Physiological concentrations of cholecystokinin stimulate amino acid-induced insulin release in humans

After a meal, hormones released from the gut potentiate insulin release. This study was undertaken to determine if physiological concentrations of plasma cholecystokinin (CCK) stimulate insulin secretion in man. Employing a specific CCK bioassay, postprandial CCK levels were determined in normal subjects. Ingestion of a mixed liquid meal stimulated an increase in circulating CCK from a mean fasting level of 0.9 +/- 0.2 (SEM) pmol/L to a mean peak level of 7.1 +/- 1.1 pmol/L within 10 min of feeding. After 30 min the mean CCK level fell to 3.5 pmol/L and remained elevated for the remainder of the 90-min experiment. Eight subjects underwent 40-min infusions of either arginine (15 g), mixed amino acids (15 g), or glucose (30 g) with or without the simultaneous infusion of CCK-8. Since CCK-8 has full biological potency, this form was chosen for infusion to reproduce total CCK bioactivity in plasma. CCK-8 was infused at rates of 12 or 24 pmol/kg X h, producing steady state plasma CCK levels of 4.5 +/- 0.7 and 8.2 +/- 1.1 pmol/L, respectively, spanning the range of normal postprandial levels. CCK alone had no effect on insulin, glucose, or glucagon levels. Administration of arginine alone stimulated insulin from a mean basal level of 12.8 +/- 1.3 microU/mL to a peak level of 41.3 +/- 5.4 microU/mL. Infusion of CCK at 12 and 24 pmol/kg X h augmented arginine-stimulated insulin levels to peaks of 62.5 +/- 13.9 and 63.0 +/- 4.0 microU/mL, respectively. Moreover, CCK nearly doubled the total amount of insulin secreted during the arginine infusion. A similar potentiation of glucagon release was found with both doses of CCK. In addition, infusion of a mixture of amino acids with and without concomitant CCK infusions revealed that CCK potentiated the insulin release induced by mixed amino acids. In contrast to the potent effect of CCK on amino acid-induced insulin release, infusions of CCK together with glucose caused no enhancement of glucose-stimulated insulin release. These results demonstrate that physiological concentrations of CCK potentiate amino acid (but not glucose)-induced insulin secretion in man. These data suggest, therefore, that CCK may have a role in man as a modulator of insulin release.     

Role of cholecystokinin in the regulation of the interdigestive phase of pancreatic secretion

The rate of pancreatic secretion during the interdigestive state varies with the phase of interdigestive motility. During phases II and III of interdigestive motility, pancreatic secretion is greatest, and minimal during phases I and IV. Pancreatic polypeptide and motilin have been reported to be increased during phases II and III but do not appear to be responsible for the stimulation of pancreatic secretion. We have investigated the role of cholecystokinin (CCK) in regulating pancreatic secretion during the interdigestive state. Eight volunteers underwent a study of interdigestive duodenal motility with a catheter that collected pancreatic secretions at the ligament of Treitz. The phase of motility was correlated with the output of trypsin and the plasma CCK levels. The output of trypsin during phases II and III was 0.9 +/- 0.2 and 1.0 +/- 0.2 mg/kg/h, respectively, and decreased to 0.3 +/- 0.1 mg/kg/h during phase IV-I (p less than 0.05). To determine if the output of trypsin during phases II and III was responsible for the increases in plasma CCK, the effect of intraduodenal trypsin, 3 mg/kg/h, in five volunteers was determined. The infusion significantly increased the output of trypsin to a mean of 3.1 +/- 1.9 mg/kg/h (p less than 0.05). The plasma CCK concentration increased with intraduodenal trypsin from 20.4 +/- 5 to 26.4 +/- 3.7 pg/ml (p less than 0.05). The infusion study was repeated in two volunteers with heat-inactivated trypsin. The mean CCK level rose from 19.6 +/- 4 to 23.8 pg/ml.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gallbladder Function and Plasma Cholecystokinin Levels in Diabetes Mellitus

Contractile motility of the gallbladder and plasma cholecystokinin (CCK) responses to egg yolk administration were studied in 28 diabetic patients and 12 normal subjects. The patients were divided into three groups: group A (n = 10) had no diabetic neuropathy, group B (n = 8) had diabetic neuropathy with little autonomic neuropathy, and group C (n = 10) had advanced diabetic autonomic neuropathy. In groups A and B, contraction of the gallbladder after egg yolk administration was not significantly different from that of normal subjects. However, in group C, gallbladder contraction was impaired (p less than 0.01-0.05), compared with that in normal subjects. After the administration of egg yolk, plasma CCK levels increased from 12.4 +/- 4.5 to 25.3 +/- 12.0 pg/ml in normal subjects. In group A, plasma CCK levels increased from 17.9 +/- 8.5 to 39.3 +/- 14.2 pg/ml, and in group B, from 15.2 +/- 5.1 to 38.3 +/- 9.9 pg/ml. In group C, however, plasma CCK levels increased from 33.1 +/- 13.9 to 72.4 +/- 31.9 pg/ml, and fasting CCK levels and responses to egg yolk were significantly higher than those in normal subjects and in groups A and B (p less than 0.01-0.05). In conclusion, this study showed that in a group of diabetic patients with autonomic neuropathy, gallbladder contraction was impaired despite the exaggerated CCK response to egg yolk.     

Effect of Intraduodenal and Intravenous Amino Acids on Proximal Gastric Motor Function in Man

The present study was performed to investigate the effect of amino acids during the intestinal and postabsorptive phase of digestion on proximal gastric motor function measured with an electronic barostat. Eight healthy volunteers participated in three experiments performed during continuous infusion of: (1) intravenous and intraduodenal saline, (2) intraduodenal amino acids, and (3) intravenous amino acids. Both intraduodenal and intravenous amino acids induced gastric relaxation and increased gastric compliance. Only during intraduodenal amino acids did plasma CCK levels increase significantly. Correlation between intragastric volume measurements (with pressure set at MDP + 2 mm Hg) and plasma CCK levels was 0.90 (P < 0.001) during the early intestinal phase. Relaxation of the proximal stomach is related to plasma CCK in the early intestinal phase, whereas in the postabsorptive phase of amino acids other mechanisms play a role in proximal gastric relaxation.     

RESPONSE OF CIRCULATING SOMATOSTATIN, INSULIN, GASTRIN AND GIP, TO INTRADUODENAL INFUSION OF NUTRIENTS IN NORMAL MAN

We have studied the effect of direct infusion of nutrients into the duodenum of normal subjects on circulating plasma somatostatin, insulin, gastrin and gastric inhibitory polypeptide (GIP) levels. Six normal subjects were given on four separate occasions 150 ml of isotonic solutions containing 100 calories of carbohydrate, protein, or fat, and a control solution of saline, by infusion into the second part of the duodenum. Plasma somatostatin rose slightly after carbohydrate, mean basal 30 +/- 3 pg/ml, peak 46 +/- 16 pg/ml at 15 min; and more markedly after protein, peak 57 +/- 9 pg/ml at 30 min. However, fat was the most potent intraduodenal stimulus to plasma somatostatin release into circulation, peak 101 +/- 11 pg/ml at 30 min. The plasma insulin rise was greatest after carbohydrate, peak 68 +/- 10 i.u., but there was a significant rise after protein also, peak 34 +/- 6 i.u. Plasma gastrin rose significantly after protein only, peak 70 +/- 22 pg/ml. Plasma GIP rose markedly after carbohydrate, basal 506 +/- 50 pg/ml, peak 1480 +/- 120 pg/ml. Protein was also a potent stimulus of circulating plasma GIP release, peak 1200 +/- 190 pg/ml, while fat was the least potent, peak 730 +/- 190 pg/ml. Thus, calorie for calorie, fat is the most potent intraduodenal nutrient stimulus of circulating somatostatin. We postulate therefore that somatostatin may be an enterogastrone--a circulating hormone released by intraduodenal fat which inhibits gastric acid secretion. Fat is the least potent intraduodenal nutrient stimulus of circulating GIP release. This is evidence against the hypothesis that circulating GIP acts as an enterogastrone.     

High Plasma Cholecystokinin Levels in Patients with Chronic Pancreatitis Having Abdominal Pain

Plasma cholecystokinin (CCK) responses after ingestion of a test meal in patients with mild chronic pancreatitis having abdominal pain were studied with a radioimmunoassay using the CCK specific antiserum (OAL-656) produced by a novel immunization procedure. Mean concentration of the fasting plasma CCK determined using CCK-8 as a standard was 31.5 +/- 5.8 pg/ml in six patients who had mild impaired exocrine function with pain, and was significantly higher than 10 healthy subjects (9.8 +/- 1.8 pg/ml). In those patients, the ingestion of a liquid test meal led to a peak of 75.1 +/- 25.4 pg/ml at 30 min, and the 120-min integrated CCK response (5427 +/- 1217.3 pg X min/ml) was significantly higher than in healthy subjects (1538 +/- 110.1 pg X min/ml).     

Cholecystokinin is not a physiological regulator of gastric pepsin secretion in rats

The physiological relevance of cholecystokinin (CCK) in gastric pepsin secretion is unclear, although CCK has been reported to stimulate pepsin secretion in intact animals and in dispersed chief cell. To clarify the physiological role played by this peptide in pepsin secretion, we determined the effects of intravenous infusions of CCK on gastric pepsin release, and investigated the effect of endogenous CCK released by small amounts of trypsin inhibitor on pepsin secretion in conscious rats. The infusion of CCK-8 at 1 nmol/kg per h resulted in a plasma CCK concentration of 204 pM and a 2.5-fold increase in pepsin secretion compared to the baseline rate. The infusion of CCK-8 at 0.3 nmol/kg per h resulted in a plasma CCK concentration of 41.8 pM and also caused a significant increase in pepsin secretion compared to the baseline rate. However, the infusion of CCK-8 at 0.1 nmol/kg per h (plasma CCK level, 19.9 pM), which is still far beyond the physiological plasma levels of CCK, did not significantly affect pepsin secretion. In addition, the intraduodenal infusion of soybean trypsin inhibitor increased the plasma CCK concentration to 4.4 pM, a value comparable to that observed after feeding (3.3 pM), but again, this had no effect on gastric pepsin secretion. We conclude that CCK is not a physiological regulator of gastric pepsin secretion in rats.     

Effects of intravenous infusion of amino acids on cholecystokinin release and gallbladder contraction in humans

We investigated the effect of intravenous infusions of the therapeutically available amino acid solutions Moripron and Morihepamin (Roussel Morishita, Osaka, Japan) on gallbladder contraction and cholecystokinin (CCK) release in healthy male volunteers. Plasma CCK levels were measured by radioimmunoassay, using the antibody OAL-656, which is specific for the aminoterminus of CCK-8 and thus recognizes biologically active forms of all CCKs. The volume of the gallbladder was calculated by ultrasonographic measurements. Intravenous infusion of Moripron at the rate of 3.33 ml/min for 60 min, caused gallbladder contraction, with a peak response of 31.3±8.6% of the fasting volume at 45–60 min, and a significant increase in plasma CCK concentration, from 1.8±0.2 pmol/l to a peak of 9.9±1.5 pmol/l, at 30–45 min. The maximum gallbladder contraction and the peak CCK release during the Moripron infusion were not significantly different from findings after a test meal. There was a close relationship between the peak plasma CCK concentration and the maximal gallbladder contraction during the administration of Moripron, and this agent, even when infused at the rate of 1.67 ml/min, significantly increased plasma CCK levels and gallbladder contraction. Intravenous infusion of Morihepamin had no significant influence on gallbladder volume or plasma CCK levels. The discrepancy in responses appeared to be related to differences in composition between Moripron and Morihepamin, and not to the total dose of amino acid. Intravenous infusions of amino acids appear to have different effects on gallbladder contraction and plasma CCK secretion depending on the amino acids composition. Our findings suggest that an intravenous infusion of Moripron could be used for the prophylaxis of acute acalculous cholecystitis and sludge formation due to reduced biliary motility in patients on total parenteral nutrition.     

Modulation of Gallbladder Contraction by Pirenzepine in Humans

Objectives : The mechanism (s) by which cholinergic innorvatiun modulates gallbladder contraction are not fully understood. To elucidate the role of muscarinic M, receptors in the mediation of gallbladder contraction, we investigated gallbladder volume reduction, plasma cholecystokinin (CCK). and pancreatic polypeptide (I'P) responses in humans during cephalic and intestinal phases of a meal under M, muscarinic receptor blockade with pirenzepine. Methods : In eight healthy subjects, intruduodenal meal- and in seven subjects, sham feeding-induced gallbladder volume reduction was measured by real-time ultrasonography during saline or piren/-epine administration. Plasma CCK and PP were measured by radioimmunoassay. Results : Pirenzepine partially inhibited gallbladder volume reduction in response to an intraduodenal fatty meal. The integrated gallbladder volume reduction over 120 min was 4462 ± 445%.min compared with 6879 ± 279%.min in the saline control group ( p < 0.01). Integrated plasma CCK and PP responses were unchanged in the presence of pirenzepine. Pirenzepine abolished sham feeding-induced gallbladder contraction and plasma PP response. Sham feeding with either isotonic saline or pirenzepine infusion did not modify fasting plasma CCK levels. Conclusion : M, muscarinic receptors play an important role in the intestinal and cephalic phases of gallbladder contraction. Plasma CCK response to intraduodenal meal is not influenced by M, muscarinic receptor blockade with pirenzepine.     

Effect of exogenous cholecystokinin (CCK)-8 on food intake and plasma CCK, leptin, and insulin concentrations in older and young adults: evidence for increased CCK activity as a cause of the anorexia of aging.

Healthy aging is associated with reductions in appetite and food intake--the so-called anorexia of aging, which may predispose to protein-energy malnutrition. One possible cause of the anorexia of aging is an increased satiating effect of cholecystokinin (CCK). To investigate the impact of aging on the satiating effects of CCK, 12 young and 12 older healthy subjects received 25-min iv infusions of saline (control) and CCK-8, 1 ng/kg per min or 3 ng/k per min, on 3 separate days before a test meal. Older subjects ate less than young subjects, and food intake was suppressed 21.6% by CCK-8, compared with the control day (P < 0.05). The suppression of energy intake by CCK-8 in older subjects was twice that in young subjects (32 +/- 6% vs. 16 +/- 6% SEM, P < 0.05) and was related to plasma CCK-8 concentrations, which were higher at baseline (P < 0.05) and increased more during CCK-8 infusions in older than young subjects (P < 0.01). The extent of suppression of food intake per given rise in plasma CCK-8 concentrations did not differ between the two age groups (P = 0.35). Endogenous CCK concentrations were higher at baseline in older subjects (P < 0.001) and decreased during the CCK-8 but not control infusions (P < 0.01), suggesting that CCK suppresses its own release. Plasma leptin concentrations were not affected by CCK infusion, whereas postprandial insulin concentrations were lowered and the peak postprandial glucose concentration was delayed but not affected by CCK-8 infusion. Because older people retain their sensitivity to the satiating effects of exogenous CCK and plasma endogenous CCK concentrations are higher in older people, increased CCK activity may contribute to the anorexia of aging.     

Regulation of plasma cholecystokinin levels by bile and bile acids in the rat

To determine whether intraduodenal bile acids inhibit pancreatic secretion and cholecystokinin (CCK) release independent of pancreatic proteases, experiments were conducted in rats with bile and pancreatic juice chronically diverted to the ileum. Diversion of bile and pancreatic juice increased plasma CCK concentration to 19.1 +/- 4.0 pmol/L. Intraduodenal sodium taurocholate (78 mumol/h) reduced plasma CCK concentration to 6.6 +/- 1.5 pmol/L after 1 hour, but values increased to 17.3 +/- 2.3 pmol/L after 13.5 hours despite continued taurocholate infusion. Pancreatic protein secretion was also significantly but transiently inhibited by taurocholate. However, neither acute nor chronic intraduodenal bile infusion significantly reduced plasma CCK concentration compared with sodium bicarbonate infusion (13.4 +/- 1.9 pmol/L vs. 15.0 +/- 1.7 pmol/L, respectively). Chronic (13.5 hours) intraduodenal infusion of taurocholate plus pancreatic juice caused a sustained reduction of plasma CCK level to 3.1 +/- 0.5 pmol/L, which significantly increased to 9.4 +/- 1.1 pmol/L after cessation of taurocholate but with continued infusion of pancreatic juice. The results indicate that bile does not inhibit CCK release and that bile acids do not physiologically inhibit pancreatic secretion or CCK release independent of the presence of pancreatic proteases.     

Effect of bombesin and cholecystokinin on plasma immunoreactive trypsin in humans

Since bombesin is a potent stimulus of the release of cholecystokinin (CCK), it has been suggested that the stimulatory effect of bombesin on pancreatic enzyme secretion is mediated by CCK. The present study was undertaken to determine the role of CCK in the bombesin-induced stimulation of plasma immunoreactive trypsin. Plasma CCK was measured by radioimmunoassay using the antibody T204, which binds to all biologically active sulfated COOH-terminal CCK-peptides. Plasma trypsin was also measured by radioimmunoassay. Infusion of 5 ng/kg/min bombesin in 6 healthy volunteers increased plasma CCK from 1.2 +/- 0.2-8.9 +/- 0.7 pM (p less than 0.0001). The peak increment in plasma CCK during bombesin (9.3 +/- 0.6 pM) was accompanied by a significant rise in plasma trypsin from 206 +/- 21-334 +/- 44 ng/ml (p less than 0.01). However, when similar increases in plasma CCK were achieved by infusion of 0.018 CU/kg/min CCK-33 (9.9 +/- 0.8 pM) or by intraduodenal instillation of 250 ml 20% Intralipid (9.7 +/- 1.9 pM), no significant changes in plasma trypsin were observed. It is therefore concluded that the stimulatory effect of bombesin on plasma immunoreactive trypsin is not mediated by CCK.     

High Plasma Concentrations of Endothelin-like Immunoreactivities in Patients with Hepatocellular Carcinoma

The plasma levels of endothelin-like immunoreactivities (ET-IR) of patients with hepatocellular carcinoma (HCC) were compared with those of patients with liver cirrhosis (LC), using a specific radioimmunoassay for endothelin-1. The mean concentration of plasma ET-IR of 21 HCC patients (30.3 ±8.5 pg/ml, n = 21) (means ± SD) was markedly higher than those in LC (22.1 ±4.7 pg/ml, n = 16) ( p < 0.01), which were also elevated compared with those in normal subjects (9.4 ± 1. 6 pg/ml, n = 91). Moreover, the level of plasma ET-IR reflected the tumor size of HCC patients, which was estimated by the ultrasonic and computed tomographic examinations. Although there was no relation to other biochemical parameters indicating liver function or tumor markers such as α-fetoprotein, a good positive correlation was obtained between plasma ET-IR and C-reactive protein (CRP) concentrations of HCC patients ( r = 0.805, p < 0.01). We measured the tissue contents of ET-IR in HCC and its adjacent LC tissue, but failed to find any significant difference between the mean content of HCC (0.50 ± 0.38 ng/g) and LC (0.44 ± 0.28ng/g). The endothelial cell damage due to cancer growth may not be responsible for the high concentrations of plasma ET-IR of HCC, because plasma thrombomodulin concentrations were not correlated with plasma ETIR levels in HCC patients. Our study implies that the high plasma concentration of ET-IR is pathogenomonic to HCC, although the site of production is still debatable.     

Regulation of pancreatic endocrine function by cholecystokinin: studies with MK-329, a nonpeptide cholecystokinin receptor antagonist

A cholecystokinin (CCK) receptor antagonist, MK-329, was used to explore the physiological role of CCK in regulating pancreatic endocrine function in humans. The ability of CCK to increase plasma pancreatic polypeptide (PP) concentrations and blockade of this effect with MK-329 were evaluated in a double blind, balanced, four-period cross-over study. Eight subjects received single oral doses of 0.5, 2, or 10 mg MK-329 or placebo, followed by an iv infusion of CCK-8 (34 ng/kg.h). In placebo-treated subjects, PP increased from basal levels of 70 +/- 15 (+/- SE) to peak values of 291 +/- 58 pg/mL after CCK infusion (P less than 0.05 compared to basal). This increase in plasma PP concentration was inhibited in a dose-dependent fashion by MK-329, with 10 mg antagonizing the stimulatory effect of CCK infusion by nearly 80%. Second, the effect of MK-329 on meal-stimulated pancreatic endocrine responses was evaluated by giving placebo or 10 mg MK-329 2 h before ingestion of a mixed meal. Eight subjects were treated in a randomized two-period cross-over fashion. With placebo treatment, peak postprandial plasma insulin, glucagon, and glucose concentrations were 101 +/- 8 microU/mL, 195 +/- 15 pg/mL, and 150 +/- 10 mg/dL, respectively (all P less than 0.05). The integrated PP response following the meal was 56.3 +/- 11.1 ng/mL.minute. With MK-329 treatment, the integrated PP concentration was reduced to 33.9 +/- 2.2 ng/mL.min (P less than 0.05 compared to placebo treatment). Mean postprandial insulin, glucagon, and glucose concentrations did not differ between placebo and MK-329 treatments. We conclude that CCK receptor blockade with 10 mg MK-329 does not alter plasma insulin, glucagon, or glucose responses to a mixed meal. However, the observation that physiological concentrations of CCK increase plasma levels of PP, and the finding that CCK receptor blockade selectively attenuates the postprandial increase in plasma PP concentrations support a physiological role for CCK in regulating PP secretion.     

Somatostatin analog, SMS 201-995, inhibits pancreatic exocrine secretion and release of secretin and cholecystokinin in rats.

We studied the effect of a synthetic octapeptide somatostatin analog, SMS 201-995 (sandostatin), on pancreatic exocrine secretion and on plasma secretin and cholecystokinin (CCK) levels in vivo in anesthetized rats. The exocrine pancreas was stimulated by either intravenous infusion of both secretin (0.06 CU/kg/h) and cholecystokinin octapeptide (CCK-8) (0.03 micrograms/kg/h) or intraduodenal infusion of oleic acid (pH 6.5) in a dose of 0.25 mmol/h. Intravenous administration of SMS 201-995 in three different doses of 100, 200, and 400 ng/kg/h resulted in dose-related inhibition of pancreatic secretion in terms of volume, bicarbonate, and amylase stimulated by exogenous secretin and CCK. Intraduodenal oleic acid stimulated pancreatic secretion, including volume, bicarbonate, and amylase, and this was accompanied by a significant elevation in the plasma concentrations of secretin and CCK. Intravenous administration of SMS 201-995 in the three different doses described above caused dose-dependent suppression of the increase in pancreatic exocrine secretion as well as the plasma concentration of secretin and CCK induced by intraduodenal infusion of oleic acid. It is concluded that SMS 201-995 inhibits pancreatic exocrine secretion and the release of endogenous hormones, such as secretin and CCK, in rats.     

Evidence for modulation of motilin secretion by pancreatico-biliary juice in health and in chronic pancreatitis

The gut hormone motilin can initiate the interdigestive migrating motor complex. There are synchronous cyclic changes in plasma motilin-like immunoreactivity (MLI) levels and pancreatico-biliary secretion during the interdigestive period which may be causally related. The purpose of this study was to investigate the role of pancreatico-biliary secretion into the gut as a modulator of plasma MLI concentrations. In six healthy subjects, the mean basal plasma MLI level was 130 +/- 16 pg/ml. Infusion of cholecystokinin octapeptide (CCK-8) stimulated MLI secretion, with an integrated (30 min) response of 2028 +/- 340 pg/min X ml. Intraduodenal perfusion of pancreatico-biliary juice produced a similar increase in plasma MLI, with a 30 min integrated response of 2190 +/- 270 pg/min X ml. Neither enzyme activity, osmolarity, or pH accounted for the response. In six patients with exocrine pancreatic insufficiency, although their mean basal plasma MLI concentration of 205 +/- 44 pg/ml was significantly higher than that observed in healthy subjects, there was no significant plasma MLI increase after CCK-8 infusion. Pancreatic exocrine secretion was severely compromised in these patients, as evidenced by the markedly reduced peak lipase (3.8 +/- 0.6 kU/h) and trypsin (2.4 +/- 0.5 kU/h) outputs. In contrast, infusion of pancreatico-biliary juice obtained from healthy subjects caused a rise in plasma MLI, with a 60 min integrated response of 3912 +/- 1031 pg/min X ml, which was similar to that of 3947 +/- 472 pg/min X ml in healthy subjects. We conclude that there is an undefined factor in pancreatico-biliary juice that stimulates MLI release. A deficiency of pancreatic exocrine secretion may be responsible for the impaired MLI response to CCK-8 stimulation in chronic pancreatitis. Since MLI is known to initiate the formation of the interdigestive migrating motor complexes, diminished motilin release secondary to pancreatic exocrine deficiency may result in disordered gastrointestinal motor activity in patients with chronic pancreatitis.     

Effects of pharmacologic hyperglucagonemia on plasma amino acid concentrations in normal and diabetic man

Four normal and five insulin dependent diabetic men received a 2 h pharmacologic glucagon infusion (50 ng/kg/min) resulting in plasma glucagon levels (4400 pg/ml) similar to those seen in glucagonoma patients. In normal subjects in whom plasma insulin concentrations rose significantly (239 uU/ml) and the blood level of 15 of the 18 amino acids measured fell significantly. In contrast, in the diabetic men who secreted no insulin in response to glucagon (no rise in C-peptide levels), only 10 of 18 amino acid levels fell significantly. The branched chain amino acids valine, leucine and isoleucine, as well as tyrosine and phenylalanine were among the 8 amino acids which showed no change in response to glucagon in the diabetics. Thus, glucagon appears to have no acute affect on branched chain amino acid levels in man.     

Low Plasma Cholecystokinin Response after Ingestion of a Test Meal in Patients with Chronic Pancreatitis

Postprandial responses of plasma cholecystokinin (CCK) in patients with severe chronic pancreatitis (n = 7) were studied. Plasma CCK level rose from 11.2 +/- 1.8 pg/ml at the basal level to a maximum of 23.3 +/- 3.0 pg/ml at 10 min after the ingestion of a liquid meal in healthy subjects (n = 6). However, such significant plasma CCK response to the meal was not observed in patients with chronic pancreatitis in whom CCK levels rose from a basal level of 9.7 +/- 0.91 pg/ml to a peak of 13.8 +/- 1.6 pg/ml at 60 min. It is suggested that the low response of CCK after the meal might reflect impaired function of the enteropancreatic axis to intraluminal stimuli in patients with severe chronic pancreatitis.     

Effect of CCK on food intake in man: physiological or pharmacological effect?

The present study was designed to determine in humans the dose of CCK which suppresses food intake. 18 male subjects received in randomized order either i.v. saline or Thr28 Nle31 CCK 25-33 (CCK-9) at 100 or 500 pmol/kgh, respectively. In addition, 7 subjects received CCK together with the opiate receptor antagonist naloxone to examine if activation of endogenous opioids might interfere with the potential satiating effect of CCK. Food intake during saline was 32 +/- 2 sandwiches (mean +/- SEM), during CCK-9 100 pmol/kgh 28 +/- 2 (n.s.) and only 12 +/- 3 during CCK-9 500 pmol/kgh (p less than 0.01). The respective water intake was 730 +/- 70 ml, 590 +/- 60 ml (n.s.) and 320 +/- 50 ml (p less than 0.01). Naloxone further reduced food and water intake during high but not low dose CCK or saline. During saline postprandial insulin levels rose by 49 +/- 6 microU/ml within 45 min which was attenuated during low dose (23 +/- 6 microU/ml; p less than 0.01) and high dose CCK-9 (1 +/- 1 microU/ml; p less than 0.001). Plasma glucagon did not change in control or CCK experiments. The postprandial rise of pancreatic polypeptide was attenuated during high dose CCK. Naloxone had no effect on the hormonal response except for a prolonged reduction of insulin and glucose levels following high dose CCK + naloxone. Plasma CCK levels rose by 5.4 pmol/l in controls but by 55 and 255 pmol/l during the low and high dose CCK infusion, respectively. These data demonstrate that suppression of food intake in man by i.v. CCK is a pharmacological rather than a physiological effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of cholecystokinin in the negative feedback control of pancreatic enzyme secretion in conscious rats

Using a specific radioimmunoassay for cholecystokinin (CCK) we have studied the relation between circulating CCK concentrations and the feedback regulation of pancreatic enzyme secretion in conscious rats. Recirculation of diverted bile-pancreatic juice into the duodenum or intraduodenal perfusion of trypsin during biliary-pancreatic juice diversion produced basal output of amylase and trypsin and low portal CCK levels (less than 10 pmol/L). Biliary-pancreatic juice diversion or inactivation of trypsin caused increased CCK concentrations (peak values 50-100 pmol/L) and enzyme outputs. During biliary-pancreatic juice diversion, infusion of the CCK receptor antagonist proglumide suppressed the enzyme response without altering the increase in CCK. Measurement of portal and peripheral CCK during biliary-pancreatic juice diversion yielded values of 131 +/- 37 and 32 +/- 5 pmol/L, respectively. The peripheral CCK levels corresponded to concentrations achieved during exogenous CCK-8 infusion which resulted in similar enzyme outputs. Gel chromatography of portal plasma during diversion of biliary-pancreatic juice revealed one peak of CCK corresponding to CCK-8, and a larger peak eluted between CCK-33 and CCK-8, probably representing CCK-22. Similar CCK components were found in water extracts of jejunal mucosa, whereas the acetic acid extracts mainly contained CCK-33/39. We conclude that the negative feedback regulation of pancreatic enzyme secretion in rats is mediated by the release of CCK from the intestine and that the major molecular form of CCK in plasma is probably CCK-22.