Jejunal bypass stimulation of pancreatic growth and cholecystokinin secretion in rats: importance of luminal nutrients.

The effect of jejunal bypass on pancreatic growth and plasma cholecystokinin (CCK) was investigated in rats. Rats underwent bypass of jejunum or sham operation. Rats with jejunal bypass were further divided into three groups; one group received a continuous infusion of a partially hydrolysed liquid diet (Vital) into the bypassed jejunum; a second group received the nutrient solution mixed with trypsin and infused into the bypassed jejunum; the third bypass group did not receive infusion of nutrient or trypsin into the jejunum. Jejunal bypass alone did not significantly stimulate pancreatic growth or DNA content at one or two weeks postoperative. Infusion of nutrient solution into the bypassed jejunum stimulated pancreatic growth and DNA content, with maximal increases of 185% and 181% for pancreatic weight and DNA content, respectively, at two weeks. This coincided with significant increases in postabsorptive plasma CCK concentrations. Infusion of pancreatic proteases into the bypassed jejunum partially reversed the effects of nutrient infusion. These results suggest that exclusion of bile-pancreatic juice or pancreatic proteases from the jejunum does not lead to maximal release of CCK unless the jejunum receives luminal nutrients. It is proposed that CCK release from rat jejunum occurs spontaneously in the absence of pancreatic proteases, and that luminal nutrients in bypassed jejunum increase plasma CCK and stimulate pancreatic growth by maintaining synthesis of CCK.

Effect of atropine on rat pancreatic secretory response to trypsin inhibitors and protein.

The effect of atropine on the exocrine pancreatic secretory response to intestinally infused trypsin inhibitor and protein in conscious rats was investigated. Bile and pancreatic juice were collected and continuously returned to the intestine throughout all experiments. Ovomucoid trypsin inhibitor (OMTI) was infused at 1, 3, 6, 12, and 30 mg/h id, simultaneously with intravenously infused atropine (100 micrograms X kg-1 X h-1) or 0.15 M NaCl. Casein was infused at 300 mg/h id with or without intravenous atropine. Atropine inhibited basal pancreatic protein and fluid secretion 65.7 and 24.7%, respectively. Atropine had no effect on incremental (above basal) pancreatic protein and fluid output during infusion of maximally effective doses of OMTI (12 and 30 mg/h) and increased the incremental responses to submaximal doses of OMTI and to casein. The results are consistent with the hypothesis that cholecystokinin mediates negative feedback regulation by luminal proteases and that cholinergic mechanisms are not directly involved in this regulatory mechanism.

Plasma cholecystokinin and pancreatic growth during adaptation to dietary protein.

The relationship among plasma cholecystokinin (CCK), pancreatic growth, and food intake was studied in rats over a 2-wk period of adaptation from a very low-protein to a very high-protein diet. Rats adapted to a control diet (5% casein) were killed at 0900 (without fasting) at 0 h, 12 h, 24 h, 48 h, 7 days, or 14 days after transfer to a high-protein diet (75% casein). CCK was measured by bioassay using isolated pancreatic acini. Plasma CCK in high protein-fed rats was increased approximately threefold in the first 24 h, but returned to control (approximately 2.5 pM) values by day 7. Pancreatic weight, DNA, protein, and chymotrypsin(ogen) significantly increased to maximal values by day 7 in high protein-fed rats. Food intake in high protein-fed rats was inhibited by 47% after 24 h but returned to control values by day 7. The results indicate that high-protein diets initially increase CCK release and increase pancreatic protease secretory capacity and that, when pancreatic protease secretion is sufficient to match protein digestive requirements, the stimulus for CCK secretion is reduced and plasma CCK returns to normal. The pronounced but transient inhibition of food intake in high protein-fed rats is consistent with a role for CCK in regulation of food intake.

Effect of diversion of bile-pancreatic juice to the ileum on pancreatic secretion and adaptation in the rat.

Cannulas were implanted to collect bile and pancreatic juice, and the collected secretions were pumped back into the intestine at the level of the duodenum or the proximal ileum. The effect of 6 days of such treatment on pancreatic secretion and on pancreatic growth was determined. The effect on pancreatic secretion was studied by measuring the pancreatic secretory response to a stimulus, provided by acute diversion of bile-pancreatic juice from the proximal intestine. Trophic effects were studied in a separate group of rats by measuring pancreatic weight, protein content, and chymotrypsin activity after an overnight fast. Stimulated pancreatic secretion was 2.1 times greater for protein output and 3.4 times greater for fluid output in rats with chronic diversion of bile-pancreatic juice to the ileum. Pancreatic weight, protein content, and chymotrypsin activity were increased 2.6, 2.9, and 4.8 times, respectively, by chronic diversion of bile-pancreatic juice to the ileum. These results indicate that pancreatic hypertrophy and hyperplasia reported in rats with bile-pancreatic duct transposition to the ileum are the result of loss of feed-back inhibition from bile-pancreatic juice in the proximal intestine.

Effect of pancreatic secretions on transit in bypassed loops of intestine in rats.

The influence of intraluminal infusions of saline and a pancreatic juice-bile salt mixture on transit was determined in bypassed segments of intestine in rats. Animals underwent bypass of 70% of their jejunoileum and insertion of a catheter into the proximal end of the bypassed segment. After recovery from operation, each animal was placed into a harness that allowed free movement while fluids could be infused into the bypassed segment. Beginning on the first postoperative day, the bypassed loops were infused with either saline or a pancreatic juice-bile salt mixture. Transit in these animals was determined on the third day after operation. Other animals received no infusions and were tested either on the third or the 35th day after operation. Animals that received no infusions had low rates of transit when tested either in the fasted or fed condition three days after operation. Saline infusions resulted in a slight increase in transit in fasted animals only. Transit rates were increased to a greater degree following infusion of the pancreatic juice-bile salt mixture than with saline, especially in fasted animals in whom the rates approached those seen in the uninfused, fasted animals that were tested 35 days after operation. These findings are consistent with the hypothesis that the reduced transit seen in the bypassed loops of rats three days after operation may be due to intestinal contents characterized by deficiencies in pancreatic juice and bile salts.

Glucagon and insulin release in totally gastrectomized rats.

In the fasting state, totally gastrectomized rats had higher glycemia, higher glucagonemia and lower insulinemia than normal rats. However, they are not prediabetic or diabetic, because after a glucose tolerance test the response of glucagon secretion, though accentuated at the beginning, decreased sharply when insulin secretion was stimulated. The evolution of glucagonemia and insulinemia indicated that the positive-negative feedback of the couple alpha-beta cells of islets of Langerhans still regulated glucose homeostasis. Hypoglycemia seen after the glucose test in operated rats disappeared when soluble starch replaced glucose. With soluble starch, hyperglycemia, hyperglucagonemia and hyperinsulinemia were less marked than with glucose at 30 min. Therefore, we conclude that 1) Gastrectomy, in removing the stomach with all its physiological role, has conferred to the operated rat in the fasting state a new level of hormonal glucose counterregulation close to the diabetic or prediabetic situation; but once the animal is fed, its endocrine pancreas responses quite normally, and 2) In the sugar tolerance test, soluble starch induces less release of glucagon and insulin than glucose.

Effects of nutrients on acid secretion by innervated total gastric pouch in conscious rats.

In conscious rats with innervated total gastric pouches, intravenous infusion or duodenal intubation with fat and glucose decreased gastric acid secretion while amino acids produced the opposite effect. Intravenous infusion of amino acids strongly increased plasma gastrin, but fat and glucose had no effect. Plasma gastrin increased after duodenal intubation with all three nutrients, amino acids being the most effective. Mechanisms of action of gastrin release and acid secretion are discussed concerning the route of nutrients administration which could play a role in the liberation of known or unknown stimulatory or inhibitory factors from intestinal cells.

Secretions of isolated total gastric pouches in fasting and fed rats.

In the fasting state, the secretions of isolated total gastric pouches were higher than what was found in classical gastric fistulae. Serum gastrin was lower in operated rats than in normal non-operated rats. The proximal duodenum would contain a substance which inhibited volume and acidity secretion and stimulated pepsin secretion. This role could be developed upon secretin and its family present in high concentration in the upper duodenum. If the vagus was necessary to volume and acid secretion, its action on pepsin secretion was strengthened by the proximal duodenum. After an intestinal meal, all secretions were enhanced, confirming the hypothesis that the intestine would contain an hormone which would act through the vagus, principally for volume and acid secretions and partially for pepsin secretion.