Gastric inhibitory polypeptide (GIP) and insulin release in duodenal ulcer patients.

To investigate the role of gastric inhibitory polypeptide (GIP) in the hypersecretion of glucose-stimulated insulin release in duodenal ulcer disease, serum glucose, insulin, and immunoreactive GIP (IR-GIP) were measured in 18 healthy subjects and 10 duodenal ulcer patients after glucose ingestion. Although the serum glucose and insulin were significantly greater (P less than 0.05) at 15 and 60 min in the ulcer group, the total integrated glucose areas were similar (20,552 +/- 837 vs. 19,154 +/- 745 mg-min/ml). In contrast, the total integrated insulin area was significantly greater (P less than 0.05) in the ulcer patients (12,873 +/- 2,082 vs. 8,216 +/- 1,072 micro U-min/ml). Mean IR-GIP levels were significantly greater (P less than 0.05) in the ulcer group at 15-120 min of the study, as was the total integrated area (244,755 +/- 34,934 vs. 126,595 +/- 17,468 pg-min/ml). The exaggerated insulin release to oral glucose may be due to the synergistic action of higher blood glucose and greater IR-GIP release in this disease.

Early surgical treatment of gastrinoma.

Medical treatment of the Zollinger-Ellison syndrome has been generally accepted because of the proven efficacy of the histamine (H2)-receptor antagonists in achieving symptomatic relief, and because of early reports indicating that few, if any, gastrinomas were resectable for cure. Gastrin radioimmunoassay (RIA) has made earlier and more certain diagnosis possible, and therefore reevaluation of the surgical management of gastrinomas is necessary. Experience with 60 gastrinoma patients is reported. Comparison between the pregastrin RIA years (before 1970) and post-gastrin RIA years was made to determine whether there was evidence to support the continuation of medical treatment without attempts to resect the gastrinoma. Twenty-five cases were diagnosed in the pre-RIA years. Age at diagnosis ranged from 17 to 68 years (median, 45 years). All patients were operated on. Metastases were found in 56 percent. No tumor was identified in 8 percent. Tumor was resected for "cure" (normal fasting gastrin levels for two years postoperatively) in one patient. Seventeen patients have died, and tumor was the cause of death in 70 percent. The five-year survival rate was 44 percent; the 10-year survival rate was 40 percent. Thirty-five cases were diagnosed after 1970. Age at diagnosis ranged from 39 to 61 years (median, 46 years). Thirty patients were operated on. Metastases were identified in 23 percent and no tumor was found in 17 percent. Tumor was resected for "cure" in 30 percent of patients. Seven patients have died and tumor caused death in 42 percent. The five-year survival rate was 82 percent; the 10-year rate was 64 percent. Advances in diagnosis and surgical technique since 1970 have made early operative treatment applicable in patients with gastrinoma. Because death in most cases is caused by progression of the tumor, an aggressive surgical approach to resect the tumor is advised soon after the diagnosis of Zollinger-Ellison syndrome is established.

Role of peptide radioimmunoassay in understanding peptide-peptide interactions and clinical expression of gastroenteropancreatic endocrine tumors.

Peptide radioimmunoassay has become an important clinical and research tool in understanding the role of peptides in the pathophysiology of gut endocrine tumor syndromes. A gut peptide radioimmunoassay laboratory has been established for the diagnosis and clinical monitoring of endocrine tumors of the gastroenteropancreatic (GEP) system. Radioimmunoassay has enhanced our awareness that co-occurring peptide interactions may modify and ultimately influence the clinical expression of these tumors. Furthermore, it has helped develop a rationale for the use of prototype peptides such as somatostatin and its long-acting analogue Sandostatin (SMS 201-995) in the management of GEP tumors. This group's experience, as well as the experience of other investigators, is presented, and the clinical utility of peptide radioimmunoassay in the field of gut endocrinology is demonstrated.

Medical therapy of VIPomas.

VIP-secreting tumors are rare, but they produce a dramatic clinical picture, the most prominent feature of which is profuse, watery diarrhea and hypokalemia. A definitive diagnosis is aided by the determination of plasma VIP concentrations through the use of the sensitive radioimmunoassays that are now available. Intestinal secretion resulting from the direct action of VIP on the intestinal epithelial cell receptors accounts for the loss of fluid and electrolytes in patients with VIPoma. The hypokalemia is the result of passive and VIP-induced active secretion of potassium by colonic epithelial cells. Surgery is the most definitive treatment of VIPoma; pharmacotherapy is extremely important in controlling symptoms and stabilizing the patient prior to surgery. Sandostatin and glucocorticoids are well established agents in the management of the secretory diarrhea; other pharmacologic agents, including clonidine, indomethacin, phenothiazines, lithium carbonate, and propranolol, may be helpful in selected patients but require further study. The most potent and promising drug for the treatment of VIPoma is a new peptidomimetic agent--Sandostatin. This metabolically stable synthetic analogue of somatostatin appears, in part, to inhibit the release of VIP from the tumor and the secretion of chloride by the intestine. In addition to controlling the diarrhea, it may have a direct effect on the tumor in reducing its size.

Observations on the effect of a somatostatin analog in the Zollinger-Ellison syndrome: implications for the treatment of apudomas.

Somatostatin is known to inhibit hormone release and gastrointestinal secretion and hence may be useful in the treatment of amine precursor uptake, decarboxylase tumors. Clinical application has been limited by the short half-life, potency, and specificity of the natural hormone. Our study evaluated the effect of a synthetic analog of somatostatin, SMS 201-995 (Sandoz, Inc., E. Hanover, N.J.) on basal and stimulated gastrin release and gastric acid secretion in 10 patients with the Zollinger-Ellison syndrome. In experiment 1, H2-receptor antagonists were discontinued for 48 hours; SMS 201-995, 1 microgram/kg, was given subcutaneously; gastrin and SMS levels in plasma were determined by radioimmunoassay; and gastric secretion was measured and titrated at 0, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, and 18 hours. The mean +/- SEM baseline gastrin level (1526 +/- 733 pg/ml) was significantly inhibited for 16 hours (p less than 0.05, paired t test). Gastric secretion was neutralized for as long as 18 hours (p 0.05). In experiment 2, three patients received either a secretin (2 U/kg) or a calcium stimulation test (2 mg/kg) with or without pretreatment with SMS 201-995, 1 microgram/kg, subcutaneously. The mean +/- SEM interpreted change in gastrin (ng X 60 min/ml) without SMS 201-995, 36.8 +/- 11 (secretin), and 129 +/- 30 (calcium) were reduced with SMS 201-995 to -1.1 +/- 0.76 (secretin) and -29 +/- 28 (calcium) (p less than 0.05). In the Zollinger-Ellison syndrome, SMS 201-995 caused significant and long-lasting inhibition of both tumor gastrin release and gastric acid secretion, probably by direct action on both the gastrinoma and the stomach. SMS 201-995 blocks acid secretion and secretin- and calcium-stimulated gastrin release, indicating that SMS 201-995 inhibits peptide secretion by postreceptor mechanisms. SMS 201-995 will be useful in the palliative treatment of apudomas.

Effect of somatostatin analogue (SMS 201-995) on molecular species of gastrin in gastrinoma.

Somatostatin analogue (SMS 201-995) has been shown to decrease total serum gastrin in patients with gastrinoma; however, the gastrin level rarely returns to normal, despite the near-complete inhibition of acid secretion. This implies that SMS may have an inhibitory action on the biologically active molecular species of gastrin and have little effect on biologically inactive species. To test this hypothesis, we determined the effect of SMS on the molecular species of gastrin in eight patients with the Zollinger-Ellison syndrome. Serum obtained before treatment and 6 hours and 18 hours after treatment (SMS 1 microgram/kg, subcutaneously) was sampled and assayed for molecular species of gastrin by means of gel filtration chromatography and fractional quantitation of gastrin species by radioimmunoassay. There was a significant decrease in the amount of G-34 and G-17 species. BBG and G-14 decreased, a change not significant at 6 hours but significant 18 hours after SMS. The distribution of the various molecular species as a percent of total immunoreactive gastrin was analyzed before and after SMS. There was a shift in the distribution of the molecular species, so that 6 hours after SMS treatment nearly 50% of total gastrin activity was accounted for by BBG and component I. SMS seems to have a different potency to inhibit release of the various gastrin molecular species. This observation may explain the failure of total gastrin levels to return to normal after SMS treatment in patients with the Zollinger-Ellison syndrome.

Treatment of endocrine and nonendocrine secretory diarrheal states with Sandostatin.

Endocrine tumors of the gastroenteropancreatic (GEP) axis elaborate excessive amounts of peptides that are potent intestinal secretagogues. The actions of these peptides on intestinal transport of water and electrolytes lead to the accumulation of fluid in the intestinal lumen and diarrhea. One of the most clinically relevant secretagogues is vasoactive intestinal polypeptide (VIP). Other relevant secretagogues elaborated from tumors are serotonin, prostaglandins, and kinins. Sandostatin (octreotide, Sandoz, Basle, Switzerland), a long-acting octapeptide analog of somatostatin, inhibits experimentally induced intestinal secretion and has been used successfully to treat patients with secretory diarrhea refractory to other pharmacotherapy. The effective dose is in the range of 50 to 200 micrograms, given subcutaneously two or three times daily. The mechanism for the inhibitory effect on secretion is not clearly understood but it appears to involve inhibition of the adenylate cyclase-cyclic adenosine monophosphate system as well as interference with calcium as an intercellular mediator of enterocyte secretion. A particularly interesting use of this drug has been to treat the watery diarrhea seen in patients with acquired immunodeficiency syndrome. It is also effective in other types of secretory diarrhea not associated with endocrine tumors. These include diabetic diarrhea, idiopathic secretory diarrhea of infancy, and high output ileostomy diarrhea.

Octreotide inhibits increases in short-circuit current induced in rat colon by VIP, substance P, serotonin and aminophylline.

We investigated the effect of octreotide (OCT), a stable somatostatin analog, (OCT) on changes in short-circuit current (Isc) induced by vasoactive intestinal peptide (VIP), aminophylline, serotonin (5-HT) and substance P. OCT significantly decreased basal Isc at a concentration of 10(-9) M; the maximum decrease in Isc was observed at 10(-6) M. OCT (10(-7) M) significantly inhibited the intestinal secretory response to all the secretagogues studied. The maximum Isc response was reduced when tissues were stimulated with VIP (184.9 +/- 18.0 vs. 119.7 +/- 14.1, P less than 0.05), 5-HT (135.1 +/- 14.4 vs. 79.5 +/- 13.4, P less than 0.05) and substance P (156.0 +/- 19.2 vs. 30.7 +/- 5.4, P less than 0.01). In the case of aminophylline, the concentration-response curve was shifted to the right but the maximum response was not reduced. Because VIP and aminophylline increase cAMP while 5-HT and substance P stimulate intestinal secretion principally by a calcium linked mechanism, we conclude that OCT inhibits Isc in rat colon by more than one mechanism.

Treatment of psoriasis with chronic subcutaneous administration of somatostatin analog 201-995 (sandostatin). I. An open-label pilot study.

Increased levels of human growth hormone (HGH) may correlate with the severity of psoriasis and native somatostatin (SRIF) may improve it by inhibiting HGH release. The synthetic SRIF analog, SMS 201-995, is a potent and long-lasting HGH inhibitor. Nine patients with chronic plaque psoriasis completed 12 weeks of open treatment with SMS 201-995. Overall improvement was minimal to marked in six patients and unchanged in three; none worsened. Means of 24-hour pooled HGH (1.7 +/- 0.7 micrograms/L) and fasting plasma somatomedin-C (SM-C) (0.45 +/- 0.22 U/mL) were normal at baseline and were not significantly altered by treatment. A high frequency of gastrointestinal side effects occurred, but no patient discontinued treatment because of them. SMS 201-995 may be a useful therapy for psoriasis, but its mechanism of action is unknown. Double-blind placebo-controlled trials are currently in progress to confirm the efficacy of SMS 201-995 in psoriasis.

The response of a non-functional VIP- and somatostatin-containing tumour to tolbutamide in vitro.

A patient with a tumour containing clinically non-expressive somatostatin (SRIF) and vasoactive intestinal peptide (VIP) was studied in vivo with basal and tolbutamide-provoked SRIF and VIP measurements and failed to respond to tolbutamide infusion. An acute cell dispersion model was used to study this tumour after resection. Incubation of tumour cells in tolbutamide (2 mg/ml) resulted in increases in intracellular SRIF but not in the levels of SRIF released into the incubating medium. In contrast, incubation of tumour cells with tolbutamide decreased supernatant (extracellular) and total (intracellular) VIP by 50%, suggesting a local peptide-peptide modulation of VIP release by high intracellular levels of SRIF or, alternatively, suppression of VIP synthesis and/or release by tolbutamide. Failure of 'nonfunctional' tumours to produce symptoms or abnormal plasma peptide levels may be due to defects in peptide release or complex paracrine peptide-peptide interactions.

Acute and chronic effects of ethanol on fluid transport in the human small intestine.

The effect of acute and chronic administration of ethanol on jejunal and ileal water and electrolyte transport was studied in healthy volunteers by the triple lumen intestinal perfusion technique. The acute perfusion of a glucose-free electrolyte solution containing 2 to 10 g per 100 ml of ethanol in the jejunum or ileum did not cause any significant alterations of sodium or water transport. In contrast, the administration of a folate-deficient diet and ethanol for 2 weeks produced a marked reduction in sodium and water absorption or a small net secretion (control, mean +/-SE: H2O = 0.91 +/- 0.06 ml per min, Na = 130 +/- 8 micronEq per min per 30 cm of intestine versus H2O = -0.13 +/- 0.14 ml per min, Na = -20 +/- 29 micronEq per min per 30 cm, P less than 0.001). These changes were not accompanied by a reduction in serum folate levels. The administration of ethanol with a folate-supplemented diet also produced significant but less pronounced changes in sodium and water transport control: H2O = 1.33 +/- 0.2 ml per min, Na = 185 +/- 34 micronEq per min per 30 cm of intestine versus H2O = 0.48 +/- 0.17 ml per min, Na =65 +/- 16 micronEq per min per 30 cm of intestine, P less than 0.05). From this study it appears that the diarrhea seen in chronic alcoholics can be explained in part by the effect of ethanol on intestinal sodium transport, without any accompanying changes in serum folate levels.

Silent pancreatic pseudocyst. An unusual cause of extrahepatic biliary obstruction.

Extrahepatic biliary obstruction due to mechanical obstruction of the common bile duct is a relatively rare complication of pancreatic pseudocyst. When jaundice does occur, clinical or laboratory evidence of associated primary hepatobiliary disease or acute pancreatitis has invariably been present. The patient described had a 3-month history of painless juandice, 40-lb weight loss, pruritus, and hepatomegaly, but no clinical or biochemical evidence of acute or chronic pancreatitis. After initial evaluation, including an abdominal echogram and a transhepatic cholangiogram, carcinoma of the head of the pancreas was diagnosed preoperatively. At laparotomy, a small pancreatic pseudocyst obstructed the terminal portion of the common bile duct. This case illustrates that a pancreatic pseudocyst should be considered in the differential diagnosis of obstructive jaundice, even in the absence of clinical evidence of pancreatitis or pseudocyst formation.

Colonic absorption of unconjugated bile acids: perfusion studies in man.

Colonic absorption of three major unconjugated bile acids--cholate, chenodeoxycholate, and deoxycholate--was measured under steady-state conditions using a technique of colonic perfusion in healthy volunteers. Aqueous solutions at pH 8.0 and varying in concentration from 1 mM to 10 mM were used. The rate of chenodeoxycholate absorption averaged nine times that of cholate absorption; deoxycholate absorption was somewhat less than that of chenodeoxycholate absorption, averaging six times that of cholate. At concentrations below 5 mM, the rate of absorption of bile acids was directly proportional to concentration, so that "clearance" could be calculated. Clearance values for a 1-mM solution (ml/min/colon, mean +/- SE) were: chenodeoxycholate, 9.84 +/- 1.0; deoxycholate, 7.0 +/- 1; and cholate, 0.82 +/- 0.10. Since absorption was proportional to concentration in the lumen, and was more rapid for the dihydroxy acids, the major mechanism of absorption was thought to be passive nonionic diffusion. Maximal rates of bile acid absorption were calculated from a 1-mM solution and found to be as high as 4.2 g/day for chenodeoxycholate, 3.2 g/day for deoxycholate, and 0.5 g/day for cholate, and the rate would be still greater for more concentrated solutions. Colonic absorption may contribute significantly to conservation of the dihydroxy bile acid pool, especially in conditions of bile acid malabsorption.

Stimulation of gastric inhibitory polypeptide in normal and duodenal ulcer patients.

To investigate the role of gastric inhibitory polypeptide (GIP), a potent inhibitor of gastric acid secretion, in the hypersecretion associated with duodenal ulcer, we compared the serum GIP concentrations in 11 healthy subjects and 16 duodenal ulcer patients after the stimulation of GIP release by a mixed meal. Fasting and postprandial serum gastrin and GIP concentrations were measured by radioimmunoassay at frequent intervals after the ingestion of a test meal. The duodenal ulcer patients showed an augmented and significantly greater release of GIP as well as of gastrin compared to normal subjects. These results indicate that a defective GIP release cannot account for the gastric hypersecretion seen in patients with duodenal ulcer. The mechanism of the increased GIP response in patients with duodenal ulcer is not clear from these studies.

Effects of caffeine and coffee on fluid transport in the small intestine.

Although caffeine is known to stimulate small intestinal water secretion in man, no available studies have examined the effect of coffee on small intestinal fluid transport. We have studied the effect of both coffee and caffeine on jejunal sodium and water transport by the triple lumen intestinal perfusion technique. Both caffeine and coffee solutions had equivalent caffeine concentrations, approximating the caffeine concentration in one cup of coffee. Control and coffee perfusion resulted in net absorption of 0.9 +/- 0.2 and 1.1 +/- 0.3 ml per min per 30 cm, respectively, whereas caffeine perfusion resulted in net water secretion of 2.4 +/- 0.4 ml per min per 30 cm (P less than 0.02). Net sodium absorption was observed with control and coffee solutions with a mean absorption of 190 +/- 32 and 184 +/- 40 muEq per min per 30 cm, respectively. Net sodium secretion of 334 +/- 25 muEq er min per 30 cm was observed during caffeine perfusion (P less than 0.02). We conclude that coffee perfusion has no significant effect on sodium and water transport in the jejunum in spite of the marked secretory effects of caffeine solutions. The results of this study yield further support to the suggestion that the effects of caffeine may not be similar to the effects of caffeine-containing compounds such as coffee.