Plasma cholecystokinin response to oral fat in patients with Billroth I and Billroth II gastrectomy

The present study was undertaken to determine whether bypassing the duodenum in patients with Billroth II gastrectomy affects plasma cholecystokinin (CCK) release in response to ingestion of fat. Plasma CCK concentrations were measured by radioimmunoassay using two antibodies; antibody 1703 binds to all carboxyl-terminal CCK-peptides containing at least 14 amino acid residues, while antibody T204 is specific for the sulphated tyrosine region of CCK. There were no significant differences among fasting plasma CCK concentrations in seven patients with Billroth II gastrectomy (1.3 +/- 0.4 fmol/ml, antibody 1703; 2.6 +/- 0.4 fmol/ml, antibody T204), six patients with Billroth I gastrectomy (0.6 +/- 0.3 fmol/ml, antibody 1703; 2.9 +/- 0.5 fmol/ml, antibody T204), and nine normal subjects (0.7 +/- 0.1 fmol/ml, antibody 1703; 1.9 +/- 0.3 fmol/ml, antibody T204). Ingestion of 250 ml 20% Intralipid induced similar increases in plasma CCK in patients with Billroth II gastrectomy (11.2 +/- 2.0 fmol/ml, antibody 1703; 10.1 +/- 2.4 fmol/ml, antibody T204) as in patients with Billroth I gastrectomy (11.8 +/- 2.0 fmol/ml, antibody 1703; 8.4 +/- 1.1 fmol/ml, antibody T204). However, the increments in plasma CCK in patients with gastrectomy (11.5 +/- 1.4 fmol/ml, antibody 1703; 9.3 +/- 1.4 fmol/ml, antibody T204) were significantly (p less than 0.01) greater than those in normal subjects (4.7 +/- 0.8 fmol/ml, antibody 1703; 4.1 +/- 0.7 fmol/ml). Similarly, the integrated plasma CCK secretion in patients with Billroth II gastrectomy (510 +/- 58 fmol/ml X 120 min, antibody 1703; 458 +/- 69 fmol/ml X 120 min, antibody T204) and in patients with Billroth I gastrectomy (457 +/- 143 fmol/ml X 120 min, antibody 1703; 365 +/- 61 fmol/ml X 120 min, antibody T204) were significantly (p less than 0.05) greater than in normal subjects (230 +/- 49 fmol/ml X 120 min, antibody 1703; 162 +/- 24 fmol/ml X 120 min, antibody T204). It is concluded that the plasma CCK response to oral fat is significantly greater in patients with partial gastrectomy than in normal subjects, and that patients with Billroth I and Billroth II gastrectomy have similar increases in plasma CCK after ingestion of fat.     

Delayed plasma cholecystokinin and gallbladder responses to intestinal fat in patients with Billroth I and II gastrectomy

This study was undertaken to examine the intestinal phase of cholecystokinin (CCK) secretion and gallbladder contraction in patients who had undergone partial gastrectomy. Plasma CCK concentrations, measured by radioimmunoassay, and gallbladder contraction, measured by cholescintigraphy, were studied after intestinal administration of fat. Fasting plasma CCK concentrations were in the same range in nine patients who had undergone Billroth I gastrectomy (1.0 +/- 0.2 pmol/L), in nine patients who had undergone Billroth II gastrectomy (1.4 +/- 0.2 pmol/L), and in nine normal subjects (1.5 +/- 0.4 pmol/L). The peak increments in plasma CCK after intestinal fat were significantly (p less than 0.05) lower in patients with partial gastrectomy (5.4 +/- 0.6 pmol/L) compared with normal subjects (7.9 +/- 0.8 pmol/L). The integrated plasma CCK secretion was significantly (p less than 0.01 to p less than 0.05) reduced during the first 30 minutes in patients after Billroth I (74 +/- 11 pmol/1.30 min) and Billroth II gastrectomy (51 +/- 11 pmol/1.30 min) compared with normal subjects (122 +/- 18 pmol/1.30 min). Similarly, the start of gallbladder emptying was significantly (p less than 0.05) delayed in patients after partial gastrectomy. After 1 hour, however, the integrated plasma CCK response and gallbladder emptying were in the same range in Billroth I patients (186 +/- 34 pmol/1.60 min, 60% +/- 7%), Billroth II patients (175 +/- 17 pmol/1.60 min, 63% +/- 7%) and normal subjects (190 +/- 18 pmol/1.60 min, 55% +/- 6%). It is concluded that in patients who have undergone partial gastrectomy plasma CCK and gallbladder responses to intestinal fat are significantly delayed but reach normal levels beyond 30 minutes.     

Plasma cholecystokinin response to a liquid fat meal in vagotomized patients.

Since previous studies have suggested that in patients with truncal vagotomy (TV) the plasma cholecystokinin (CCK) secretion in response to nutrients is impaired, we have measured the plasma CCK response to a liquid fat meal (250 ml 20% Intralipid) in six patients with TV and pyloroplasty. We have compared the results with those obtained in eight normal subjects, six patients with duodenal ulcer, and eight patients with highly selective vagotomy (HSV). Plasma CCK concentrations were measured by a sensitive and specific radioimmunoassay employing antibody T204 directed against the sulphated tyrosine region of CCK. Basal plasma CCK concentrations were not significantly different among the four groups studied (2.1 +/- 0.4 pmol/l in normal subjects, 2.8 +/- 0.5 pmol/l in duodenal ulcer patients, 3.1 +/- 0.5 pmol/l in patients with TV, and 2.7 +/- 0.5 pmol/l in patients with HSV). The increments in plasma CCK after ingestion of the fat meal in patients with TV (15.7 +/- 3.1 pmol/l) and HSV (14.9 +/- 1.6 pmol/l) were significantly higher (p less than 0.01) than those in normal subjects (4.8 +/- 0.9 pmol/l) and in patients with duodenal ulcer (5.5 +/- 0.6 pmol/l). Similarly, the integrated plasma CCK secretions in patients with TV (554 +/- 139 pmol/l, 120 min) and in patients with HSV (876 +/- 132 pmol/l, 120 min) were significantly increased (p less than 0.05) compared to those in normal subjects (187 +/- 29 pmol/l, 120 min) and in patients with duodenal ulcer (264 +/- 35 pmol/l, 120 min). It is concluded that patients with TV and HSV show an increased plasma CCK secretion in response to a liquid test meal.     

Release of cholecystokinin and gallbladder contraction before and after gastrectomy.

The contraction of the gallbladder by ultrasonography and release of cholecystokinin (CCK) by specific radioimmunoassay in response to the ingestion of oral fatty meal before and 1 month after gastrectomy in five patients with early gastric cancer was studied. Before gastrectomy, basal concentrations of CCK (13.4 +/- 2.3 pmol/L) rose significantly to a maximum of 23.3 +/- 3.6 pmol/L at 20 minutes after ingestion of oral fatty meal, and remained significantly elevated during the study. Gallbladder contraction began as CCK concentrations rose, demonstrating significant correlation with plasma CCK. One month after gastrectomy, CCK showed a rapid and greater response to the ingestion of fatty meal, attaining a maximum of 53.7 +/- 7.3 pmol/L at 10 minutes, then gradually falling to basal level. The maximal contraction of the gallbladder after gastrectomy was almost the same as before gastrectomy (62.7 +/- 4.0% of original area), showing a significant correlation with plasma CCK, but refilling of the gallbladder was induced earlier with corresponding reduction of plasma CCK. Simultaneous measurement of plasma concentrations of pancreatic polypeptide revealed a fairly similar response to plasma CCK before and after gastrectomy. The release of CCK is the chief mechanism by which the ingestion of a fatty meal causes contraction of the gallbladder even after gastrectomy as well as before gastrectomy.     

Plasma cholecystokinin and pancreatic polypeptide response after radical pancreatoduodenectomy with Billroth I and Billroth II type of reconstruction.

This study was conducted to elucidate plasma cholecystokinin (CCK) and pancreatic polypeptide (PP) response after pancreatoduodenectomy and to compare response of CCK and PP in patients who had pancreatoduodenectomy with Billroth I and Billroth II type of reconstruction. Basal levels of plasma CCK were significantly lower in patients who had pancreatoduodenectomy (9.6 +/- 0.8 pmol/L) than in the control (preoperative patients: 14.6 +/- 2.0 pmol/L) probably because of the removal of the entire duodenum due to pancreatoduodenectomy, since vagotomy, which is concomitantly brought about by pancreatoduodenectomy, does not appear to interfere with release of CCK. Significant amounts of CCK (integrated CCK: 497 +/- 111 pmol-120 min/L), although less amounts than in the preoperative patients (integrated CCK: 901 +/- 167 pmol-120 min/L), were still released in response to oral fatty meal after pancreatoduodenectomy. Plasma CCK response to oral fatty meal was significantly greater in patients who had pancreatoduodenectomy with Billroth I type of reconstruction (integrated CCK: 705 +/- 153 pmol-120 min/L) than in patients who had pancreatoduodenectomy with Billroth II type of reconstruction (248 +/- 63 pmol-120 min/L). Simultaneous measurement of plasma levels of PP revealed complete abolishment of PP response by pancreatoduodenectomy. Since PP secretion can be produced by vagal stimulation, it is most likely that the decreased PP secretion is due to vagotomy rather than removal of the duodenum and pancreas. Significant amounts of CCK released after pancreatoduodenectomy, in which the main sources of release of CCK are removed, may suggest the compensatory mechanism of the remnant upper small intestine. This study also suggests the necessity of re-evaluating Billroth I type of anastomosis as a physiologic reconstruction procedure for the remnant alimentary tract after pancreatoduodenectomy.     

Pancreatic exocrine secretion. Release of gastrin and cholecystokinin in response to bombesin in pigs

The objective of this study was to determine whether bombesin can stimulate pancreatic exocrine secretion and release of cholecystokinin-33 and gastrin in pigs. Bombesin (1 microgram/kg-hr) was infused intravenously in six conscious piglets for one hour, and pancreatic secretions, plasma, and serum were collected. Cholecystokinin-33 and gastrin were measured by specific radioimmunoassays. Pancreatic secretory volume increased from a basal value of 1.5 +/- 0.5 mL/15 min to 10.4 +/- 1.7 mL/15 min. Pancreatic protein output increased from basal values of 7.9 +/- 2.4 mg/15 min to 88.9 +/- 25.4 mg/15 min. Plasma cholecystokinin-33 increased significantly from a basal concentration of 130 +/- 40 pg/mL to 275 +/- 100 pg/mL, as did gastrin (40.7 pg/mL to 200 +/- 27 pg/mL). Our findings demonstrated that bombesin stimulates exocrine pancreatic secretion in pigs; we conclude that this stimulation is due largely to the release of cholecystokinin.     

Evidence that the cholinergic enteropancreatic reflex may be independent of cholecystokinin release.

Studies were performed in four dogs with chronic gastric and pancreatic fistulas following intraduodenal perfusion with 10 mmole hr-1 of sodium oleate for 30 minutes. Radioimmunoassay (RIA) of plasma CCK LI was undertaken by an RIA method using labeled, desulfated CCK 8 I125 and an antiserum raised to CCK 8. The detection limit for the assay was 0.25 to 0.5 fmole and the lowest detectable plasma level was 5 to 10 fmoles ml-1. Since there was equal cross-reactivity to gastrin, a gastrin-specific assay also was employed to evaluate any changes in gastrin levels. After oleate infusion the plasma CCK increment above basal was 50 +/- 11 fmoles ml-1, with return to basal levels after 60 minutes. Administration of atropine significantly (P less than 0.01) inhibited the release of CCK in the first 20 minutes. Thereafter CCK release was not reduced. Plasma gastrin values did not change before and after oleate perfusion. Pancreatic protein output increased from 72 +/- 12 to 420 +/- 55 mg/10 min-1 after oleate administration. However, after atropinization the rise in pancreatic protein output was significantly lower (152 +/- 36 mg/10 min-1) (P less than 0.01). We have shown that, using our RIA method, there is a measurable rise in plasma CCK LI after intraduodenal oleate. After atropinization the CCK response was decreased significantly during the first 30 minutes, but was virtually unchanged during the second 30 minutes, when the fall in pancreatic protein output was most marked. We conclude that the cholinergic mechanism which plays a role in the endogenous stimulation of pancreatic protein secretion by intraduodenal oleate cannot be explained simply be decreased CCK release. This mechanism may be hormonal, distinct from secretin, or neural possibly, via activation of an enteropancreatic reflex.     

Beta-adrenergic regulation of gastrin release from gastrinoma cells

The effect of epinephrine on the plasma gastrin level was investigated in three patients with Zollinger-Ellison syndrome (ZES) and in 14 normal subjects. Two ZES patients had undergone total gastrectomy, and the third had undergone subtotal gastrectomy before our study. A significant increase in plasma gastrin, from 23 +/- 5 pg/ml to 53 +/- 20 pg/ml, in response to intravenous epinephrine (40 ng/kg.min), was observed in the normal subjects. This response was completely abolished by beta-blockade. In the ZES patients, epinephrine (40 ng/kg.min) also resulted in an increase in the plasma concentration of gastrin. The basal and maximum concentrations of gastrin were 580 and 1680 pg/ml in patient 1, 145000 and 320000 pg/ml in patient 2, and 200 and 1800 pg/ml in patient 3, respectively. beta-Adrenergic blockade suppressed the epinephrine-stimulated gastrin release in these patients as well. Graded intravenous doses of epinephrine given to the ZES patients resulted in elevation of the plasma gastrin in a dose-dependent manner. Insulin hypoglycemia caused an increase in both plasma epinephrine and plasma gastrin in ZES patients and normal subjects. A significant correlation between plasma gastrin and epinephrine during insulin hypoglycemia was observed in both groups. Exercise, with use of a bicycle ergometer, resulted in an increase in plasma epinephrine. An increase in plasma gastrin with exercise was observed in the ZES patients, and this was also suppressed by beta-blockade. The results suggest that gastrinoma cells, like normal G cells, are equipped with beta-adrenergic receptors that regulate gastrin release.     

Effect of colectomy on cholecystokinin and gastrin release.

Studies were conducted to determine the effect of resection of the colon on the release of cholecystokinin (CCK) and gastrin. A standard food stimulation test was performed in five dogs. Peripheral blood samples were collected for future measurement of CCK and gastrin by specific radioimmunoassay. Each dog underwent subtotal colectomy with side-to-end ileoproctostomy. The food stimulation test was repeated at approximately weekly intervals for eight weeks after colectomy. Basal plasma CCK levels of 139 +/- 21 pg/ml before colectomy did not change after colectomy. Total amount CCK released after food was increased significantly at both four (5.94 +/- 0.78 ng min/ml) and eight (13.00 +/- 2.72 ng min/ml) weeks after colectomy in comparison with that observed prior to colectomy (2.94 +/- 0.54 ng min/ml). Basal serum gastrin levels of 28 +/- 9 pg/ml did not change significantly after colectomy. Total amount of gastrin released after food was increased significantly at both two (8651 +/- 2294 pg min/ml) and three (6940 +/- 1426 pg min/ml) weeks after operation, but at none of the later weeks. The precolectomy output, used for comparison, was 5608 +/- 1346 pg min/ml. It was concluded that resection of the colon leads to an increase in release of CCK and gastrin after food stimulation. This finding provides further evidence that the colon contains a factor that inhibits the release of CCK and gastrin, and that the colon functions as an endocrine organ.     

A role for atrial natriuretic peptide in endothelin-induced natriuresis.

Systemic administration of low-dose endothelin increases urinary sodium excretion rate despite mild to moderate reductions in renal plasma flow and glomerular filtration rates. The role of atrial natriuretic peptide in endothelin-induced natriuresis was investigated. Administration of 2.50 pmol/min of endothelin to euvolemic rats resulted in increases in plasma atrial natriuretic peptide levels from 127 +/- 18 to 169 +/- 23 pg/mL. However, a lower dose of endothelin (0.63 pmol/min) or saline did not increase plasma levels of atrial natriuretic peptide. Mean arterial pressure was unchanged at the lower dose of endothelin and increased only slightly in rats receiving 2.5 pmol/min. To assess functional significance, renal responses to endothelin (2.5 pmol/min) in the absence and presence of a specific anti-rat atrial natriuretic peptide antibody were compared. Equivalent reductions in renal blood flow were observed. Urinary sodium excretion rates increased significantly in non-ANP-antibody-treated rats by 33 +/- 7 and 82 +/- 20% at 10 and 30 min, respectively. Atrial natriuretic peptide antibody blunted markedly endothelin-induced natriuresis: urinary sodium excretion rates changed insignificantly by 18 +/- 10 and 30 +/- 14%, respectively. Thus, endothelin infusion results in increases in plasma atrial natriuretic peptide levels, which may contribute to endothelin-induced natriuresis, providing evidence for potentially significant interactions between these peptide hormones in the regulation of sodium balance and renal vascular tone.     

Lack of an acute effect of ghrelin on markers of bone turnover in healthy controls and post-gastrectomy subjects

BACKGROUND: Ghrelin is a gut-brain peptide that powerfully stimulates appetite and growth hormone secretion and is also known to directly regulate osteoblast cell function in vitro and in animal models. Little is known about the effects of ghrelin on bone turnover in humans. As the stomach is the main site of ghrelin synthesis, gastrectomy patients are deficient in ghrelin; they are also prone to osteopenia and osteomalacia. HYPOTHESIS: Ghrelin may play a role in bone regulation in humans; ghrelin deficiency following gastrectomy is associated with the disrupted regulation of bone turnover seen in these subjects. SUBJECTS AND METHODS: In a randomised, double-blind, placebo-controlled study 8 healthy controls and 8 post-gastrectomy subjects were infused with intravenous ghrelin (5 pmol/kg/min) or saline over 240 min on different days. Subjects were given a fixed energy meal during the infusion. Ghrelin, GH, type-1 collagen beta C-telopeptide (betaCTX), a marker of bone resorption, and procollagen type-1 amino-terminal propeptide (P1NP), a marker of bone formation, were measured. RESULTS: Fasting ghrelin was significantly lower in the gastrectomy group during the saline infusion (226.1+/-62.0 vs. 762+/-71.1 ng/l p<0.001). Growth hormone was significantly higher at 90 min after the ghrelin infusion, compared to saline in both healthy controls (61.1+/-8.8 vs. 1.4+/-0.6 mIU/l p<0.001) and gastrectomy subjects (61.1+/-11.8 vs. 0.9+/-0.2 mIU/l p<0.001) confirming the ghrelin was bioactive. Gastrectomy subjects were significantly older and had significantly higher plasma betaCTX than healthy controls at all time points (ANOVA p=0.009). After adjustment for age and BMI ghrelin was found to be a significant predictor of baseline plasma betaCTX and was inversely correlated with baseline plasma betaCTX (beta=-0.54 p=0.03 R2=26%). However, there was no significant effect of the ghrelin infusion on plasma betaCTX or P1NP in either subject group. CONCLUSIONS: Ghrelin infusion has no acute effect on markers of bone turnover in healthy controls and post-gastrectomy subjects, but is inversely correlated with bone resorption.     

Intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic response

Because absence of the glucagon response to falling plasma glucose concentrations plays a key role in the pathogenesis of iatrogenic hypoglycemia in patients with insulin-deficient diabetes and the mechanism of this defect is unknown, and given evidence in experimental animals that a decrease in intraislet insulin is a signal to increased glucagon secretion, we examined the role of endogenous insulin in the physiological glucagon response to hypoglycemia. We tested the hypothesis that intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic-adrenomedullary, sympathetic neural, and parasympathetic neural-response and a low alpha-cell glucose concentration. Twelve healthy young adults were studied on three separate occasions. Insulin was infused in hourly steps in relatively low doses (1.5, 3.0, 4.5, and 6.0 pmol.kg(-1).min(-1)) from 60 through 300 min on all three occasions. Plasma glucose levels were clamped at euglycemia ( approximately 5.0 mmol/l, approximately 90 mg/dl) on one occasion and at hourly steps of approximately 4.7, 4.2, 3.6, and 3.0 mmol/l ( approximately 85, 75, 65, and 55 mg/dl) from 60 through 300 min on the other two occasions. On one of the latter occasions, the beta-cell secretagogue tolbutamide was infused in a dose of 1.0 g/h from 60 through 300 min. Hypoglycemia with tolbutamide infusion, compared with similar hypoglycemia alone, was associated with higher (P < 0.0001) C-peptide levels (final values of 1.0 +/- 0.2 vs. 0.1 +/- 0.0 nmol/l), higher (P < 0.0001) rates of insulin secretion (final values of 198 +/- 60 vs. 15 +/- 4 pmol/min), and higher (P < 0.0001) insulin levels (final values of 325 +/- 30 vs. 245 +/- 20 pmol/l) as expected. The glucagon response to hypoglycemia was prevented during tolbutamide infusion (P < 0.0001). Glucagon levels were 17 +/- 1 pmol/l at baseline on both occasions, 14 +/- 1 vs. 15 +/- 1 pmol/l, respectively, during the initial hyperinsulinemic euglycemia, and 15 +/- 1 vs. 22 +/- 2 pmol/l, respectively, during hypoglycemia with and without tolbutamide infusion. Autonomic-adrenomedullary (plasma epinephrine), sympathetic neural (plasma norepinephrine), and parasympathetic neural (plasma pancreatic polypeptide)-responses to hypoglycemia were not reduced during tolbutamide infusion. We conclude that intraislet hyperinsulinemia prevents the glucagon response to hypoglycemia despite an intact autonomic response and a low alpha-cell glucose concentration.     

Gastrin-dependent inhibitory effects of octreotide on the genesis of gastric ECLomas.

BACKGROUND. The efficacy of octreotide in the regulation of endocrine tumor secretion and symptomatology has been well documented. Its effects on neuroendocrine tumor generation and cell proliferation are less well understood. The purpose of this study was to determine if blockade of somatostatin receptors by octreotide would alter gastrin levels and influence enterochromaffin-like (ECL) cell proliferation. METHODS. The well-established gastric ECLoma model of the rodent, mastomys, was used. Animals received loxtidine (1 mg/kg/day), an irreversible H2 blocker, and subcutaneous slow release, octreotide pellet implants (150 or 300 micrograms/kg/day) or placebo pellets for a 4-month period. RESULTS. Control parameters for gastric mucosal thickness, plasma gastrin level, ECL cell density, and bromodeoxyuridine-positive cells were 517 +/- 20 microns, 46.1 +/- 11.4 pmol/L, 7.4 +/- 0.9 cells/visual field, and 13.8 +/- 2.6 cells/visual field, respectively. After loxtidine-placebo treatment all values were significantly increased (p < 0.05; 883 +/- 70 microns, 192.8 +/- 10.6 pmol/L, 97 +/- 16.2 cells/visual field, and 51.7 +/- 19.2 cells/visual field, respectively). High dose octreotide significantly inhibited all parameters (668 +/- 3.5 microns, 66.2 +/- 20.5 pmol/L, 37.0 +/- 8.0 cells/visual field, and 10.9 +/- 2.2 cells/visual field; p < 0.05). Low dose octreotide failed to significantly inhibit ECL cell density mucosal thickness, or cell proliferation. CONCLUSIONS. Irreversible H2 receptor blockade results in hypergastrinemia and ECL cell tumor generation. Hypergastrinemia, ECL cell hyperplasia, and cell proliferation are significantly inhibited by in vivo blockade of somatostatin receptors by administration of octreotide.     

Effect of glyburide on glycemic control, insulin requirement, and glucose metabolism in insulin-treated diabetic patients

Glycemic control and glucose metabolism were examined in 5 patients with insulin-dependent diabetes mellitus (IDDM) and 8 insulin-treated non-insulin-dependent diabetes mellitus (NIDDM) patients before and after 2 mo of therapy with glyburide (20 mg/day). Glycemic control was assessed by daily insulin requirement, 24-h plasma glucose profile, glucosuria, and glycosylated hemoglobin. Insulin secretion was evaluated by glucagon stimulation of C-peptide secretion, and insulin sensitivity was determined by a two-step euglycemic insulin clamp (1 and 10 mU X kg-1. X min-1) performed with indirect calorimetry and [3-3H]glucose. In the IDDM patients, the addition of glyburide produced no change in daily insulin dose (54 +/- 8 vs. 53 +/- 7 U/day), mean 24-h glucose level (177 +/- 20 vs. 174 +/- 29 mg/dl), glucosuria (20 +/- 6 vs. 35 +/- 12 g/day) or glycosylated hemoglobin (10.1 +/- 1.0 vs. 9.5 +/- 0.7%). Furthermore, there was no improvement in basal hepatic glucose production (2.1 +/- 0.2 vs. 2.4 +/- 0.1 mg X kg-1 X min-1), suppression of hepatic glucose production by low- and high-dose insulin infusion, or in any measure of total, oxidative, or nonoxidative glucose metabolism in the basal state or during insulin infusion. C-peptide levels were undetectable (less than 0.01 pmol/ml) in the basal state and after glucagon infusion and remained undetectable after glyburide therapy. In contrast to the IDDM patients, the insulin-treated NIDDM subjects exhibited significant reductions in daily insulin requirement (72 +/- 6 vs. 58 +/- 9 U/day), mean 24-h plasma glucose concentration (153 +/- 10 vs. 131 +/- 5 mg/dl), glucosuria (14 +/- 5 vs. 4 +/- 1 g/day), and glycosylated hemoglobin (10.3 +/- 0.7 vs. 8.0 +/- 0.4%) after glyburide treatment (all P less than or equal to .05). However, there was no change in basal hepatic glucose production (1.7 +/- 0.1 vs. 1.7 +/- 0.1 mg X kg-1 X min-1), suppression of hepatic glucose production by insulin, or insulin sensitivity during the two-step insulin-clamp study. Both basal (0.14 +/- 0.05 vs. 0.32 +/- 0.05 pmol/ml, P less than .05) and glucagon-stimulated (0.24 +/- 0.07 vs. 0.44 +/- 0.09 pmol/ml) C-peptide levels rose after 2 mo of glyburide therapy and both were correlated with the decrease in insulin requirement (basal: r = .65, P = .08; glucagon stimulated: r = .93, P less than .001).(ABSTRACT TRUNCATED AT 400 WORDS)     

Management and long-term results in patients with two-thirds gastrectomy and stomal ulcer

In 67 patients with two-thirds gastrectomy and endoscopically proven stomal ulcer, serum gastrin levels were measured under basal conditions and after intravenous infusion of bombesin (15 ng/kg/ min), calcium (4 mg/kg/hour) and secretin (2 units/ kg). All patients underwent medical or surgical therapy. The long-term results were evaluated according to the Visick grading system (average follow-up, 3.1 years).     

Evidence that cholecystokinin interacts with specific receptors and regulates insulin release in isolated rat islets of Langerhans

To determine the nature of the pancreatic islet cell cholecystokinin (CCK) receptor, we studied CCK receptor binding and biologic activity in isolated rat pancreatic islets. Binding of 70 pM 125I-CCK to collagenase-prepared isolated rat pancreatic islets at 24 degrees C was one-half maximal after 5 min and maximal at 60 min. At 60 min, specific binding was 12% of total radioactivity per 100 micrograms islet protein; nonspecific binding (in the presence of 1 microM CCK 8) was less than 2% of total radioactivity. Unlabeled CCK 33 inhibited labeled hormone binding one-half maximally at 2 nM; Scatchard analysis showed one binding site (Kd, 2.3 +/- 0.4 nM; Bmax, 8.1 pmol/mg protein). The agonist selectivity of this binding site was: CCK 8 = CCK 33 greater than desulfated-CCK 8 greater than CCK 4. Two CCK antagonists were studied; N-carbobenzoxy-L-tryptophan was more potent than dibutyryl-cGMP. When the effect of CCK on insulin release from the islets was studied, the order of potency of CCK agonists and antagonists on insulin secretion was the same as the order of their ability to inhibit 125I-CCK binding. The effect of CCK on insulin secretion was dependent on the glucose concentration in the media. CCK had no effect at 5.6 mM glucose and was fully effective at 11.0 mM glucose. These data, therefore, indicate that: specific binding sites for CCK are present in rat pancreatic beta cells; and CCK acts in concert with glucose to stimulate insulin secretion.     

Modulatory effect of glucose, amino acids, and secretin on CCK-8-induced somatostatin and pancreatic polypeptide release in dogs

Protein- and fat-rich test meals elicit a strong stimulatory effect on postprandial somatostatin (SLI) and pancreatic polypeptide (PP) release, whereas carbohydrate-rich meals rather attenuate the response of both hormones. Since there is evidence that intestinal hormones might contribute to the postprandial SLI and PP response, it was the aim of the present study to determine in dogs the effect of low-dose cholecystokinin octapeptide (CCK-8) on basal hormone levels and also during a background infusion of amino acids or glucose. In a group of six conscious dogs, sulfated CCK-8 was infused intravenously (i.v.) via a hindleg vein at stepwise increasing infusion rates of 10, 30, and 50 pmol X kg-1 X h. The infusion of CCK was applied during a background infusion of saline (2 ml/min), glucose (0.2 g/min), or an amino acid mixture (8.5%, 2 ml/min). CCK-8 had no effect on plasma insulin and glucagon levels under all experimental conditions. Plasma SLI levels were significantly stimulated by all doses of CCK. This stimulatory effect was similar during background infusions of either saline, glucose, or amino acids, respectively. Pancreatic polypeptide (PP) levels rose 200-300 pg/ml during CCK plus saline. This was slightly attenuated by glucose. During CCK plus amino acids, the PP response was augmented to 600-800 pg/ml. Since secretin is also released after the ingestion of a meal and intraduodenal acidification is a potent stimulus not only of secretin but also of gastric and pancreatic SLI release, the effect of secretin was examined additionally.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypergastrinemia after vagotomy is not associated with decreased gastric somatostatin

Although hypergastrinemia occurs after vagotomy, the mechanisms responsible are not understood. Somatostatin (SRIF) is a peptide that inhibits gastrin release, is present within the gastric fundus and antrum, and is under vagal control. In this study we have investigated the hypothesis that hypergastrinemia is associated with a decrease in gastric SRIF. We examined tissue levels of SRIF in gastric mucosa and muscle wall in rabbits undergoing vagotomy and pyloroplasty compared with sham-operated controls. We also compared the release of SRIF from gastric glands in response to vasoactive intestinal peptide and calcitonin gene-related peptide. Vagotomy resulted in an increase in gastrin compared with controls in both antrum (1062 +/- 176 pmol/gm vs 484 +/- 48 pmol/gm) and plasma (236 +/- 72 pmol/L vs 29 +/- 4 pmol/L; p less than 0.05). This was accompanied by an increase in the number of gastrin cells (25 +/- 4 vs 9 +/- 3; p less than 0.05). No significant differences were observed in gastric SRIF levels in either the fundus or antrum (p greater than 0.5). In addition, there were no differences in the release of SRIF from gastric glands of vagotomized animals compared with controls in response to vasoactive intestinal peptide and calcitonin gene-related peptide (p greater than 0.5). These data suggest that the elevations in plasma and antral gastrin levels after vagotomy are not a result of alterations in gastric SRIF.     

Pancreatic somatostatin is a mediator of glucagon inhibition by hyperglycemia

We have previously shown that a nonimmunoreactive analogue of somatostatin, (D-Ala5, D-Trp8)-somatostatin, differentially inhibits pancreatic somatostatin secretion without inhibiting insulin or glucagon secretion. During normoglycemia, suppression of pancreatic somatostatin with this analogue increases glucagon and insulin secretion, suggesting that pancreatic somatostatin tonically inhibits glucagon and insulin secretion by a paracrine mechanism. In our study, we used this analogue to determine whether endogenous pancreatic somatostatin has a role in the inhibition of glucagon secretion by hyperglycemia. The experiments were performed in pentobarbital-anesthetized, laparotomized dogs. To measure the pancreatic output of somatostatin directly, pancreatic venous blood was sampled from the right lobe of the dog pancreas, and the pancreatic blood flow was measured. In the first set of experiments, glucagon secretion was suppressed by a glucose infusion (200 mg/kg bolus and 20 mg X kg-1 X min-1 i.v.) for 3 h. Plasma glucose rose from 102 +/- 6 to 365 +/- 34 mg/dl. Pancreatic insulin output increased 10-fold, pancreatic somatostatin output increased from 1.2 +/- 0.3 to 3.0 +/- 0.8 ng/min, and pancreatic glucagon output was suppressed from 1.4 +/- 0.7 to 0.5 +/- 0.1 ng/min. After 2 h of glucose infusion, an infusion of the analogue (5.5 micrograms/min i.v.) reversed both the stimulation of somatostatin and the suppression of glucagon without significantly changing either the plasma glucose level or the pancreatic insulin output. In a second set of experiments, basal somatostatin output was suppressed by the analogue (5.5 micrograms/min i.v.) for 15 min before the administration of glucose.(ABSTRACT TRUNCATED AT 250 WORDS)