24 It would seem reasonable, therefore, to speculate that a variety of stimuli normally serving to enhance pancreatic enzyme secretion might secondarily promote the release of pancreatic glucagon as a negative feedback on the release of pancreatic enzymes. The glucagon-like peptide derived from the intestinal mucosa might then primarily serve to regulate the secretin-stimulated fraction of bicarbonaterich fluid. Differing blood levels of circulating active hormones could in part be responsible for apparent differences in response to pancreatic glucagon and intrajejunal glucose, based on dose-response relationships of two peptides acting on a common receptor.25 The use of a hyperosmotic glucose solution might lead one to consider the possibility that significant amounts of extracellular fluid entered the gut lumen with a consequent reduction in plasma volume and release of antidiuretic hormone. While antidiuretic hormone has been shown to inhibit pancreatic secretion,26 the rapid onset of secretory suppression in our study would seem to rule out such a sequence of events. Although reduction in recovered secretory volume following intrajejunal glucose administration could in part reflect changes in gastrointestinal motor function, leading to less satisfactory recovery of secretions, such a mechanism would not explain the concomitant reduction in bicarbonate concentration. Similarly, an inhibitory effect on secretin-stimulated hepatic bile secretion could in part account for the decrease in volume of recovered duodenal juice. Such an effect would, however, tend to increase rather than decrease the bicarbonate concentration of the recovered fluid since the bicarbonate cojlcentration of

6 May 1971 GLUCOSE AND PANCREATIC EXOCRINE FUNCTION 869 hepatic bile is considerably less than that of secretin-stimulated secretion. The possible direct role of insulin in producing the observed early changes in pancreatic exocrine secretion will require further investigation. The persistence of high plasma illi levels during a return to normal pancreatic secretory values does not favor such a mechanism. REFERENCES 1. Dyck WP, Rudick J, Hoexter B, et al: Influence of glucagon on pancreatic exocrine secretion. Gastroenterology 56: , Dyck WP, Texter EC Jr, Lasater JM, et al: Influence of glucagon on pancreatic exocrine secretion in man. Gastroenterology 58: , Unger RH, Ohneda A, Valverde I, et al: Characterization of the responses of circulating glucagon-like immunoreactivity to intraduodenal and intravenous administration of glucose. J Clin Invest 47:48-65, Samols E, Tyler J, Megyesi C, et al: Immunochemical glucagon in human pancreas, gut and plasma. Lancet 2: , Van Slyke DD, Neill JM: The determination of gases in blood and other solutions by vacuum extraction and manometric measurement. J BioI Chern 61: , Cotlove E, Trantham HV, Bowman RL: An instrument and method for automatic, rapid, accurate and sensitive titration of chloride in biological samples. J Lab Clin Med 51: , Lowry OH, Rosebrough NJ, Farr AL, et al: Protein measurements with the folin phenol reagent. J BioI Chern 193: , Dubowski KM: An o-toluidine method for bodyfluid glucose determination. Clin Chern 8: , Morgan CR, Lazarow A: Immunoassay of insulin: two antibody system. Plasma insulin levels of normal, subdiabetic and diabetic rats. Diabetes 12: , Hazzard WR, Crockford PM, Buchanan KD, et al: A double antibody immunoassay for glucagon. Diabetes 17: , Wang CC, Grossman MI: Physiological determination of release of secretin and pancreozymin from intestine of dogs with transplanted pancreas. Arner J Physiol 164: , Young JD, Lazarus L, Chisholm DJ: Radioimmunoassay of secretin in human serum. J Nucl Med9: , Sum PT, Preshaw RM: Intraduodenal glucose infusion and pancreatic secretion in man. Lancet 2: , Go VLW, Hofmann AF, Summerskill WHJ: Pancreozymin bioassay in man based on pancreatic enzyme secretion: potency of specific amino acids and other digestive products. J Clin Invest 49: , Lawrence W Jr, Khentigan A, Hudock J, et al: The effect of intra duodenal administration of hypertonic glucose solution on external pancreatic secretion. Surgery 49: , Hudock JJ, Vanamee P, Lawrence W Jr: The effect of methyl dopa upon pancreatic secretory response to intrajejunal hypertonic glucose solution. Surgery 60: , Hudock JJ, Khentigan A, Vanamee P, et al: The effect of serotonin and serotonin antagonists on external pancreatic secretion in dogs. J Surg Res 3: , Drapanas T, Shim WKT: Pancreatic secretion in the experimental dumping syndrome. Ann Surg 154: , Schapiro H, Britt LG, Evans SR, et al: Effect of infusion of hypertonic fluids into the upper intestines on pancreatic secretion. Arner J Surg 113:65-69, Unger RH, Ketterer H, Dupre J, et al: The effects of secretin, pancreozymin and gastrin on insulin and glucagon secretion in anesthetized dogs. J Clin Invest 46: , Buchanan KD, Vance JE, Morgan A, et al: Effect of pancreozymin on insulin and glucagon levels in blood and bile. Arner J PhysioI215: , Ohneda A, Ketterer H, Eisentraut AM, et al: Effect of glucose and amino acids on glucagon secretion (abstr). Clin Res 15:62, Bocek RM, Peterson RD, Beatty CH: Effect of glucagon on amino acid metabolism (abstr). Fed Proc 19:149, Curry DM, Beaton GH: Glucagon administration in pregnant rats. Endocrinology 63: , Grossman MI: Gastrin, cholecystokinin, and secretin act on one receptor. Lancet 1: , Banks PA, Rudick J, Janowitz HD, et al : Action of antidiuretic hormone on pancreatic exocrine secretion. Surg Forum 18: , 1967