Cholecystokinin is a physiological hormonal mediator of fat-induced inhibition of gastric emptying in man

The effect of cholecystokinin-33 on gastric emptying was studied in eight healthy men. The test meal was a firm custard pudding, labelled with 99mTc-Chelex-100 particles. Gastric emptying rate was measured, using a dual-headed gamma camera, and was expressed as the half time of the emptying curve. Plasma cholecystokinin concentrations were determined by radioimmunoassay. Subjects were studied three times: (i) during infusion of saline; during cholecystokinin infusion, (ii) 0.375 IDU kg-1 h-1 and (iii) 0.75 IDU kg-1 h-1. Furthermore, plasma cholecystokinin was determined after a regular meal. During saline, plasma cholecystokinin increased minimally. After the regular meal it increased from 1.6 to 6.5 pmol l-1 at 30 min, decreasing to 5.3 pmol l-1 at 60 min. During the lower and higher doses of cholecystokinin it increased from 1.0 and 1.4 to 4.5 and 7.3 pmol l-1, respectively. The lower and higher doses significantly (P less than 0.05) increased half emptying time, from 45 +/- 8 to 86 +/- 17 and 198 +/- 50 min, respectively. Cholecystokinin is most likely a physiological hormonal mediator of fat-induced inhibition of gastric emptying.     

Role of the gastric phase in fat-induced gallbladder contraction and cholecystokinin secretion in humans

The present study was undertaken to investigate the role of the gastric phase of fat-induced gallbladder contraction and endogenous cholecystokinin (CCK) secretion in humans. Gallbladder emptying, measured by cholescintigraphy, and endogenous CCK secretion, measured by radioimmunoassay, were studied in healthy subjects after both intragastric and intra-intestinal administration of corn oil. In addition, patients with partial gastrectomy were investigated to study the effect of accelerated gastric emptying. In the healthy subjects, intragastric administration of fat resulted in a significantly (P less than 0.05) later increase in plasma CCK levels (20 +/- 2 min) compared to intraintestinal fat (5 +/- 1 min). Similarly, the onset of gallbladder emptying was significantly (P less than 0.05) delayed after intragastric fat (20 +/- 2 min) compared to intestinal fat (10 +/- 1 min). In the healthy subjects the integrated plasma CCK response to intragastric fat was significantly (P less than 0.005-P less than 0.01) reduced from 10 to 30 min. In the patients with partial gastrectomy the rise in plasma CCK (10 +/- 1 min) and the onset of gallbladder emptying (15 +/- 2 min) were in the same range after intra-intestinal and intragastric fat. No significant differences in plasma CCK levels, integrated CCK response or gallbladder emptying were found in the patients according to the site of fat application. It is concluded that endogenous CCK secretion and gallbladder emptying in response to intragastric fat are significantly delayed in healthy subjects but not in patients with partial gastrectomy, in whom gastric emptying is accelerated.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased plasma cholecystokinin levels and small gall bladders in adult patients with cystic fibrosis.

1. In patients with cystic fibrosis, abnormalities in plasma cholecystokinin level and gall-bladder emptying may contribute to the development of maldigestion and gall-stones. 2. Therefore, we have measured plasma cholecystokinin levels and gall-bladder volumes before and after ingestion of a standard breakfast in eight adult patients with cystic fibrosis and in eight normal control subjects. 3. In the patients with cystic fibrosis basal (2.8 +/- 0.4 pmol/l; P less than 0.05, t-test) and maximum post-prandial (5.7 +/- 0.5 pmol/l; P less than 0.05, t-test) plasma cholecystokinin levels were significantly higher than those in the control subjects (1.9 +/- 0.1 pmol/l, and 4.5 +/- 0.2 pmol/l, respectively). On the other hand, integrated plasma cholecystokinin secretion in response to the meal was similar (t-test, P = 0.4 versus control subjects). The increased plasma cholecystokinin levels in the patients with cystic fibrosis were accompanied by reduced gallbladder volumes in both the basal (7.8 +/- 2.1 cm3 versus 20.9 +/- 2.3 cm3 in control subjects; P less than 0.005, t-test) and the post-prandial state (2.2 +/- 1.0 cm3 versus 4.8 +/- 0.8 cm3 in control subjects; P = 0.06, t-test). Gall-bladder emptying in the patients with cystic fibrosis was well preserved (70 +/- 7% versus 78 +/- 9% in control subjects; P = 0.4, t-test). 4. In comparison with normal control subjects, patients with cystic fibrosis have an increased basal plasma cholecystokinin level and a reduced gall-bladder volume, whereas post-prandial gall-bladder emptying and plasma cholecystokinin secretion are not significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiological role for cholecystokinin in reducing postprandial hyperglycemia in humans.

It is known that the ingestion of glucose alone causes a greater increase in plasma glucose levels than ingestion of the same amount of glucose given with other nutrients. Since physiological plasma concentrations of cholecystokinin (CCK) prolong gastric emptying, it is proposed that after a meal, CCK may modify plasma glucose levels by delaying glucose delivery to the duodenum. To evaluate the effect of CCK on oral glucose tolerance, plasma CCK, insulin, and glucose levels and gastric emptying rates were measured in eight normal males before and after the ingestion of 60 g glucose with the simultaneous infusion of either saline or one of two doses of CCK-8 (12 or 24 pmol/kg per h). Gastric emptying rates were measured by gamma camera scintigraphy of technetium 99m sulfur colloid and plasma CCK levels were measured by a sensitive and specific bioassay. Basal CCK levels averaged 1.0 +/- 0.1 pM (mean +/- SEM, n = 8) and increased to 7.1 +/- 1.1 pM after a mixed liquid meal. After glucose ingestion, but without CCK infusion, CCK levels did not change from basal, and the gastric emptying t1/2 was 68 +/- 3 min. Plasma glucose levels increased from basal levels of 91 +/- 3.9 mg/dl to peak levels of 162 +/- 11 mg/dl and insulin levels increased from 10.7 +/- 1.8 microU/ml to peak levels of 58 +/- 11 microU/ml. After glucose ingestion, with CCK infused at 24 pmol/kg per h, plasma CCK levels increased to 8 pM and the gastric emptying t1/2 increased to 148 +/- 16 min. In concert with this delay in gastric emptying, peak glucose levels rose to only 129 +/- 17 mg% and peak insulin levels rose to only 24.2 +/- 4.2 microU/ml. With CCK at 12 pmol/kg per h, similar but less dramatic changes were seen. To demonstrate that endogenous CCK could modify the plasma glucose and insulin responses to oral glucose, oral glucose was given with 50 g of lipid containing long-chain triglycerides. This lipid increased peak CCK levels to 3.7 +/- 0.9 pM. Concomitant with this rise in CCK was a delay in gastric emptying and a lowering of plasma glucose and insulin values. To confirm that CCK reduced hyperglycemia by its effect on gastric motility, 36 g glucose was perfused directly into the duodenum through a nasal-duodenal feeding tube in four subjects. With duodenal perfusion of glucose, there was no change in plasma CCK levels, but plasma glucose levels increased from basal levels of 93+/-5 to 148+/-6 mg/dl and insulin levels rose from 10.6+/-3.5 to 29.5+/-5.2 microU/ml. When CCK was infused at 24 pmol/kg per h, neither the plasma glucose nor insulin responses to the duodenal administration of glucose were modified. Thus we conclude that CCK, in physiological concentrations, delays gastric emptying, slows the delivery of glucose to the duodenum, and reduces postprandial hyperglycemia. These data indicate, therefore, that CCK has a significant role in regulating glucose homeostasis in human.     

Regulation of gastric emptying in humans by cholecystokinin.

In the present study we used a bioassay system for measuring plasma cholecystokinin (CCK) to evaluate whether CCK has a physiologic role in regulating gastric emptying in humans. Plasma CCK levels and gastric emptying after ingestion of a mixed liquid meal were determined in five normal male volunteers. Fasting CCK levels averaged 0.8 +/- 0.1 pM and increased to 6.5 +/- 1.0 pM within 10 min of drinking the mixed meal. CCK levels remained elevated for up to 90 min. Gastric emptying after a meal was slow; at the end of the 90 min 68% of the original volume remained in the stomach. The rate of gastric emptying of water was then measured in the same individuals with a simultaneous infusion of either saline, or one of two doses of CCK (12 pmol/kg per h and 24 pmol/kg per h). With the saline infusion, plasma CCK levels did not increase above basal and gastric contents emptied rapidly. At the end of 90 min only 7% of the original volume remained in the stomach. The lower dose of CCK resulted in a plasma level of 3.4 pM which both reproduced the average postprandial plasma level and caused a significant delay in gastric emptying. The higher dose of CCK achieved plasma levels of 8 pM and resulted in a delay in gastric emptying that was similar to that seen with the mixed meal. Since exogenous CCK at concentrations which occur postprandially delays gastric emptying, we conclude that CCK is a physiologic regulator of gastric emptying.     

Effect of rectal distension on gallbladder emptying and circulating gut hormones

BACKGROUND: Abnormalities of upper gut motility, including a delay of gastric emptying and small bowel transit, found in patients with constipation may be secondary to factors originating in the colon or rectum as a result of faecal stasis. The aim was to determine if stimulation of mechanosensory function by rectal distension affects postprandial gallbladder emptying and release of gastrointestinal peptides participating in control of upper gut motility. MATERIALS AND METHODS: Eight healthy volunteers were studied with an electronic barostat and a plastic bag positioned in the rectum. Intrabag pressure was maintained at minimal distension pressure + 2 mmHg on one occasion and on a pressure that induced a sensation of urge on the other. Gallbladder volume and plasma concentrations of cholecystokinin (CCK), pancreatic polypeptide (PP) and peptide YY (PYY) were measured before and after ingestion of a 450-kcal mixed liquid meal. RESULTS: Rectal distension enhanced maximum gallbladder emptying from 66 +/- 7% to 78 +/- 5% (P < 0.05). Distension tended to increase integrated plasma PYY from 77 +/- 30 pM min to 128 +/- 40 pM min in the first hour after the meal (P = 0.08) and it suppressed integrated plasma PP from 1133 +/- 248 pM min to 269 +/- 284 pM min in the second hour (P < 0.05). Integrated plasma CCK concentrations were not significantly affected. CONCLUSION: Mechanosensory stimulation of the rectum enhances postprandial gallbladder emptying and influences postprandial release of gut hormones involved in the regulation of gastrointestinal motility in healthy subjects. These mechanisms may play a role in the pathogenesis of the upper gastrointestinal motor abnormalities observed in constipated patients.     

Human pancreatic and biliary responses to physiological concentrations of cholecystokinin octapeptide

To determine the functional significance of physiological plasma concentrations of cholecystokinin, five volunteers each received graded doses of intravenous infusions of cholecystokinin octapeptide (CCK-8). At each dose plasma concentrations of CCK-8 were determined and pancreatic and biliary outputs were measured. Threshold plasma concentrations of CCK-8 for augmenting pancreatic trypsin secretion were undetectable (less than 3 pmol/l), and maximal trypsin output of 21.9 +/- 1.95 k-i.u./30 min was produced by 17.1 +/- 6.4 pmol of CCK-8/1. Calculated halfmaximal output was produced by 4.7 pmol of CCK-8/1. Maximal trypsin output during infusions of CCK-8 was significantly less than that after a combination of the CCK-like peptide, caerulein, and secretin (32.95 +/- 2.16 k-i.u./30 min, P less than 0.001). Biliary bile acid and bilirubin outputs were significantly augmented only when plasma concentrations of CCK-8 were greater than 5 pmol/l. Plasma concentrations of CCK-8 in the low picomolar range exert significant effects on pancreatic and biliary secretion. CCK-8 fulfills the criteria for a circulating hormone.     

Effects of a novel cholecystokinin (CCK) receptor antagonist, MK-329, on gallbladder contraction and gastric emptying in humans. Implications for the physiology of CCK.

To explore the physiology of cholecystokinin (CCK) in humans, we investigated the effect on gallbladder contraction and gastric emptying of a recently developed CCK receptor antagonist, MK-329. In a double-blind, four-period crossover study eight subjects received single doses of 0.5, 2, or 10 mg MK-329, or placebo, followed by an intravenous infusion of CCK-8 (30 pmol/kg.h). In placebo-treated subjects gallbladder volumes decreased on average to 43% of initial volumes after 2 h of CCK infusion. MK-329 caused a dose-dependent inhibition of CCK-stimulated gallbladder contraction with 10 mg producing complete blockade (P less than 0.01, cf. placebo). Gallbladder contraction and gastric emptying rates after a mixed meal were then measured in a two-period crossover study. Subjects received placebo or 10 mg of MK-329 2 h before eating. Gastric emptying of both solids and liquids was measured simultaneously by gamma scintigraphy. In placebo-treated subjects plasma CCK levels increased postprandially to 2.3 pM, gallbladder volumes decreased 68.4 +/- 3.8% (SE), and the times for 50% emptying of liquids and solids from the stomach were 58 +/- 10 and 128 +/- 8 min, respectively. In MK-329-treated subjects there was a marked elevation in peak CCK levels to 13.8 pM (P less than 0.01, cf. placebo), and gallbladder contraction was completely inhibited. Solid and liquid emptying rates were unaffected. These findings demonstrate that (a) MK-329 is a potent, orally active antagonist of CCK in humans, and (b) CCK is the major regulator of postprandial gallbladder contraction. These data also support the concept of negative feedback regulation of CCK secretion and suggest that mechanisms other than CCK play a dominant role in the regulation of postprandial gastric emptying rates.     

Radioimmunoassay of cholecystokinin in plasma

A sensitive and specific radioimmunoassay for cholecystokinin (CCK) has been developed. Synthetic unsulfated carboxy-terminal fragment, CCK-8, was radioiodinated by the conventional Chloramine-T method. Antibodies were raised against sulfated CCK-8 covalently coupled to bovine thyroglobulin via 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. By purification, highly immunoreactive 125I-labeled CCK-8 was obtained. The antiserum was highly avid, and plasma could be assayed directly. The detection limit of the assay was 5 pmol of sulfated CCK-8 per liter. The assay measured fragments CCK-8, CCK-33, and CCK-39 with equimolar potency. CCK-4, gastrin, and vasoactive intestinal polypeptide were not detected, even at higher concentrations. The concentration of CCK, as the sum of these CCK peptides, in plasma during fasting was low (10.5 +/- 2.1 pmol/L, mean +/- SEM) but still detectable in all normal subjects examined (range, 6.4-20.1 pmol/L). After ingestion of a test meal, CCK in plasma increased rapidly, peaking at 41.3 (SEM 5.7) pmol/L at 40 min and remaining high for 3 h after the meal. This supports the concept that CCK has important roles in digestion and absorption.     

Evaluation of a radioimmunoassay for cholecystokinin in human plasma

A sensitive and specific radioimmunoassay for cholecystokinin (CCK) in human plasma was developed using an antiserum specific for sequence 26-29 of CCK-33 and 125I-Bolton-Hunter labelled sulphated CCK-8 as tracer. Plasma was extracted in 96% ethanol before assay. The detection limit of the assay was 0.3 pmol/l. CCK-33 and CCK-8 were stable in plasma at 0 degree C for at least 3 h, but CCK-8 was degraded at 21 degrees C. The trypsin inhibitor, aprotinin, did not affect the degradation of CCK-8, while the aminopeptidase inhibitor, bestatin, had a significant inhibitory effect. The basal plasma concentration of CCK in 44 normal subjects was 1.6 +/- 0.2 pmol/l, ranging from undetectable (less than 0.3 pmol/l) to 4.4 pmol/l. After the ingestion of a mixed meal in seven normal subjects, concentrations of plasma CCK rose from 2.0 +/- 0.2 to 7.4 +/- 0.7 pmol/l. Diurnal registration in nine people showed similar increments after each meal. The validity of the assay was further substantiated by a strong correlation between CCK measurements of identical samples with other CCK specific antisera.     

Effect of synthetic human glucose-dependent insulinotropic polypeptide (hGIP) on the release of insulin in man

During an oral glucose tolerance test (oGTT) and an isoglycaemic intravenous glucose infusion, blood glucose and the responses of insulin and glucose-dependent insulinotropic polypeptide (GIP) were measured in six healthy volunteers. On a subsequent occasion a constant infusion of human synthetic GIP (2 pmol kg-1 min-1 for 30 min and 0.5 pmol kg-1 min-1 for another 30 min was given to each subject, again with a simultaneous infusion of glucose to maintain isoglycaemia to the oGTT. During the oGTT, plasma GIP concentrations rose from 92 +/- 18 pmol 1(-1) to 257 +/- 42 pmol 1(-1) 60 min after ingestion of glucose (mean +/- SEM). When glucose was administered intravenously plasma GIP levels did not rise significantly over basal. The infusion of hGIP mimicked the physiological plasma GIP response after oral glucose during the first 60 min of the study. Plasma insulin concentrations were significantly lower between 45 and 60 min than during the oGTT (438 +/- 67 vs. 200 +/- 48 pmol 1(-1); P less than 0.02; 465 +/- 96 vs. 207 +/- 48 pmol 1(-1); P less than 0.01). However, the total and incremental integrated insulin responses during the first 60 min of the study were, though lower, not significantly different from the oGTT experiment when glucose and hGIP were infused simultaneously. Thus, in the presence of mild physiological hyperglycaemia, human GIP is able to enhance the initial insulin response almost equivalently to the stimulus provided by oral glucose. Decreased insulin concentrations during porcine GIP infusions in previous experiments might be due to sequence differences between human and porcine GIP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pressor effect of arginine vasopressin in progressive autonomic failure

The blood pressure (BP) and heart rate (HR) responses to 5 min incremental intravenous infusions of noradrenaline (NA) and arginine vasopressin (AVP) were investigated both in patients with progressive autonomic failure (PAF) and in normal volunteers. Stepwise infusion of NA at rates of 300-3000 pmol min-1 kg-1 produced a bradycardia and a dose related increase in BP in normal subjects. In subjects with PAF there was no significant HR response but the dose-BP response was shifted to the left with significant pressor responses at infusion rates of 60-300 pmol min-1 kg-1. Stepwise infusion of AVP at 0.2-5.0 pmol min-1 kg-1 caused transient bradycardia but no pressor response in seven normal volunteers. Further increases in AVP infusion in three other subjects achieved plasma AVP levels as high as 3000-4000 pmol/l, and still no significant pressor response was observed. Stepwise infusion of AVP at 0.05-2.0 pmol min-1 kg-1 in the eight subjects with PAF resulted in a pressor response without any change in HR. During this infusion plasma AVP increased from 0.8 +/- 0.2 (mean +/- SEM) to 30 +/- 2 pmol/l. A significant pressor response was already apparent at a plasma AVP level of 5.5 +/- 1.8 pmol/l.     

The effect of equicaloric medium-chain and long-chain triglycerides on pancreas enzyme secretion

It has been shown previously that medium chain triglycerides (MCT) do not affect gallbladder emptying and cholecystokinin (CCK) release. The effect of MCT on exocrine pancreas secretion in humans is unknown. We have compared the effect of enteral administration of MCT versus long chain triglycerides (LCT) on exocrine pancreatic secretion. Eight healthy subjects (three female, five male; mean age 22 +/- 1.9 years) participated in two experiments, performed in random order. Duodenal contents, obtained by aspiration, were used to calculated the output of pancreatic enzymes and bilirubin. An equicaloric amount of either MCT or LCT (2 kcal min-1) oil was continuously administered in the proximal jejunum for 2 h. Gallbladder volume was measured by ultrasonography and blood samples were drawn for determination of CCK. The experiments consisted of 1 h basal secretion, 2 h of continuous oil administration and 1 h poststimulation. During the LCT feeding the pancreatic enzyme secretion, bilirubin output, gallbladder emptying and CCK release increased significantly (P < 0.05) over basal levels. MCT had no effect on pancreatic enzyme secretion nor gallbladder emptying or CCK release. We conclude that enteral administration of MCT in the proximal jejunum does not stimulate exocrine pancreatic secretion nor gallbladder contraction or CCK release, in contrast to an equicaloric amount of LCT.     

Cholecystokinin bioactivity in human plasma. Molecular forms, responses to feeding, and relationship to gallbladder contraction.

A sensitive and specific bioassay for the measurement of cholecystokinin (CCK) in human plasma was developed to determine the molecular forms of CCK in circulation, CCK responses to feeding, and the physiologic role of CCK in gallbladder contraction. First, plasma was quantitatively extracted and concentrated with octadecylsilylsilica, and the extracts were then assayed for their ability to stimulate amylase release from isolated rat pancreatic acini. Acini were highly sensitive to CCK whereas gastrin reacted only weakly in this system. With the assay, plasma levels of cholecystokinin octapeptide (CCK-8) bioactivity as low as 0.2 pM were detectable. CCK bioactivity in plasma was inhibited by the CCK antagonist, bibutyryl cyclic guanosine monophosphate, and was eliminated by immunoadsorption with an antibody directed against the carboxyl terminus of CCK. Detection of fasting levels of CCK was possible in all individuals tested and averaged 1.0 +/- 0.2 pM (mean +/- SE, n = 22) CCK-8 equivalents. Plasma CCK biological activity was normal in patients with gastrin-secreting tumors. After being fed a mixed liquid meal, CCK levels rose within 15 min to 6.0 +/- 1.6 pM. The individual food components fat, protein, and amino acids were all potent stimulants of CCK secretion; in contrast, glucose caused a significant but smaller elevation in plasma CCK levels. Gel filtration studies identified three major forms of CCK bioactivity in human plasma: an abundant form that eluted with CCK-33, a smaller form that eluted with CCK-8, and an intermediate form that eluted between CCK-33 and CCK-8. Ultrasonic measurements of gallbladder volume indicated that this organ decreased 51% in size 30 min after feeding a mixed liquid meal. This contraction occurred coincidentally with the increase in plasma CCK levels. Next CCK-8 was infused to obtain CCK levels similar to postprandial levels. This infusion caused a decrease in gallbladder volume, similar to that seen with a meal. The present studies indicate, therefore, that CCK can be bioassayed in fasting and postprandial human plasma. These studies also suggest that CCK may be an important regulator of gallbladder contraction.     

Effect of low protein diet on the renal response to meat ingestion in diabetic nephropathy

We measured the renal haemodynamic and proteinuric response to a meat meal (MM) in ten persistently proteinuric insulin-dependent diabetic patients in a randomized cross-over study of 3 weeks on low protein diet (LPD) or normal protein intake (NPD). On LPD, protein intake (0.64 +/- 0.05 vs 1.15 +/- 0.09 g kg-1 body weight (BW) per day, P less than 0.001), plasma urea (6.6 +/- 1.3 vs 11.0 +/- 2.0 mmol l-1, P less than 0.01) and urea appearance (0.06 +/- 0.01 vs 0.16 +/- 0.03 gN kg-1 body weight per day, P less than 0.001) were lower. Baseline glomerular filtration rate (GFR), renal plasma flow (RPF) and renal vascular resistance (RVR) were similar on the two diets and there were no significant average changes in these variables after the meat meal on either diet (NPD, before vs after MM: GFR: 67 +/- 11 vs 71 +/- 13 ml min-1 1.73 m-2; RPF: 479 +/- 70 vs 512 +/- 81 ml min-1 1.73 m-2; RVR: 181 +/- 45 vs 179 +/- 52 mmHg min-1 l-1); (LPD, before vs after MM: GFR: 64 +/- 10 vs 67 +/- 11 ml min-1 1.73 m-2; RPF: 506 +/- 60 vs 533 + 52 ml min-1 1.73 m-2; RVR: 151 +/- 28 vs 146 +/- 32 mmHg min-1 l-1). However, all patients with baseline GFR above 60 ml min-1 1.73 m-2 showed a GFR rise in response to the meat meal on both diets, while patients with lower baseline values tended to reduce their GRF.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oxyntomodulin: a potential hormone from the distal gut. Pharmacokinetics and effects on gastric acid and insulin secretion in man

Synthetic oxyntomodulin, a predicted product of the glucagon gene, which is produced in the human lower intestinal mucosa, was infused in doses of 100 and 400 ng kg-1 h-1 into six volunteers to study its pharmacokinetics and effects on pentagastrin-stimulated gastric acid secretion (100 ng kg-1 h-1). The concentration of oxyntomodulin in plasma measured with a cross-reacting glucagon assay increased from 37 +/- 5 to 106 +/- 17 and 301 +/- 40 pmol l-1, respectively. The metabolic clearance rate was 5.2 +/- 0.7 ml kg-1 min-1 and the half-life in plasma was 12 +/- 1 min. Oxyntomodulin reduced the pentagastrin-stimulated acid secretion by 20 +/- 9% during the low-rate infusion (P less than 0.05) and by 76 +/- 10% during the high-rate infusion (P less than 0.05). In accordance with the homology with glucagon, there was a small, significant rise in plasma concentrations of insulin and insulin C-peptide during oxyntomodulin infusion. Oxyntomodulin may therefore be included among the potential incretins and enterogastrones in man.     

Identification and measurement of molecular variants of cholecystokinin in duodenal mucosa and plasma. Diminished concentrations in patients with celiac disease.

The amount and type of cholecystokinin (CCK) in duodenal extracts and plasma of celiac patients and normal subjects was studied by radioimmunoassay and gel filtration. In both groups there were similar patterns of molecular forms in extracts of duodenal biopsies, but concentrations in celiac disease were significantly depressed. In boiling water extracts of duodenal mucosa from both groups a factor with the properties of the COOH-terminal octapeptide of cholecystokinin predominated, but there were also significant amounts of a larger molecular weight form. In acid extracts of mucosa a factor with the properties of the 33 or 39 residue form was identified in amounts that were approximately 25% those of CCK8; there were also similar amounts of an acid-soluble form that had an apparent molecular weight higher than CCK39. Plasma immunoreactive cholecystokinin was studied after concentration by immunoaffinity adsorption and fractionation by gel filtration. In normal subjects fasting CCK-like immunoreactivity was less than 0.8 pmol/liter, and after a light breakfast increased to 2.0 +/- 0.7 (range 1.0 to 4.8) pmol/liter; CCK8-like activity accounted for all the increased immunoreactivity. In five of six celiac patients the concentrations of both fasting and postprandial CCK-like immunoreactivity in plasma were undetectable (less than 0.8 pmol/liter). We conclude that diminished production and release of CCK could account for the impaired pancreatic and gall bladder responses to intraluminal stimuli in celiac disease.     

Plasma homocysteine in women on oral oestrogen-containing contraceptives and in men with oestrogen-treated prostatic carcinoma.

The mechanism by which oral oestrogen-containing contraceptives in women and oestrogen treatment of prostatic carcinoma in men increases the risk of vascular disease is unclear. These agents decrease serum concentrations of vitamin B12, pyridoxal 5-phosphate, and folate, all of which are essential for the metabolism of the atherogenic amino acid homocysteine. We found serum vitamin B12 concentrations to be lower in 17 women using oral contraceptives (219 +/- 84 pmol l-1) than in 13 age-matched female controls (385 +/- 129, p less than 0.001), but similar values were obtained in the two groups both for fasting plasma homocysteine concentrations (9.1 +/- 2.4 vs 9.2 +/- 3.6 mumol l-1) and for the increase in these concentrations after methionine loading (19.2 +/- 7.5 vs 17.8 +/- 5.2 mumol l-1). In five men with prostatic carcinoma, high-dose oestrogen treatment decreased serum vitamin B12 concentrations by a mean of 30% (p less than 0.05) within 4 weeks, during which fasting plasma homocysteine concentrations decreased (13.8 +/- 4.5 vs 10.5 +/- 2.8 mumol l-1) and response to methionine loading increased (12.4 +/- 3.4 vs 17.3 +/- 5.1 mumol l-1), though the latter changes were non-significant. Our findings do not support the hypothesis that hyperhomocysteinemia explains cardiovascular risk in women using oral oestrogen-containing contraceptives, or in oestrogen-treated men with prostatic carcinoma.     

Effects of pancreatic polypeptide on motilin and circulating metabolites in man

Pancreatic polypeptide was infused intravenously in healthy fasting subjects at 1 pmol kg-1 (n = 7) and 4 pmol kg-1 min-1 (n = 10) producing plasma PP concentrations of 223 +/- 37 pmol/l (mean +/- SEM) and 891 +/- 64 pmol/l respectively. These levels are similar to and four-fold higher than those seen after a normal mixed breakfast in healthy young adults. In a separate study five healthy subjects ingested a small breakfast during infusion of PP on different days at 1 pmol kg-1 min-1 and 2 pmol kg-1 min-1 respectively. PP at 1 pmol kg-1 min-1 caused a marked reduction in fasting plasma motilin concentrations to 20% of the basal level (p less than 0.001). There were, however, no significant changes in plasma concentrations of insulin, glucagon, gastrin, secretin, enteroglucagon, gastric inhibitory peptide or neurotensin. Despite previous reports possibly implicating PP in metabolism, there were no significant effects on blood levels of glucose, alanine lactate, 3-hydroxybutyrate, glycerol or non-esterified fatty acids, either in the fasting state or after the ingestion of food. Although it seems unlikely that PP is a major hormonal regulator of intermediary metabolism in man, its ability to suppress motilin at physiological concentrations suggests the possibility of an indirect influence on digestive motor function.     

Plasma concentrations of endothelin in man: arterio-venous differences and release during venous stasis

Endothelin-1 is a recently described endothelium-derived vasoconstricting peptide. Plasma concentrations of immunoreactive (IR-) endothelin were investigated in six healthy young men applying a radioimmunoassay after extraction of endothelin from plasma. In venous plasma a mean concentration of 1.3 +/- 0.4 pmol l-1 was found, whereas the mean concentration in arterial plasma was 0.9 +/- 0.4 pmol l-1 (P less than 0.005). During venous stasis for 10 min the mean plasma concentration of IR-endothelin increased about twofold, from basal 1.1 +/- 0.3 pmol l-1 to 2.1 +/- 0.3 pmol l-1 (P less than 0.01). This manoeuvre may prove helpful to investigate the control of endothelin in vivo under a variety of pathological conditions.