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Peptide receptor radionuclide therapy (PRRT) is an effective treatment for metastatic neuroendocrine tumors. Delivering a sufficient tumor radiation dose remains challenging because of critical-organ dose limitations. Adding 131 I-metaiodobenzylguanidine ( 131 I-MIBG) to PRRT may be advantageous in this regard. Methods: A phase 1 clinical trial was initiated for patients with nonoperable progressive neuroendocrine tumors using a combination of 90 Y-DOTATOC plus 131 I-MIBG. Treatment cohorts were defined by radiation dose limits to the kidneys and the bone marrow. Subject-specific dosimetry was used to determine the administered activity levels. Results: The first cohort treated subjects to a dose limit of 1,900 cGy to the kidneys and 150 cGy to the marrow. No dose-limiting toxicities were observed. Tumor dosimetry estimates demonstrated an expected dose increase of 34%-83% using combination therapy as opposed to 90 Y-DOTATOC PRRT alone. Conclusion: These findings demonstrate the feasibility of using organ dose for a phase 1 escalation design and suggest the safety of using 90 Y-DOTATOC and 131 I-MIBG., (© 2021 by the Society of Nuclear Medicine and Molecular Imaging.)

Octreotide acetate (octreotide) is the most prescribed and most studied somatostatin congener, or analog, for gastroenteropancreatic neuroendocrine tumors (GEP-NETs) and carcinoid syndrome, the latter of which may be characterized by debilitating diarrhea and flushing. Approved in the U.S. more than 30 years ago, octreotide is widely used to control the symptoms of carcinoid syndrome and has been shown to demonstrate antiproliferative activity. The two formulations available in the U.S. include a subcutaneous immediate-release (IR) injection introduced in 1989 and a long-acting repeatable (LAR) intramuscular injection approved in 1999. Lanreotide depot (lanreotide), a more recent somatostatin congener, has been available in the U.S. since 2014. Despite widespread use of octreotide LAR, several key challenges exist with the current depot-based treatment paradigm. Studies indicate that LAR formulations are associated with continued unmet patient needs, owing in part to a loss of bioactivity over time that may necessitate progressive supplemental treatment with IR octreotide to adequately control symptoms. Clinicians should understand the key differences in the pharmacokinetic profiles of the LAR and IR formulations that may contribute to bioactivity loss and somatostatin receptor desensitization. In addition, there is a need to re-evaluate the role of IR octreotide in combination with depot therapy to provide consistent bioavailability and better control of carcinoid syndrome symptoms. The purpose of this review is to explore all these issues and to re-establish a rationale for the IR formulation, particularly with respect to novel use cases and its use during the COVID-19 pandemic. IMPLICATIONS FOR PRACTICE: There is a need to re-evaluate the role of immediate-release octreotide in combination with depot therapy to provide consistent bioavailability and better control of carcinoid syndrome symptoms., (© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Purpose: Pancreatic neuroendocrine tumors (pNETs) are uncommon malignancies noted for their propensity to metastasize and comparatively favorable prognosis. Although both the treatment options and clinical outcomes have improved in the past decades, most patients will die of metastatic disease. New systemic therapies are needed., Experimental Design: Tissues were obtained from 43 patients with well-differentiated pNETs undergoing surgery. Gene expression was compared between primary tumors versus liver and lymph node metastases using RNA-Seq. Genes that were selectively elevated at only one metastatic site were filtered out to reduce tissue-specific effects. Ingenuity pathway analysis (IPA) and the Connectivity Map (CMap) identified drugs likely to antagonize metastasis-specific targets. The biological activity of top identified agents was tested in vitro using two pNET cell lines (BON-1 and QGP-1)., Results: A total of 902 genes were differentially expressed in pNET metastases compared with primary tumors, 626 of which remained in the common metastatic profile after filtering. Analysis with IPA and CMap revealed altered activity of factors involved in survival and proliferation, and identified drugs targeting those pathways, including inhibitors of mTOR, PI3K, MEK, TOP2A, protein kinase C, NF-kB, cyclin-dependent kinase, and histone deacetylase. Inhibitors of MEK and TOP2A were consistently the most active compounds., Conclusions: We employed a complementary bioinformatics approach to identify novel therapeutics for pNETs by analyzing gene expression in metastatic tumors. The potential utility of these drugs was confirmed by in vitro cytotoxicity assays, suggesting drugs targeting MEK and TOP2A may be highly efficacious against metastatic pNETs. This is a promising strategy for discovering more effective treatments for patients with pNETs., (©2020 American Association for Cancer Research.)

Background: Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome., Subjects, Materials, and Methods: Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated., Results: Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4., Conclusion: Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome., Implications for Practice: Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Hyperactivated AKT/mTOR signaling is a hallmark of pancreatic neuroendocrine tumors (PNETs). Drugs targeting this pathway are used clinically, but tumor resistance invariably develops. A better understanding of factors regulating AKT/mTOR signaling and PNET pathogenesis is needed to improve current therapies. We discovered that RABL6A, a new oncogenic driver of PNET proliferation, is required for AKT activity. Silencing RABL6A caused PNET cell-cycle arrest that coincided with selective loss of AKT-S473 (not T308) phosphorylation and AKT/mTOR inactivation. Restoration of AKT phosphorylation rescued the G1 phase block triggered by RABL6A silencing. Mechanistically, loss of AKT-S473 phosphorylation in RABL6A-depleted cells was the result of increased protein phosphatase 2A (PP2A) activity. Inhibition of PP2A restored phosphorylation of AKT-S473 in RABL6A-depleted cells, whereas PP2A reactivation using a specific small-molecule activator of PP2A (SMAP) abolished that phosphorylation. Moreover, SMAP treatment effectively killed PNET cells in a RABL6A-dependent manner and suppressed PNET growth in vivo. The present work identifies RABL6A as a new inhibitor of the PP2A tumor suppressor and an essential activator of AKT in PNET cells. Our findings offer what we believe is a novel strategy of PP2A reactivation for treatment of PNETs as well as other human cancers driven by RABL6A overexpression and PP2A inactivation.

Pretherapy PET with 86 Y-DOTATOC is considered the ideal dosimetry protocol for 90 Y-DOTATOC therapy; however, its cost, limited availability, and need for infusion of amino acids to mimic the therapy administration limit its use in the clinical setting. The goal of this study was to develop a dosimetric method for 90 Y-DOTATOC using 90 Y-DOTATOC PET/CT and bremsstrahlung SPECT/CT and to determine whether dosimetry-based administered activities differ significantly from standard administered activities. Methods: This was a prospective phase 2 trial of 90 Y-DOTATOC therapy in patients with somatostatin receptor-positive tumors. 90 Y-DOTATOC was given in 3 cycles 6-8 wk apart. In the first cycle of therapy, adults received 4.4 GBq and children received 1.85 GBq/m 2 ; the subsequent administered activities were adjusted according to the dosimetry of the preceding cycle so as not to exceed a total kidney dose of 23 Gy and bone marrow dose of 2 Gy. The radiation dose to the kidneys was determined from serial imaging sessions consisting of time-of-flight 90 Y-DOTATOC PET/CT at 5 h after therapy and 90 Y-DOTATOC bremsstrahlung SPECT/CT at 6, 24, 48, and 72 h. The PET/CT data were used to measure the absolute concentration of 90 Y-DOTATOC and to calibrate the bremsstrahlung SPECT kidney clearance data. The radiation dose to the kidneys was determined by multiplying the time-integrated activity (from the fitted biexponential curve of renal clearance of 90 Y-DOTATOC) with the energy emitted per decay, divided by the mass of the kidneys. Results: The radiation dose to the kidneys per cycle of 90 Y-DOTATOC therapy was highly variable among patients, ranging from 0.32 to 3.0 mGy/MBq. In 17 (85%) of the 20 adult patients who received the second and the third treatment cycles of 90 Y-DOTATOC, the administered activity was modified by at least 20% from the starting administered activity. Conclusion: Renal dosimetry of 90 Y-DOTATOC is feasible using 90 Y-DOTATOC time-of-flight PET/CT and bremsstrahlung SPECT/CT and has a significant impact on the administered activity in treatment cycles., (© 2018 by the Society of Nuclear Medicine and Molecular Imaging.)

Localization of the site of the unknown primary tumor is critical for surgical treatment of patients presenting with neuroendocrine tumor (NET) with metastases. Methods: Forty patients with metastatic NET and unknown primary site underwent 68 Ga-DOTATOC PET/CT in a single-site prospective study. The 68 Ga-DOTATOC PET/CT was considered true-positive if the positive primary site was confirmed by histology or follow-up imaging. The scan was considered false-positive if no primary lesion was found corresponding to the 68 Ga-DOTATOC-positive site. All negative scans for primary tumor were considered false-negative. A scan was classified unconfirmed if 68 Ga-DOTATOC PET/CT suggested a primary, however, no histology was obtained and imaging follow-up was not confirmatory. Results: The true-positive, false-positive, false-negative, and unconfirmed rates for unknown primary tumor were 38%, 7%, 50%, and 5%, respectively. Conclusion: 68 Ga-DOTATOC PET/CT is an effective modality in the localization of unknown primary in patients with metastatic NET., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood, and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs (PNET) that correlated with high-level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor-suppressor pathways in the arrested cells. Loss of p53 had no effect on the RABL6A knockdown phenotype, indicating that RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation partially restored G1 to S phase progression in RABL6A-knockdown cells, although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a novel negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients., (©2014 American Association for Cancer Research.)

Pasireotide (SOM230) is a novel multireceptor-targeted somatostatin (sst) analog with high binding affinity for sst receptor subtype 1, 2, 3 (sst(1,2,3)) and sst(5). Because of this binding profile, pasireotide may offer symptom control in patients with neuroendocrine tumors (NETs) and carcinoid syndrome no longer responsive to octreotide LAR. This was a phase II, open-label, multicenter study of pasireotide in patients with advanced NET whose symptoms of carcinoid syndrome (diarrhea/flushing) were inadequately controlled by octreotide LAR. Patients received s.c. pasireotide 150 μg twice daily (bid), escalated to a maximum dose of 1200 μg bid until a clinical response was achieved. Forty-four patients were evaluated for efficacy and 45 for tolerability. Pasireotide 600-900 μg s.c. bid effectively controlled the symptoms of diarrhea and flushing in 27% of patients. Evaluation of tumor response in 23 patients showed 13 with stable disease and ten with progressive disease at study end. The most common drug-related adverse events were nausea (27%), abdominal pain (20%), weight loss (20%), and hyperglycemia (16%) and most were of mild or moderate severity. Pasireotide 600-900 μg s.c. bid was effective and generally well tolerated in controlling the symptoms of carcinoid syndrome in 27% of patients with advanced NET refractory or resistant to octreotide LAR therapy.

A new treatment modality for inoperable or metastasized gastroenteropancreatic tumors is the use of radiolabeled somatostatin analogs. Initial studies with high doses of [(111)In-diethylenetriaminepentaacetic acid (DTPA)(0)]octreotide in patients with metastasized neuroendocrine tumors were encouraging, although partial remissions were uncommon. Another radiolabeled somatostatin analog that is used for peptide receptor radionuclide therapy (PRRT) is [(90)Y-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)(0),Tyr(3)]octreotide. Various phase 1 and phase 2 PRRT trials have been performed with this compound. Despite differences in the protocols used, complete and partial remissions in most of the studies with [(90)Y-DOTA(0),Tyr(3)]octreotide were in the same ranges, 10%-30%; these ranges were higher than those obtained with [(111)In-DTPA(0)]octreotide. Treatment with the newest radiolabeled somatostatin analog, [(177)Lu-DOTA(0),Tyr(3)]octreotate, which has a higher affinity for the subtype 2 somatostatin receptor, resulted in complete or partial remissions in 30% of 76 patients. Tumor regression was positively correlated with a high level of uptake on OctreoScan imaging, a limited hepatic tumor mass, and a high Karnofsky performance score. Treatment with radiolabeled somatostatin analogs is a promising new tool in the management of patients with inoperable or metastasized neuroendocrine tumors. Symptomatic improvement may occur with all (111)In-, (90)Y-, or (177)Lu-labeled somatostatin analogs that have been used for PRRT. The results obtained with [(90)Y-DOTA(0),Tyr(3)]octreotide and [(177)Lu-DOTA(0),Tyr(3)]octreotate are very encouraging in terms of tumor regression. Also, if kidney protective agents are used, the side effects of this therapy are few and mild, and the duration of the therapy response for both radiopharmaceuticals is more than 2 y. These data compare favorably with those for the limited number of alternative treatment approaches.

Purpose: Somatostatin (SST) analogues have been used to treat proliferative diabetic retinopathy, pseudotumor cerebri, thyroid orbitopathy, and cystoid macular edema. There is a paucity of published data in regards to cell-specific distribution of SST receptors (SSTR) in normal human eye tissues. Gene expression for all five known SSTRs in normal human ciliary body/iris, retina, choroid, and cultured retinal pigment epithelial (RPE) cells were studied., Methods: mRNA was isolated from human ocular tissues (iris/ciliary body, retina, and choroid) dissected from eight pairs of normal eyes (9-62 years) and from RPE cells grown in culture. RT-PCR was done for all five SSTRs in all analyzed tissues. Immunohistochemistry for SSTR1 and SSTR2 was performed on eight pairs of normal human eyes (28-74 years) imbedded in paraffin., Results: SSTR1 to 5 genes are expressed in retina, SSTR1 and SSTR2 genes in cultured RPE cells, and SSTR1, 2, and 4 in ciliary body and choroid. SSTR1 and SSTR2 immunoreactivity (-ir) was observed on a variety of cells within all analyzed tissues including cornea, iris, trabecular meshwork, Schlemm's canal, ciliary processes, ciliary muscle, retina, choroid, cultured RPE cells, and optic nerve., Conclusions: SSTR genes are widely expressed in normal human eye tissues, with genes for SSTR1 and SSTR2 being the most widely expressed. Genes for all SSTRs are expressed in retina. SSTR1-ir and SSTR2-ir were observed in all analyzed ocular tissues. Detailed knowledge of SSTRs distribution and function in the human eye will result in a better understanding of their role in health and disease.

We hypothesized that non-proliferating (quiescent) human vascular endothelial cells would not express somatostatin receptor subtype 2 (sst 2) and that this receptor would be expressed when the endothelial cells begin to grow. To test this hypothesis, placental veins were harvested from 6 human placentas and 2 mm vein disks were cultured in 0.3% fibrin gels. Morphometric analysis confirmed that 50-75% of cultured vein disks developed radial capillary growth within 15 days. Sst 2 gene expression was determined by reverse transcription-polymerase chain reaction (RT-PCR) analysis of the RNA from veins before culture and from tissue-matched vein disks that exhibited an angiogenic response. The sst 2 gene was expressed in the proliferating angiogenic sprouts of human vascular endothelium. The presence of sst 2 receptors on proliferating angiogenic vessels was confirmed by immunohistochemical staining and in vivo scintigraphy. These results suggest that sst 2 may be a unique target for antiangiogenic therapy with sst 2 preferring somatostatin analogues conjugated to radioisotopes or cytotoxic agents.

Neuroendocrine tumors of the cervix are rare and are often under- or misdiagnosed. Because these tumors are very aggressive, early diagnosis and subsequent treatment are warranted. We describe a 46-yr-old woman with carcinoid syndrome caused by an atypical carcinoid of the uterine cervix. At age 44, she had dysplasia on Pap smear and underwent total abdominal hysterectomy with the diagnosis of adenocarcinoma. Fourteen months postoperatively, she developed the carcinoid syndrome and was found to have numerous liver metastases. Histological and immunohistochemical investigations of biopsy specimens from the patient's liver lesions and original cervical lesion ("adenocarcinoma") suggested that this woman had a primary atypical carcinoid of the uterine cervix with metastases to the liver. Treatment with octreotide and alkylating agents decreased the episodes of flushing and diarrhea within 8 weeks. If an adenocarcinoma of the uterine cervix is diagnosed, atypical carcinoid should be in the differential diagnosis. Symptoms of the carcinoid syndrome should be pursued and, if present, a urinary 5-hydroxyindolacetic acid level should be obtained. Timely diagnosis of a neuroendocrine tumor of the cervix may improve survival.

Gastrinomas and other gastrointestinal neuroendocrine tumors may occur sporadically or as part of the inherited syndrome multiple endocrine neoplasia type 1 (MEN1). Mutations in the recently identified MEN1 gene have been described in sporadic gastrinomas and insulinomas. This study describes techniques used to identify mutations in the MEN1 gene in DNA extracted from paraffin-preserved tissue. Two novel mutations are identified in the MEN1 gene from nine archived paraffin-embedded neuroendocrine tumors, demonstrating that retrospective genetic analysis can be used to identify mutations in the MEN1 gene from preserved tissue. Conditions are provided by which paraffin-embedded tissue can be used as a source of genetic material for sequence information of sufficient quality for mutational studies of the MEN1 gene. It should also be possible to apply this retrospective genetic analysis of paraffin-embedded tissue to other disease models.

L-Carnitine plays a crucial role in the perinatal transition from carbohydrate to lipid-derived energy. To examine the potential contribution of assimilated dietary carnitine to the elevated hepatic concentrations in newborns, we measured carnitine concentrations in sow milk, jejunum, and liver, and in vitro jejunal carnitine transport in piglets aged 1-36 d. Hepatic and sow milk total carnitine concentrations peaked soon after birth and declined with age (p = 0.035 and 0.026, respectively). Although jejunal total carnitine concentrations remained stable, jejunal carnitine flux was higher at 2 d of age than in older piglets. To examine the possible signals that regulate hepatic carnitine, portal enteroinsular hormones were measured by RIA. Portal glucagon (p = 0.0006), insulin (p = 0.0001), and glucagon:insulin ratio (p = 0.037) were related to age. Portal glucagon was highest in newborns and during weaning, whereas insulin increased progressively with age; the portal glucagon:insulin ratio, like hepatic carnitine, peaked soon after birth and fell with age. A multiple regression analysis indicated a positive association between glucagon and hepatic carnitine and a negative one between insulin and hepatic carnitine (R = 0.802, p = 0.001). An overall pattern of elevated dietary carnitine levels and increased small intestinal absorption and hepatic accumulation of carnitine is noted in early development. The finding of a similar pattern in glucagon-to-insulin ratio suggests that both hormones may participate in the regulation of enterohepatic carnitine distribution in newborns.

Decreased insulin sensitivity and glucose-dependent glucose disposal (glucose effectiveness) have been demonstrated in poorly-controlled Type 1 (insulin-dependent) diabetic patients. We have therefore examined the effects of successful pancreas transplantation that results in long-term physiologic normoglycaemia as measured by insulin sensitivity index and glucose effectiveness in 14 Type 1 diabetic recipients (Group 1) using the Bergman minimal model method. Their results were compared with those of five non-diabetic patients with kidney transplant alone (Group 2) and 10 healthy control subjects (Group 3). Mean plasma glucose levels were indistinguishable in Group 1 when compared to Groups 2 and 3. However, mean basal plasma insulin levels were two- and eight-fold greater in Group 1 (36 +/- 6 microU/ml) than in Group 2 (17 +/- 7 microU/ml) and Group 3 (4.5 +/- 0.6 microU/ml), respectively. Following intravenous glucose (t = 0 min) and tolbutamide (t = 20), peak incremental insulin levels were significantly (p less than 0.001) greater in Group 1 vs Groups 2 and 3. Mean insulin sensitivity index was 65% and 50% lower in Group 1 (2.89 +/- 0.45) and Group 2 (4.11 +/- 1.30), respectively, when compared to Group 3 (8.40 +/- 1.24 x 10(-1) min-1 (microU/ml)-1. In contrast, glucose effectiveness was similar in the three groups (Group 1, 2.48 +/- 0.26; Group 2, 2.05 +/- 0.21; and Group 3, 2.10 +/- 0.17 x 10(-2).min-1). We conclude that, despite prednisone-induced insulin resistance, normal glucose tolerance is achieved by hyperinsulinaemia and normalisation of glucose-dependent glucose disposal following pancreas-kidney transplantation in Type 1 diabetic patients.

In the present study of 45 patients with Zollinger-Ellison syndrome, the frequency and clinical importance of the release of multiple gastrointestinal peptides were assessed prospectively. During an initial evaluation, extent of gastrinoma, clinical symptoms, disease duration, and presence or absence of multiple endocrine neoplasia, type I (MEN-I) were assessed. All patients had determinations of fasting plasma gastrin, human pancreatic polypeptide, motilin, neurotensin, and somatostatin; 35 had determinations of insulin and gastrin-releasing peptide and 21 had determinations of glucagon. A plasma elevation of additional peptides besides gastrin was detected in 62%, with 44% having one, 18% having two, and 0% having three additional peptides elevated. Motilin was elevated in 29%, human pancreatic polypeptide in 27%, neurotensin in 20%, and gastrin-releasing peptide in 10%, whereas insulin, glucagon, and somatostatin were not elevated in any patient. The presence or absence of elevation of any peptide did not differ in patients with or without MEN-I, with gastrinoma size, with the presence or absence of metastatic disease, or with various clinical symptoms. Patients were assessed yearly for clinical evidence of a secondary symptomatic pancreatic endocrine tumor syndrome with a median follow-up of 146 and 84 months from onset or diagnosis, respectively. Only one patient (2% of patients) developed a second syndrome (rate, 2 patients per 100 patients observed for 10 years). These results demonstrate that the plasma elevation of multiple gastrointestinal peptides is common in patients with Zollinger-Ellison syndrome; however, the rate of developing a second symptomatic pancreatic endocrine tumor syndrome is much lower than generally believed. Furthermore, no evidence is found to support the conclusions that the detection of the plasma elevation of these peptides is clinically important in assessing MEN-I status, disease extent, or presence of metastatic disease or that elevated levels of motilin, neurotensin, gastrin-releasing peptide, or human pancreatic peptide are associated with any distinct clinical symptoms. Therefore, we recommend that plasma concentrations of these additional gastrointestinal peptides should not be assessed routinely but rather only if new symptoms develop.

The present study evaluates the acute and chronic use of a long-acting somatostatin analog, octreotide acetate, in the treatment of patients with severe postgastrectomy dumping syndrome. In the acute phase, 10 patients with severe dumping were studied over 2 consecutive days before and for 3 hours after the ingestion of a 'dumping breakfast' in a randomized double-blind fashion. On one day octreotide (100 micrograms) was given subcutaneously 30 minutes before the test meal and on the other day an equal volume of vehicle was injected. An additional group of six postgastrectomy patients without dumping were studied in a similar fashion and these acted as controls. During placebo treatment the test meal resulted in an immediate increase (p less than 0.01) in the pulse rate and in plasma levels of glucose, glucagon, pancreatic polypeptide, neurotensin, and insulin. Similar changes were seen in the control group with respect to placebo; however glucagon and neurotensin (p less than 0.05) did not show the same magnitude of increase as seen with placebo. Treatment with octreotide acetate prevented the development of both vasomotor and gastrointestinal symptoms and completely ablated all of the above responses in plasma peptides. These changes were associated with complete ablation of diarrhea (p less than 0.001). Pretreatment with octreotide acetate completely suppressed the rise in plasma insulin response to the meal and this ablated the late hypoglycemia of dumping. Treatment with octreotide acetate resulted in delayed gastric emptying and transit time (578 +/- 244 minutes) versus 76 +/- 23 minutes with placebo and 125 +/- 36 minutes in controls (p less than 0.05). Chronic daily treatment with octreotide acetate resulted in minimal side effects. These patients demonstrated a stable fasting plasma glucose, normal liver function tests, and an average weight gain of 11% during a 12-month period. In addition most patients were able to resume employment. The long-acting somatostatin analog, octreotide acetate, is highly effective in preventing the development of symptoms of severe dumping syndrome, both vasomotor and gastrointestinal.

The purpose of the study was to examine the gastrointestinal hormone responses to meals in morbidly obese patients before and after Roux-en-Y gastric bypass (GBP; n = 9) or vertical banded gastroplasty (VBG; n = 7). On consecutive days before and after operation, we measured changes in peripheral blood levels of glucose, insulin, enteroglucagon, serotonin, vasoactive intestinal polypeptide (VIP), and cholecystokinin (CCK) in response to a standardized glucose or protein-fat meal. The percentage of excess weight lost at 6 months after operation was 66.3% +/- 4% and 41.8% +/- 5% for GBP and VBG, respectively (p less than 0.01). The 3-hour integrated glucose response to a glucose meal decreased from 145.3 +/- 33.7 to 75.8 +/- 15.7 g min/L (p less than 0.02) after GBP. This was associated with a decrease in 3-hour integrated insulin response from 22.8 +/- 8.2 to 10.5 +/- 4.9 mU min/L. Vertical banded gastroplasty patients had lesser reductions of hyperglycemia and hyperinsulinemia. Neither the CCK, serotonin, nor VIP responses to meals were altered by either operation. The 3-hour integrated enteroglucagon response to glucose increased markedly in GBP patients after operation from 11.8 +/- 6 to 133.4 +/- 38 nmol min/mL (p less than 0.02). This increase in enteroglucagon occurred at the same time as development of dumping symptoms, which occurred exclusively in GBP patients after glucose but not protein. We conclude that (1) GBP surgery for morbid obesity results in amelioration of glucose intolerance and hyperinsulinemia, (2) CCK does not mediate an endocrine satiety effect of surgery, (3) GBP is associated with an exaggerated enteroglucagon response to glucose, and (4) enteroglucagon appears to be a marker of the dumping syndrome in GBP patients.

Functional gastrin-containing tumor cells were maintained for up to 8 wk without fibroblastoid cell overgrowth. Short-term cultures consisted mainly of colonies composed of small polygonal cells, 70%-90% of which stained positive for immunoreactive gastrin. Cultures exhibited limited growth but viability remained high for 2-3 wk. Culture medium contained component I, and gastrin 34, 17, and 14. With time the major C-terminal gastrin species in medium changed from gastrin 17 at 3 days to gastrin 34 at 5 wk. Extracts of cultured cells contained gastrin 34, 17, and 14; gastrin 17 was the major form detected at all times. Ultrastructurally, cultured tumor cells retained morphological integrity for several weeks; however, with time changes in the appearance of the secretory granules accompanied by evidence of cellular retrodifferentiation were gradually observed. Secretin, gastrin-releasing peptide, 8-bromoadenosine 3':5'-cyclic monophosphate, and phorbol, 12-myristate, 13-acetate stimulated the release of gastrin from cultured cells in a time-dependent fashion. Secretin, bombesin, gastrin-releasing peptide, L-tryptophan, and ethylamine stimulated gastrin release in a dose-dependent fashion. Somatostatin 14 inhibited secretin, bombesin, and gastrin-releasing peptide stimulated gastrin release but did not alter basal release. Cultured cells demonstrated de novo gastrin synthesis, evidenced by their ability to incorporate radiolabeled amino acids into immunoadsorbable gastrinlike material. Primary cultures of gastrin-containing tumor cells free from stromal contamination offer unique advantages for studies of factors that regulate the synthesis and secretion of gastrin and may prove of potential value for studies on cell differentiation and growth.

Nine patients with psoriasis vulgaris were treated for 12 weeks with somatostatin analog, octreotide acetate (SMS 201-995) 50 or 100 micrograms by subcutaneous injection every 12 hours. The purposes of the study were to determine: (1) levels of insulin, glucose, glucagon, pancreatic polypeptide (PP), and SMS 201-995 after a subcutaneous injection of SMS 201-995 and ingestion of a standardized meal; (2) nocturnal (0200 h) thyroid stimulating hormone (TSH) levels before, during, and after treatment; and (3) the pharmacokinetics of SMS 201-995. Insulin peaks at 30 minutes were blunted from 65.8 +/- 11.0 mu U/mL without treatment to 26.7 +/- 8.6 mu U/mL and 7.7 +/- 2.0 mu U/mL after the 50- and 100-micrograms doses, respectively. Glucagon levels remained constant during the meal and were not affected by the 50-micrograms dose. Mean glucose levels were significantly elevated during insulin suppression. PP was also rapidly suppressed by SMS 201-995 and remained so for 4 hours after the injection. Nocturnal TSH was blunted after 12 weeks of treatment (P less than or equal to .05). T4 and T3 resin uptake showed no depression, and patients remained clinically euthyroid. The plasma peak of SMS 210-995 occurred 30 minutes postinjection and half-life was longer than 2 hours. After chronic administration of SMS 201-995, insulin was suppressed with resultant mild carbohydrate intolerance that persisted throughout the treatment course.

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.

An 8-mo-old male child presented with generalized flushing and apnea which followed irritation of a 1.5 x 0.5 cm cutaneous mastocytoma on the left upper arm. Peripheral venous blood samples were drawn before and after manipulation of the tumor, immediately after excision, and again 30 days later. The plasma vasoactive intestinal polypeptide level before excision was high (345 pg/ml) and was accompanied by low acid secretion (15.4 mEq/L) and hypergastrinemia (209 pg/ml), all of which returned to normal after excision of the tumor (50 pg/ml, 35.7 mEq/L, and 131 pg/ml, respectively). Serum histamine levels were undetectable. Histology of the tumor showed only mast cells and no enterochromaffin tissue. The immunoreactive vasoactive intestinal polypeptide content of the tumor was 28 ng/g wet wt and the extracted vasoactive intestinal polypeptide was immunologically indistinguishable from natural porcine vasoactive intestinal polypeptide. The child has remained asymptomatic postoperatively. We conclude that the symptoms associated with this mastocytoma may have been produced by oversecretion of vasoactive intestinal polypeptide and not histamine.

Infusion of vasoactive intestinal polypeptide (VIP) is known to cause intestinal secretion in animal models. The present study was designed to answer the question whether VIP has a similar effect on the human intestine. Pure porcine VIP was administered by constant i.v. infusion to healthy subjects while their jejunum was perfused with a plasma-like electrolyte solution. At the lowest VIP infusion rate (100 pmol/kg/hr), plasma VIP levels rose two- to four-fold, and there was an increase in the transmucosal potential difference but no change in sodium chloride absorption. At higher VIP infusion rates (200 and 400 pmol/kg/hr), VIP plasma concentrations rose to levels commonly observed in patients with pancreatic cholera syndrome. At these levels VIP caused a dose-dependent decrease of water and sodium absorption. Chloride absorption changed to secretion, while bicarbonate movement remained completely unaffected. Chloride secretion was active, since it occurred against an electrical and chemical gradient. All changes induced by VIP were reversible after discontinuance of VIP infusion. Our observations suggest that elevated levels of circulating VIP are capable of affecting water and ion movement in the human jejunum. They lend support to the hypothesis that high levels of circulating VIP may be a mediator of secretory diarrhea in some patients with pancreatic cholera syndrome.

In 16 consecutive patients with systemic mastocytosis, we prospectively evaluated a variety of gastrointestinal functions and examined how they relate to the occurrence of gastrointestinal symptoms. Nine patients had either a duodenal ulcer or duodenitis. Hypersecretion of gastric acid was present in 6 patients, and in these patients the mean basal acid output was 20.7 +/- 4.1 mEq/h (range 14-39 mEq/h). Impaired small intestinal absorption occurred in 5 patients, although this was usually mild. The mean fractional emptying rate of liquids for all patients (14.7% +/- 2.3% per minute) did not differ from that for controls (10.7% +/- 0.6% per minute). Mean mouth-to-cecum transit time measured by breath hydrogen testing was the same among patients (87.7 +/- 6.7 min) and controls (86.7 +/- 8.0 min). Plasma histamine concentrations were increased in all patients (mean 1886 pg/ml, range 480-7450) and correlated with the basal acid output (r = 0.64, p less than 0.02) but not maximal acid output or the presence or absence of pain or diarrhea. Mean fasting plasma concentrations of motilin, substance P, and neurotensin from 6 patients did not differ significantly from controls, whereas gastrin and vasoactive intestinal peptide were significantly less than in controls (p less than 0.01). Gastrointestinal symptoms, consisting of abdominal pain or diarrhea, occurred in 80% of patients. Abdominal pain classified as dyspeptic was usually associated with acid-peptic disease of the duodenum and hypersecretion of gastric acid, whereas abdominal pain of a nondyspeptic character was not. Only in those cases of diarrhea consisting of greater than 200 g stool/day was gastric acid hypersecretion frequently found. Neither fecal urgency nor nondyspeptic pain could be accounted for by alterations of gastrointestinal transit. These results demonstrate that gastrointestinal symptoms, peptic disease, and mild malabsorption are much more common than described previously in patients with systemic mastocytosis. Furthermore, the results provide no evidence for the contention that altered gastrointestinal transit is involved in the pathogenesis of these symptoms.

Based on studies in animals and humans, it has been suggested that nausea activates the hypothalamo-neurohypophyseal system with resultant increases in circulating concentrations of oxytocin or vasopressin. The purpose of these studies was to determine in humans whether nausea is associated with increases in circulating concentrations of neurohypophyseal hormones or various enteropancreatic peptides (vasoactive intestinal polypeptide, substance P, or pancreatic polypeptide). Nausea, induced by intravenous infusion of apomorphine, was associated with fivefold to 75-fold increases in plasma vasopressin concentrations in 7 subjects (mean increase, 41-fold), with no change in plasma oxytocin levels. Furthermore, nausea was associated with sevenfold to 16-fold increases in plasma pancreatic polypeptide concentrations (mean increase, ninefold), with no change in plasma levels of vasoactive intestinal polypeptide or substance P. In 1 subject refractory to nausea, there was no increase in plasma vasopressin or pancreatic polypeptide concentrations with apomorphine. These studies indicate that nausea in humans is associated with vasopressin and pancreatic polypeptide release.

A 7-year-old spayed female Cocker Spaniel was hospitalized with a history of chronic vomiting, anorexia, and weight loss. Laboratory abnormalities included leukocytosis, metabolic alkalosis, hypoglycemia, hypoproteinemia, and hyperinsulinemia. Gastroscopy and ultrasonography revealed multiple gastric masses and a possible pancreatic mass, respectively. Examination of tissues obtained at necropsy showed a pancreatic adenocarcinoma with hepatic metastasis, gastric hypertrophy, and multiple duodenal ulcers. Immunocytochemical staining of the neoplasia was positive for pancreatic polypeptide (PP) and insulin and negative for gastrin, calcitonin, adrenocorticotropic hormone (ACTH), serotonin, L-enkephalin, chromagranin, glucagon, and somatostatin. Subsequent serum gastrin and PP assays showed a fasting hypergastrinemia with a normal response of gastrin to provocative testing and extremely increased PP values. The high PP values may have resulted in the vomiting and gastrointestinal ulceration. A PP-secreting tumor has not previously been reported in the dog.

Twelve men with abnormally high insulin responses to a sucrose load and 12 normal men were fed diets containing 0, 7.5, or 15% of the calories as fructose for 5 weeks each. The diets contained approximately 43% of the calories as total carbohydrate, 42% as fat and 15% as protein. Mean insulin responses of the hyperinsulinemic men were initially 235% of control responses. Plasma glucose concentrations 1 hour after the sucrose load were significantly higher in hyperinsulinemic men than in controls. There were no initial differences between the two groups in glucagon or gastric inhibitory polypeptide (GIP) responses. Consumption of 7.5 and 15% Fructose diets increased fasting plasma glucose and GIP responses in both groups. Consumption of the 15% fructose diet resulted in significantly higher insulin and glucose responses than consumption of the other two diets. These results indicate that moderate levels of dietary fructose can produce undesirable changes in glucose metabolism of both normal and hyperinsulinemic men.

Zollinger-Ellison syndrome is usually caused by a gastrin-secreting tumor in or near the pancreas. We describe a patient in whom an ovarian cystadenocarcinoma was the cause of the syndrome. The patient presented with a short history of peptic ulceration and development of a large pelvic mass. Investigations demonstrated a basal acid output of 37.8 mEq/h and a maximal acid output of 36.0 mEq/h, and the plasma concentration of gastrin was 830 pg/ml (normal less than 100). Secretin and calcium infusion tests were positive, and a meal test was compatible with Zollinger-Ellison syndrome. Imaging studies demonstrated a normal liver and pancreas but a large cystic right ovarian mass. Resection of the mass resulted in a marked reduction in gastric acid output, a fall in plasma gastrin concentration to normal, negative calcium and secretin tests, and a normal (positive) meal test. Histology of the mass showed it to be a mucinous cystadenocarcinoma. The tumor stained with immunoperoxidase technique was positive for gastrin, and the cyst fluid contained high concentrations of gastrin and calcitonin. One year later, the patient has no biochemical or imaging evidence of tumor. Ovarian, gastrin-producing tumors and pancreatic gastrinomas cannot be distinguished by provocative tests, and negative imaging studies do not exclude a pancreatic tumor. Patients with an ovarian mass and Zollinger-Ellison syndrome should have a bilateral oophorectomy and a careful exploration of the pancreatic area.

The addition of fructose to natural meals elicits lower serum glucose and immunoreactive insulin responses when compared with that of sucrose and starch meals. Differences in rates of splanchnic glucose appearance and peripheral glucose disposal may be partly responsible. To evaluate the role of both parameters after different carbohydrate-enriched meals, we measured the arterialized venous blood glucose, immunoreactive insulin and gastric inhibitory polypeptide concentrations in seven Type 2 diabetic patients after ingestion of isocaloric test meals. Measurements were made in a random manner on three separate occasions. Fructose, sucrose, and bread supplementation constituted 68% of the total carbohydrate content of each meal. Rates of total glucose appearance, glucose utilization and metabolic clearance rates of glucose were determined by the D3-H-3 glucose prime-continuous infusion technique. The mean fasting glucose levels were similar in the three groups. Mean peak glucose concentrations and integrated incremental areas were significantly lower (p less than 0.02) after the fructose-enriched meals compared with that of either sucrose or bread. The basal arterialized venous blood glucose levels were similar in all three groups. The mean incremental integrated arterialized venous blood glucose area was significantly lower in the fructose group when compared with the sucrose (p less than 0.05) and bread (p less than 0.02) groups. The mean fasting gastric inhibitory polypeptide levels were similar in the three groups. However, the mean incremental integrated gastric inhibitory polypeptide areas were significantly lower in the fructose group compared with the sucrose and bread groups (p less than 0.01 and p less than 0.05 respectively). Basal hepatic glucose outputs were not significantly different in the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Physiologic evidence that vasoactive intestinal polypeptide (VIP) regulates esophageal smooth muscle in the opossum has been gathered without knowledge of the distribution of VIP in that organ. We examined planar sections stained for VIP by the avidin-biotin complex method, measured VIP content in mucosa and muscularis propria by radioimmunoassay, and compared neural structures reactive to VIP antiserum with those revealed by osmication in the presence of zinc iodide. Immunoreactive terminal nerves interlaced smooth muscle bundles in all layers in all smooth muscle regions, formed loose tangled knots about widely dispersed muscle cells in striated muscle, and supplied vessels and submucosal glands. Bipolar interstitial cells in the circular muscle layer stained by osmication were not VIP-immunoreactive. Perikarya in both submucous and myenteric plexuses were VIP-immunoreactive. Vasoactive intestinal polypeptide-immunoreactive oval cells with round unstained nuclei and a faintly granular cytoplasm were scattered in the muscle in all regions and were concentrated in the planes of the plexuses. Vasoactive intestinal polypeptide content of muscularis propria in the smooth muscle esophageal body exceeded (p less than or equal to 0.05) that in the striated muscle esophageal body and the sphincter region, but contents in the latter two regions did not differ (p greater than or equal to 0.05). Mucosal content exceeded that of muscularis propria. The broad distribution and diversity of immunoreactive structures suggest that VIP may have functions in this organ besides the regulation of smooth muscle.

To determine the site of endogenous release of gastric inhibitory polypeptide (GIP), glucose perfusions (556 mmoles per liter) of duodenum, proximal jejunum, midjejunum, and ileum were performed in human volunteers using an occluding balloon perfusion technique. Preperfusion GIP concentrations were below assay sensitivity (125 pg per ml) in all subjects. After glucose perfusion, maximal serum GIP concentrations for the four groups were: duodenum, 1383 +/- 152 pg per ml; proximal jejunum, 904 +/- 87 pg per ml; midjejunum, 545 +/- 91 pg per ml, and ileum 305 +/- 38 pg per ml. Integrated GIP secretion was significantly greater with duodenal perfusion (111 +/- 21 ng-min ml-1) d proximal jejunal perfusion (69 +/- 5 ng-min ml-1), as compared to either midjejunal (47 +/- 7 ng-min ml-1) or ileal (25 +/- 6 ng-min ml-1) perfusions. Peak serum insulin concentrations and integrated insulin secretion were also significantly greater with perfusion of the duodenum or proximal jejunum. Serum glucose concentrations, integrated serum glucose, and glucose absorption were similar for the four areas perfused. The results of this study indicate that the proximal small intestine is the primary site of endogenous GIP release in man, but that smaller quantities are also released by the distal small bowel.

Pancreatic islet peptides, as well as other gastrointestinal hormones, have been implicated in both the pathogenesis of obesity and the etiology of associated metabolic derangements. This study evaluated the pancreatic islet and gastrointestinal (GI) hormone response to oral glucose in 20 morbidly obese (151% above ideal body weight) patients. Glucose intolerance, hyperinsulinism, and exaggerated gastric inhibitory polypeptide (GIP) release occurred following glucose ingestion. Significant release of PP occurred in 14 patients, while only six patients had release of somatostatin. No significant changes in plasma concentrations of glucagon occurred. Since GIP is insulinotropic in the presence of hyperglycemia, the hyperinsulinism of morbid obesity may be secondary to the abnormally high glucose-stimulated GIP levels in these patients. Failure of glucagon suppression in response to oral glucose many contribute to the hyperglycemia noted. Somatostatin and pancreatic polypeptide may be responsible for some of the metabolic derangements of morbid obesity.

Changes in serum total amylase, pancreas-specific isoamylase and pancreatic polypeptide activities were measured in six dogs following multiple intramuscular injections of xylazine at 0.5 mg/kg of body weight. The activities of those analytes did not change over 24 hours of study.

Vasoactive intestinal peptide (VIP) levels were quantified by radioimmunoassay in three strata of hamster bowel wall, namely, epithelial cells isolated by a vibration technique, scrapings of the vibrated intestine, and in the remaining muscle. Expressed on a wet weight basis, highest levels of the peptide (as a percentage of total bowel wall content) were found in the muscle (72%) followed by high levels in scrapings of denuded villi (27%). Villus and crypt epithelial cells, isolated as one fraction, contained very low levels (less than 1%) of total VIP. To correct for differences in water content of the various strata, data were also calculated on the basis of tissue protein. When expressed in this manner, scrapings of denuded villi and the remaining muscle, both areas of dense autonomic innervation, were virtually equal in their VIP content (mean +/- SE, 9.5 +/- 4 and 11 +/- 2 ng per mg of protein, respectively). However, the VIP concentration of the cells was over two orders of magnitude less than the muscle or scrapings of denuded villi (0.02 +/- 0.007 ng per mg of protein). These results suggest that VIP is concentrated with or near the neural elements of the gut.

Twelve carbohydrate-sensitive and 12 normal men were selected for the study. Carbohydrate-sensitivity was based on an abnormal insulin response to a sucrose load. The subjects were fed a diet consisting of 45% of the calories as carbohydrate, 40% fat and 15% protein for 5 days prior to a sucrose or invert sugar tolerance test. In a crossover design, subjects were given 2 g/kg body weight of sucrose or invert sugar, and responses of insulin, glucose, fructose and gastric inhibitory polypeptide (GIP) were determined. Blood samples were taken at 0, 0.5, 1, 2 and 3 hours after being given the test loads. Insulin and glucose levels were significantly higher in carbohydrate-sensitive as compared to normal men. Glucose and GIP did not show any significant differences between the two carbohydrate loads. At 1 hour, the carbohydrate-sensitive men given sucrose had significantly higher insulin levels than carbohydrate-sensitive men given invert sugar (disaccharide effect). At 1, 2 and 3 hours, the disaccharide effect was shown in the fructose levels of the carbohydrate-sensitive men. In normal men, the disaccharide effect with levels of fructose was seen at 0.5 and 3 hours. This study indicates that the disaccharide effect on blood insulin cannot be explained by differences in gastric inhibitory polypeptide in unadapted human subjects.

This study evaluates the hypothesis that cholecystokinin (CCK) relaxes the sphincter of Oddi via vasoactive intestinal polypeptide (VIP). Isolated canine sphincter of Oddi were suspended in organ baths under standard conditions. Responses to cholecystokinin octapeptide (CCK-8) and VIP were recorded on a pen recorder via an isometric transducer. 10(-11)-10(-7) M CCK-8 and 4 X 10(-11)-5 X 10(-7) M VIP generated dose-related sphincter of Oddi relaxation, which was unaffected by atropine, propranolol, and phentolamine. The effect of CCK-8 was antagonized by dibutyryl cGMP (Bt2 cGMP) (10(-3) M), the VIP-antagonist (N-Ac-Tyr1, D-Phe2)-growth hormone-releasing factor-(1-29)-NH2, and abolished by tetrodotoxin. In contrast, VIP's relaxing action was tetrodotoxin insensitive. 10(-11)-10(-7) M CCK-8 stimulated dose-dependent release of VIP (0.5-2.2 fm/ml.mg tissue), which was not inhibited by atropine, propranolol, and phentolamine, but was antagonized by 10(-3) M Bt2 cGMP and tetrodotoxin. In addition CCK-8 and VIP generated dose-related (10(-10)-10(-7) M) increases in sphincter of Oddi cAMP levels that were not affected by atropine, propranolol, and phentolamine. Furthermore, 10(-5)-10(-2) M 8-bromo-cAMP caused dose-dependent relaxation of the sphincter of Oddi. In separate studies, a 2-h incubation in physiological solution containing 12 parts/1,000 of rabbit VIP antiserum antagonized sphincter relaxation caused by 4 nM CCK-8 and 6 nM VIP. The antiserum also significantly decreased the sphincter of Oddi cAMP level stimulated by 4 nM CCK-8 by 48 +/- 15%. These studies demonstrate that CCK-8 relaxes the canine sphincter of Oddi via a noncholinergic, nonadrenergic neural pathway involving VIP. The intracellular mechanism mediating CCK/VIP relaxation involves generation of cAMP.

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.