Exposure to higher levels of fat in the diet increases the secretion of fat-digesting enzymes in pancreatic juice. This study examines the functional consequences of this phenomenon and demonstrates that adapting rats to high fat (triglyceride) loads increases the release of cholecystokinin (CCK) and the pancreatic secretory response to intraduodenal fat. Lipolytic activity in the small intestine was also higher in adapted rats. Exchanging pancreatic juice from unadapted rats with pancreatic juice from adapted rats decreased the response to fat in adapted rats and increased the response to fat in unadapted rats. Infusing oleic acid into unadapted rats stimulated CCK secretion and pancreatic exocrine secretion to levels observed with triglycerides in adapted rats. Pancreatic exocrine secretion in response to intraduodenal fat in rats adapted to a high-fat (20%) diet were significantly higher than the responses seen in rats fed a low-fat (5%) diet. Adaptation to fat increases the pancreatic secretory and plasma CCK responses to fat, apparently by increasing the efficiency of triglyceride digestion and thereby increasing CCK release.

The role of fat in regulation of pancreatic secretion was studied in conscious rats by measuring pancreatic secretion and plasma cholecystokinin (CCK) and secretin responses to intraluminal infusion of fat, protein, or trypsin inhibitor via the duodenum. In rats with pancreatic juice continuously returned to the intestine, intraduodenal infusion of 20% emulsified fat (Liposyn), 10% casein, and 0.4% ovomucoid trypsin inhibitor (OMTI) stimulated equivalent increases of approximately threefold in pancreatic protein output. Proglumide reduced fat-stimulated pancreatic protein secretion by greater than 90% but did not inhibit the response to OMTI. Fat significantly increased plasma CCK from basal levels of 0.5 pM to 2-3 pM, but it was a weaker stimulant of CCK secretion than casein (peak CCK levels greater than 10 pM) or OMTI (peak CCK levels 5-6 pM). Fat significantly stimulated secretin release (21.7 pM) compared with casein (6.8 pM), OMTI (4.4 pM), and NaCl (3.5 pM). The inhibition of fat-stimulated pancreatic secretion by proglumide indicates that the small amounts of CCK released by fat are necessary for a normal pancreatic response, suggesting that this response may be the result of potentiation between secretin and small amounts of CCK.

The mechanism by which intraluminal proteases inhibit pancreatic secretion and CCK release was investigated in conscious rats. We hypothesized that the stimulation of pancreatic secretion and CCK release that occurs in the absence of luminal trypsin is caused by a trypsin-sensitive, cholecystokinin (CCK)-releasing peptide that is tonically secreted intraluminally by the small intestine. We tested whether rapid saline perfusion of the lumen of the proximal intestine in rats with jejunostomies would wash out the putative peptide, thereby inhibiting the spontaneous pancreatic secretion caused by diverting bile and pancreatic juice from the intestine. Rats were prepared with cannulas draining bile and pancreatic juice, a duodenal cannula and a jejunostomy 10-12 cm from the ligament of Treitz. During diversion of bile and pancreatic juice to the exterior, the proximal intestine was perfused with phosphate-buffered saline at 3 ml/min via the duodenal cannula and the intestinal washes collected from the jejunostomy outlet. Rapid intestinal perfusion significantly inhibited pancreatic protein and fluid secretion stimulated by diversion of bile and pancreatic juice to the exterior. Reinfusion of the concentrated intestinal washes prevented the "washout" inhibition. The active factor in the intestinal washes was heat stable and trypsin sensitive. Rapid washout perfusion of isolated jejunal loops in Thiry-Vella fistula rats reduced plasma CCK from 20.4 +/- 3.6 to 10.4 +/- 1.8 pM, and reinfusion of the washes into the loop returned plasma CCK to 17.1 +/- 3.8 pM. The results support the hypothesis that a trypsin-sensitive, CCK-releasing peptide in intestinal secretions mediates feedback regulation of pancreatic secretion in rats.

Phillips et al. [1] demonstrated abnormally rapid gastric emptying of glucose solutions in patients with recently diagnosed non-insulin-dependent diabetes mellitus (NIDDM), which contrasts with delayed gastric emptying (gastroparesis), a well-documented late manifestation of diabetes attributed to autonomic neuropathy [2]. Intravenous administration of cholecystokinin (CCK), a physiological inhibitor of gastric emptying in healthy humans [3], normalized gastric emptying of a glucose test meal in NIDDM diabetic patients and reduced the postprandial hyperglycaemia [4]. This outcome was predicted from studies in healthy human subjects which showed that CCK regulated postprandial blood glucose levels by slowing gastric emptying [5]. These studies support the hypothesis [1] that accelerated gastric emptying in early NIDDM in humans may contribute to poor glucose control by increasing the rate of glucose entry into the small intestine, thereby increasing absorption rate and exacerbating postprandial hyperglycaemia.To further examine this phenomenon, the gastric emptying of glucose was investigated in a newly Diabetologia (1997) Summary Patients with early non-insulin-dependent diabetes mellitus (NIDDM) empty glucose solutions from their stomachs more rapidly than non-diabetic control subjects, and this exacerbates postprandial hyperglycaemia.To determine if accelerated gastric emptying occurred in a rat model of NIDDM and influenced postprandial hyperglycaemia, gastric emptying of glucose was measured, and the effect of slowing the gastric emptying rate on postprandial hyperglycaemia was observed. We tested eight male obese Zucker diabetic rats and eight age-matched lean Zucker controls at 10-13 weeks of age to measure gastric emptying of glucose (by gamma scintigraphy). Rats fasted overnight were gavaged with 30 % glucose at 1 ml/100 g body weight. Separately, six Zucker diabetic rats and six lean controls were tested for sensitivity to the inhibitory effects of cholecystokinin and secretin on gastric emptying. The diabetic rats emptied glucose significantly faster than controls (t 1/2 = 37.3 ± 1.5 vs 58.8 ± 2.3 min in controls), and aging exaggerated this differential. Camostat, a stimulant of cholecystokinin and secretin release, added to the glucose meal significantly slowed gastric emptying (t 1/2 = 123 ± 23 and 166 ± 19 min, diabetic vs lean, respectively), and significantly reduced postprandial hyperglycaemia in diabetic rats. Compared to Zucker lean controls, Zucker diabetic rats were as sensitive (cholecystokinin) or more sensitive (secretin) to gastrointestinal hormones that inhibit gastric emptying. The results demonstrate accelerated gastric emptying in a rat model of NIDDM, consistant with similar observations in humans with early NIDDM. These results also support the proposal that interventions to slow gastric emptying may improve glucose control in this disease. [Diabetologia (1997) 40: 136-142]

The role of cholecystokinin (CCK) in induction and maintenance of pancreatic growth stimulated by a high-protein diet was investigated. Rats adapted to 5% casein diet were switched to 70% casein for 21 days. MK-329, a CCK receptor antagonist, was administered at 2.5 mg.kg-1.day-1 ip, beginning on day zero (day zero treatment) or day 7 (midcourse treatment) of feeding 70% casein and thereafter. Another group was returned to 5% casein after 7 days of feeding 70% casein. Feeding 70% casein significantly stimulated increases of 32, 87, 74, 216, and 1,450% in pancreatic DNA, RNA, wet weight, protein content, and chymotrypsin content, respectively. Midcourse treatment with MK-329 was more effective than day zero treatment, and it completely reversed increases in pancreatic weight and RNA content, partially reversed increases in protein and chymotrypsin content, and had no effect on DNA content. Return to 5% casein rapidly reversed increases in pancreatic parameters, except for DNA. The results indicate that CCK is essential for induction and maintenance of dietary protein-stimulated pancreatic hypertrophy.