gastrins and Insulinoma

Pancreatic neuroendocrine tumors (PNETs) are rare neoplasms representing <5% of all pancreatic malignancies with an estimated incidence of 1-1.5 cases/100,000. PNETs are broadly classified as either functional or nonfunctional. Functional PNETs include insulinomas, gastrinomas, vasoactive intestinal peptideomas, glucagonomas, and somatostatinomas. The clinical manifestations associated with these tumors are the result of excessive hormonal secretion and action. The functional nature of these tumors makes pancreatic hormone testing critical not only for initial diagnosis but also for follow-up, because they are important tumor markers. Nonfunctional PNETs typically remain clinically silent until a substantial mass effect occurs. Although the majority of PNETs occur sporadically, it is important to recognize that these tumors may be associated with a variety of familial syndromes and in many cases genetic testing of PNET patients is warranted. This article familiarizes the reader with the clinical presentation and the biochemical, radiologic, and genetic testing indicated for diagnosis and follow-up of patients with PNET.

Topics: Gastrinoma; Gastrins; Glucagon; Glucagonoma; Hormones; Humans; Hypoglycemia; Insulinoma; Neuroendocrine Tumors; Pancreatic Neoplasms; Somatostatinoma; Vasoactive Intestinal Peptide; Vipoma

Several circulating or urinary tumour markers can be used for the diagnosis and follow-up of functioning and clinically non-functioning neuroendocrine tumours of the pancreatic islet cells and intestinal tract. Among the specific tumour markers are serotonin and its metabolites--e.g. 5-hydroxyindoleacetic acid (5-HIAA)--in carcinoid tumours and the carcinoid syndrome, insulin and its precursors or breakdown products in insulinoma, and gastrin in gastrinoma. Plasma vasointestinal polypeptide (VIP) determinations have been used in the diagnosis of VIPoma, plasma glucagon for glucagonoma, and serum somatostatin for somatostatinoma. Among the tumour-non-specific markers are: chromogranins, neuron-specific enolase (NSE), alpha-subunits of the glycoprotein hormones, catecholamines, pancreatic polypeptide (PP), ghrelin and adrenomedullin.

Topics: Biomarkers; Biomarkers, Tumor; Carcinoid Tumor; Gastrinoma; Gastrins; Humans; Insulin; Insulinoma; Malignant Carcinoid Syndrome; Neuroendocrine Tumors; Pancreatic Neoplasms; Serotonin

Topics: Biomarkers; Diagnosis, Differential; Diagnostic Imaging; Diagnostic Techniques, Digestive System; Gastrinoma; Gastrins; Glucagonoma; Humans; Insulinoma; Laparoscopy; Neuroendocrine Tumors; Pancreatic Neoplasms; Receptors, Somatostatin; Secretin

Japanese clinicians and scientists have contributed significantly to reporting, investigating, and managing patients with pancreatic endocrine tumors and other multiple endocrine neoplasias for the past several decades. This article summarizes the latest progress in this field in Japan. Particularly, our contribution to the development of diagnostic and localization methods is reviewed. Further, the present use of somatostatin receptor scintigraphy and the application of the laparoscopic surgery for pancreatic endocrine tumor in Japan are discussed.

Topics: Calcium; Gastrinoma; Gastrins; Injections, Intra-Arterial; Injections, Intravenous; Insulinoma; Japan; Laparoscopy; Pancreas; Pancreatic Neoplasms; Receptors, Somatostatin; Secretin; Zollinger-Ellison Syndrome

Duodenal and pancreatic endocrine tumors are uncommon and their surgical treatment is often difficult. The management of these tumors has changed with recent advancements in tumor localization, intraoperative hormone measurements, standardized surgical techniques, and a better understanding of the genetic basis of multiple endocrine neoplasia syndrome. We present our experience with 191 endocrine tumors and elaborate the contemporary management of functioning duodenopancreatic endocrine tumors.

Topics: Duodenal Neoplasms; Endosonography; Gastrinoma; Gastrins; Gastrointestinal Agents; Humans; Insulinoma; Liver Neoplasms; Magnetic Resonance Imaging; Multiple Endocrine Neoplasia Type 1; Octreotide; Pancreatectomy; Pancreatic Neoplasms

Topics: Calcium; Calcium-Binding Proteins; Gastrinoma; Gastrins; Glucagonoma; Humans; Infusions, Intra-Arterial; Insulinoma; Pancreatic Function Tests; Pancreatic Neoplasms; Receptors, G-Protein-Coupled; Receptors, Gastrointestinal Hormone; Secretin; Vipoma

Topics: Adenoma; Carcinoid Tumor; Endocrine System Diseases; Gastrins; Gastrointestinal Diseases; Glucagonoma; Histocytochemistry; Humans; Hyperinsulinism; Immunochemistry; Insulinoma; Islets of Langerhans; Pancreatic Diseases; Pancreatic Neoplasms; Peptic Ulcer; Somatostatinoma; Stomach; Vipoma

Topics: Adenoma, Islet Cell; Gastrins; Humans; Insulin; Insulin Secretion; Insulinoma; Pancreatectomy; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

We report a rare case of functional insulinomas in a 16.7-year-old female Rhesus macaque (Macaca mulatta) that was presented with neuroglycopenic signs to the breeding colony hospital at the Tulane National Primate Research Center. At initial and follow-up examinations, the animal was consistently hypoglycaemic and was clinically maintained with additional fruits, other high-sugar food items and dextrose supplementation. Occasional episodes of seizure and collapse resolved quickly on administration of high-sugar food items. At necropsy, the uncinate process of the pancreas had a 2.2 cm diameter, red, round, firm neoplastic mass, and another neoplasm was identified on histological examination of the head of pancreas. Histologically, neoplastic cells exhibited neuroendocrine packeting, resembled pancreatic islet cells and immunolabelled for chromogranin A, synaptophysin and insulin but not for somatostatin, gastrin or pancreatic polypeptide. A few cells immunolabelled for glucagon. The clinical signs and gross and histological findings were consistent with functional insulinomas.

Topics: Animals; Chromogranin A; Female; Gastrins; Glucagon; Glucose; Hypoglycemic Agents; Insulinoma; Insulins; Macaca mulatta; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatin; Sugars; Synaptophysin

The cholecystokinin-2 receptor (CCK2R), is expressed in cancers where it contributes to tumor progression. The CCK2R is over-expressed in a sub-set of tumors, allowing its use in tumor targeting with a radiolabel ligand. Since discrepancies between mRNA levels and CCK2R binding sites were noticed, we searched for abnormally spliced variants in tumors from various origins having been previously reported to frequently express cholecystokinin receptors, such as medullary thyroid carcinomas, gastrointestinal stromal tumors, leiomyomas and leiomyosarcomas, and gastroenteropancreatic tumors. A variant of the CCK2R coding for a putative five-transmembrane domains receptor has been cloned. This variant represented as much as 6% of CCK2R levels. Ectopic expression in COS-7 cells revealed that this variant lacks biological activity due to its sequestration in endoplasmic reticulum. When co-expressed with the CCK2R, this variant diminished membrane density of the CCK2R and CCK2R-mediated activity (phospholipase-C and ERK activation). In conclusion, a novel splice variant acting as a dominant negative on membrane density of the CCK2R may be of importance for the pathophysiology of certain tumors and for their in vivo CCK2R-targeting.

Topics: Alternative Splicing; Amino Acid Sequence; Animals; Binding Sites; Carcinoma, Medullary; Chlorocebus aethiops; Cholecystokinin; COS Cells; Extracellular Signal-Regulated MAP Kinases; Gastrins; Gastrointestinal Neoplasms; Gastrointestinal Stromal Tumors; Humans; Insulinoma; Leiomyoma; Leiomyosarcoma; Molecular Sequence Data; Pancreatic Neoplasms; Protein Structure, Tertiary; Receptor, Cholecystokinin B; RNA, Messenger; Signal Transduction; Thyroid Neoplasms; Type C Phospholipases

The insulinoma syndrome is marked by fasting hypoglycemia and inappropriate elevations of insulin. The gastrinoma syndrome is characterized by hypergastrinemia, ulcer disease, and/or diarrhea. Rarely, insulinoma and gastrinoma coexist in the same patient simultaneously.. Our objective was to determine the cause of a patient's hypoglycemic episodes and peptic ulcer disease.. This is a clinical case report from the Clinical Research Center of the National Institutes of Health.. One patient with hypoglycemic episodes and peptic ulcer disease had a surgical resection of neuroendocrine tumor.. The patient was found to have a single tumor cosecreting both insulin and gastrin. Resection of this single tumor was curative.. A single pancreatic neuroendocrine tumor may lead to the expression of both the hyperinsulinemic and hypergastrinemic syndromes.

Topics: Adolescent; Female; Gastrinoma; Gastrins; Humans; Insulin; Insulinoma; Neuroendocrine Tumors; Pancreatic Neoplasms; Syndrome

Expression of gastrin, a gut hormone and growth factor, has tissue-specific transcriptional regulation and can be induced in some tumors. Previous studies have shown that a CACC cis-regulatory element is important for transcriptional activation in pancreatic insulinoma cells. To identify CACC-binding proteins, a lambda phage cDNA library derived from a rat insulinoma cell line, RIN 38A, was screened by a Southwestern method. A novel member of the Cys2-His2 zinc finger gene family was cloned and designated RIN ZF, having a cDNA sequence of 3.8 kilobases. One full-length and a shorter splice variant were sequenced and had predicted protein masses of 91.6 and 88.7 kDa. Expression of both splice forms were ubiquitous in fetal and adult rat tissues. Recombinant RIN ZF protein exhibited sequence-specific binding to the gastrin CACC element in a gel mobility shift assay. In transient transfections, both splice variants appeared to have only weak activating effects on gastrin-luciferase reporter gene transcription. Furthermore, RIN ZF coexpression with Sp1 appeared to block the strongly activating effects of Sp1 mediated through the CACC element. These findings suggest that a novel set of zinc finger proteins may help regulate gastrin gene expression by interfering with Sp1 transactivation.

Topics: Amino Acid Sequence; Animals; Base Sequence; Cloning, Molecular; DNA-Binding Proteins; Gastrins; Genes, Reporter; Insulinoma; Molecular Sequence Data; Open Reading Frames; Polymerase Chain Reaction; Promoter Regions, Genetic; Rats; RNA, Messenger; Tumor Cells, Cultured; Zinc Fingers

Interferon-alpha (IFN alpha) may exert direct inhibitory effects on cell proliferation and on the production of different peptide hormones. We investigated the effect of IFN alpha on hormone production by 15 GH-secreting pituitary adenomas, 4 clinically nonfunctioning or gonadotroph pituitary adenomas, and 4 prolactinomas in vitro. In the GH-secreting pituitary adenoma cultures, a short term (72-h) incubation with IFN alpha (50-100 U/mL) significantly inhibited GH secretion in 3 of 7 cases and PRL secretion in 6 of 7 cultures. During prolonged incubation (14 days) with IFN alpha, GH and/or PRL secretion was significantly inhibited in 7 of 8 cultures (GH, 17-78% inhibition; PRL, 39-88% inhibition). In the clinically nonfunctioning or gonadotroph cultures, incubation with IFN alpha resulted in inhibition of the secretion of gonadotropins and/or alpha-subunit in all cases (27-62%), whereas in the prolactinoma cultures PRL secretion was inhibited by IFN alpha in all cases (37-76%). The effect of IFN alpha was additive to the inhibitory effects of the dopamine agonist bromocriptine (10 nmol/L) or the somatostatin analog octreotide (10 nmol/L). The inhibition of hormone secretion by IFN alpha was accompanied by inhibition of the intracellular hormone concentrations. The effect of IFN alpha was dose dependent, with an IC50 for inhibition of hormone secretion of 2.3 +/- 0.3 U/mL (n = 5), which is relatively low compared with the concentrations that are reached in patients treated with IFN alpha for various malignancies. In conclusion, the potent antihormonal effect of IFN alpha on cultured pituitary adenomas suggests that this drug might be of benefit in the treatment of selected patients with secreting pituitary adenomas. As treatment with IFN alpha is associated with considerable adverse reactions, studies with this drug should only be considered in inoperable, invasive aggressive, and dopamine agonist- and/or somatostatin analog-resistant functioning pituitary macroadenomas.

Topics: Adenoma; Bromocriptine; Dopamine Agonists; Gastrinoma; Gastrins; Human Growth Hormone; Humans; Insulin; Insulin Secretion; Insulinoma; Interferon alpha-2; Interferon-alpha; Octreotide; Pancreatic Neoplasms; Pituitary Neoplasms; Prolactin; Prolactinoma; Recombinant Proteins; Somatostatin; Tumor Cells, Cultured

Topics: Adult; Female; Gastrins; Gastritis; Humans; Insulinoma; Pancreatic Neoplasms; Pancreatitis; Syndrome

Amidated gastrins are acid secretagogues and growth factors. Their precursor, progastrin, is a growth factor but not a secretagogue. Cleavage of progastrin at Arg94/95 determines the expression of these two alternative patterns of biological activity. We examined the hypothesis that cleavage at Arg94/95 is regulated by phosphorylation of the adjacent Ser96 residue.. Hamster insulinoma cells were stably transfected with wild-type rat preprogastrin and phosphorylation site mutants; biosynthesis was studied by a pulse-chase protocol.. Rates of cleavage at Arg94/95 were increased in Ser96-->Ala compared with wild-type progastrin. Mutation of Glu98 to Ala inhibited incorporation of [32P]phosphate into progastrin and increased the rate of cleavage at Arg94/95. Conversely, mutation of Ser96 to Asp reduced rates of cleavage at Arg94/95. Depletion of calcium stores decreased phosphorylation of Ser96 and increased cleavage at Arg94/95. Modulation of Ser96 phosphorylation also directly influenced the ratio of progastrin-cleavage products (progastrin/CFP; G17Gly/G34Gly) secreted into the medium.. Phosphorylation of progastrin is dependent on calcium stores, determines prohormone cleavage rates, and thereby controls the production of the alternative active products of preprogastrin translation.

Topics: Amino Acid Sequence; Animals; Calcium; Casein Kinases; Cricetinae; Gastrins; Insulinoma; Mutation; Peptide Fragments; Phosphorylation; Protein Kinases; Protein Precursors; Rats; Transfection; Tumor Cells, Cultured

To improve the clinical diagnosis and treatment of gastrinoma.. Twelve cases of gastrinoma found in the recent 30 years in our hospital were analyzed.. The results indicated that in addition to the typical symptoms related to gastric acid overproduction, the frequency of certain uncommon features characteristic of the disease was unusually high in our hands i.e., (1) The majority of them (7/12) had serious diarrhea, even resulting in shock. (2) Multiple endocrine neoplasia type I (MEN) was in 3 out of 12 associated in our series. (3) Multiple nodules in the duodenum (3/12) were found and in two patients were shown to be submucosal gastrinoma confirmed by pathology. (4) Multifocal lesions were found in 9 out of 12 patients, and in 7 cases at least two organs were involved. Most gastrinomas were located in the pancreas, stomach and duodenum. (5) As reported by other authors, multiple hormone secretion was common: in five of six patients the tumor secreted more than two hormones. (6) In some cases, tumors were sensitive to chemotherapy.. In our series gastrinoma was found with the feature of multiple lesions and multiple hormone secretion in addition to the typical symptoms related to gastric acid overproduction.

Topics: Adolescent; Adult; Diarrhea; Duodenal Neoplasms; Duodenal Ulcer; Female; Gastrinoma; Gastrins; Humans; Insulinoma; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatic Neoplasms; Somatostatin; Stomach Neoplasms

The gastrin gene is transiently expressed in fetal pancreatic islets during islet neogenesis but then switched off after birth when islet cells become fully differentiated. Previous studies identified a cis-regulatory sequence between -109 and -75 in the human gastrin promoter which binds islet cell-specific activators and a nonspecific repressor and thus may act as a molecular switch. The present study identified another cis-regulatory sequence (-163ACACTAAATGAAAGGGCGGGGCAG-140) which bound two islet nuclear proteins in a mutually exclusive manner, as defined by gel shift competition, methylation interference, and DNase I foot-printing assays. The general transactivator Sp1 recognized the downstream GGGCGGGG sequence, but Sp1 binding was prevented when another islet factor bound to the adjacent AT-rich sequence (CTAAATGA). This gastrin AT-rich element is nearly identical to the binding site (ATAAATGA) for the islet-specific transcription factor beta TF-1. However, the gastrin AT-binding factor appeared to differ from beta TF-1 in its gel mobility shift pattern. Transfections of rat insulinoma cells revealed that mutations which blocked binding to the AT-rich element but allowed Sp1 binding up-regulated transcriptional activity. These results suggest that the gastrin AT-binding factor blocks transactivation by Sp1 and may have a role in the repression of gastrin transcription seen at the end of islet differentiation.

Topics: Adenine; Animals; Base Sequence; Gastrins; Gene Expression Regulation; Humans; Insulinoma; Islets of Langerhans; Molecular Sequence Data; Mutagenesis; Oligodeoxyribonucleotides; Promoter Regions, Genetic; Protein Binding; Rats; Regulatory Sequences, Nucleic Acid; Sp1 Transcription Factor; Thymine; Transcription, Genetic; Tumor Cells, Cultured

Gastrin gene expression in the pancreatic islets is developmentally regulated and occurs largely during fetal life. Deletional analysis of transiently transfected rat insulinoma cells with gastrin 5'-flanking sequences in luciferase reporter genes demonstrated that the gastrin promoter sequence proximal to -111 base pairs (bp) contains the cis-regulatory elements necessary for maximal transcription. Mutational analysis identified the sequence CCCCACCCCA (-109 to -100 bp) as a positive cis-regulatory element (CACC) located 5' to a previously described negative element (-100 to -90 bp) and E-box positive element at -82 bp. Multimers of the CACC element in a heterologous promoter activated transcription independent of the other cis-regulatory elements. CACC binding proteins were purified from insulinoma cell nuclear extracts by cation exchange and affinity chromatography. Southwestern blot of nuclear extracts identified a 70-kDa CACC-binding protein. Mutational analysis of the CACC element showed a close correlation between DNA binding of this protein and transcriptional activation. Transcriptional activation by multimers of the CACC element in a heterologous promoter was detected in a variety of cell lines but was strongest in those of islet lineage. Likewise, the presence of the 70-kDa CACC-binding protein was found in many cell lines but was most abundant in the insulinoma cells. The CACC-binding protein has not been previously identified among the known pancreatic regulatory factors and may have an important role in the developmental expression of gastrin.

Topics: 3T3 Cells; Animals; Base Sequence; Cell Line; DNA Mutational Analysis; DNA-Binding Proteins; Gastrins; Gene Expression Regulation, Neoplastic; Humans; Immunoblotting; Insulinoma; Islets of Langerhans; Mice; Molecular Sequence Data; Molecular Weight; Nuclear Proteins; Pancreatic Neoplasms; Polymerase Chain Reaction; Promoter Regions, Genetic; Rats; Regulatory Sequences, Nucleic Acid; Sequence Deletion; Substrate Specificity; Transcription, Genetic; Transfection; Tumor Cells, Cultured

We reviewed the age of presentation, malignant potential, and outcome of gastrinomas and pancreatic tumors in patients with multiple endocrine neoplasm, type 1.. Screening of one very large and one smaller, possibly related family on an island, including serum gastrin estimations and, when indicated, pancreatic ultrasound.. Over 2000 family members and their family physicians were advised on screening procedures.. Data were collected and reviewed retrospectively and prospectively for all medical records, investigations, surgical procedures, and available tissue samples.. Criteria for diagnosis were established for radiological, biochemical, and histological studies.. Sixty-two patients had evidence of gastrinoma or pancreatic neoplasm. In 19 patients the diagnosis was based on demonstration of a tumor. In 21 patients the diagnosis was based on elevated serum gastrin concentration in the absence of demonstrable tumor. None of these patients required gastric surgery if they first underwent parathyroidectomy. In 18 patients the diagnosis was based on the combination of demonstrated pancreatic tumor plus elevated glucagon (two patients), gastrin (11 patients), or insulin (five patients) concentration. Peptic ulcer was difficult to control in seven of the 11 patients with elevated gastrin concentrations plus demonstrated tumor. Four patients had liver metastases that appeared to be secondary to the pancreatic gastrinoma. In patients with insulinomas, the first symptoms occurred before age 20 years. Elevated serum gastrin concentrations were not seen before age 24 years and were observed to occur for the first time in two patients after age 50 years.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Female; Follow-Up Studies; Gastrinoma; Gastrins; Glucagon; Humans; Insulin; Insulinoma; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Prospective Studies; Retrospective Studies; Zollinger-Ellison Syndrome

Our previous studies have shown that increased expression of GLUT1/erythrocyte and GLUT3/brain type glucose transporter genes in human tumors is associated with cellular transformation. We have now determined the levels of messenger RNAs (mRNAs) encoding these two glucose transporter isoforms as well as that of GLUT2/liver isoform in insulin-, glucagon-, and gastrin-secreting islet cell tumors. Northern blot analysis and reverse transcriptase-polymerase chain reaction revealed the presence of GLUT1 and GLUT3 mRNA in all human islet cell tumors and normal islets examined. In contrast, GLUT2 mRNA, which is present at high levels in normal islets, was not detected in insulinomas or other types of islet cell tumors. These results imply that GLUT1 and GLUT3 are primarily responsible for glucose uptake by these tumors.

Topics: Base Sequence; Female; Gastrinoma; Gastrins; Gene Expression; Gene Expression Regulation, Neoplastic; Glucagon; Glucagonoma; Humans; Insulin; Insulinoma; Male; Middle Aged; Molecular Sequence Data; Monosaccharide Transport Proteins; Oligodeoxyribonucleotides; Pancreatic Neoplasms; Polymerase Chain Reaction; RNA, Messenger

Somatostatin, gastrin-releasing peptide (GRP) and gastrin were measured in the stomach of rats with streptozotocin-induced diabetes, insulinoma-bearing rats and their respective controls. Rats injected with streptozotocin exhibited hyperphagia, insulinopenia and severe hyperglycemia. Stomach weights, and the concentrations and total amounts of GRP and gastrin in the stomach, were similar to nondiabetic control rats. The concentration of somatostatin in the stomach of diabetic rats was 25% greater, but the total stomach content of somatostatin was similar to that of control rats. Insulinoma-bearing rats exhibited hyperphagia, hyperinsulinemia and hypoglycemia. Concentrations of GRP and gastrin in the stomach were 72% and 19% lower, respectively, than in control rats. Despite 45% greater stomach weight, the total stomach content of GRP was 61% lower. Stomach concentrations of somatostatin, and total stomach contents of somatostatin and gastrin, were similar in insulinoma-bearing and control rats. The results demonstrate abnormalities in the stomach concentrations of regulatory peptides in rats with diabetes and insulinoma. These abnormalities are not attributable to changes in food intake alone, suggesting specific effects of these metabolic diseases on gastric regulatory peptides and gastric function.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Gastric Mucosa; Gastrin-Releasing Peptide; Gastrins; Hyperphagia; Insulin; Insulinoma; Male; Organ Size; Peptides; Rats; Rats, Inbred Strains; Somatostatin; Stomach

The insulinoma is the most common pancreas tumour with endocrine activity, with more than 2,000 cases being described in the literature worldwide. The first successful extirpation was performed by Graham in 1928. Clinical appearance is characterized by severe paroxysmal hypoglycaemia together with inadequately increased serum insulin levels. Surgery is indicated in such situations because of limited effectiveness of medicamentous therapy. Surgical approach and long-time results are discussed in this paper, with reference being made to 13 cases of the authors.

Topics: Adenoma, Islet Cell; Adult; C-Peptide; Female; Follow-Up Studies; Gastrins; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Neoplasm Recurrence, Local; Pancreatectomy; Pancreatic Neoplasms; Postoperative Complications; Reoperation

The gastrin gene is expressed in fetal pancreatic islet cells, but after birth expression is selectively repressed as the islets terminally differentiate. DNA transfection studies identified a cis regulatory domain between -108 and -76 in the gastrin promoter which controls gastrin transcription in islet cells. This cis regulatory domain comprises adjacent positive and negative elements. The negative element (-108 to -82) contains the sequence ATTCCTCT, which is also found in the negative element of the beta-interferon promoter. Gel retardation assays and DNase footprinting studies demonstrated that specific islet nuclear protein(s) bind to the gastrin negative element. In vivo competition studies demonstrated that the trans-acting factors which bind to this element specifically repress gastrin promoter activity in islet cells. Immediately downstream of the negative element lies a positive element (-82 CATATGG -76), which activates gastrin transcription in islet cells. The sequence of the positive element resembles the islet-specific enhancer elements of the insulin gene (CATCTGG/C). Gel mobility shift assays and in vivo competition studies indicate that this positive element activates the gastrin promoter by binding to the same islet cell transcription factor which binds enhancer elements in the rat insulin gene. The tandem organization of the negative and positive elements suggests that this regulatory domain may act as a switch controlling the transient transcription of the gastrin gene during fetal islet development.

Topics: Animals; Base Sequence; Cell Line; Cells, Cultured; Exons; Fetus; Gastrins; Genes, Regulator; Insulinoma; Islets of Langerhans; Molecular Sequence Data; Oligonucleotide Probes; Pancreatic Neoplasms; Plasmids; Promoter Regions, Genetic; Rats; Restriction Mapping; Transfection

The authors demonstrate three patients--two with a nesidioma of the B-cells with insulin production, the third had a nesidioma made up of non-B cells with clinical manifestations of gastrin hypersecretion. The surgical solution was successful in the patients with B-cell nesiodiomas.

Topics: Adolescent; Adult; Epilepsy; Female; Gastrins; Humans; Insulin; Insulin Secretion; Insulinoma; Male; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

Over a five-year period, we measured concentrations of gut hormones in plasma samples from 353 patients in whom diagnoses of pancreatic endocrine tumors were subsequently confirmed. A median of 19 months (range, 7 to 120) after the initial diagnosis, 24 of these patients (6.8 percent) had elevated concentrations of other hormones in association with new clinical symptoms. In 13 of these patients (8 with glucagonomas, 3 with tumors secreting vasoactive intestinal polypeptide, and 2 with insulinomas), hypergastrinemia developed along with the clinical features of a gastrinoma; 5 patients died of gastrointestinal perforation or bleeding, apparently caused by this second tumor. We conclude that patients with pancreatic endocrine tumors, regardless of their initial clinical picture, require continued surveillance for new elevations of hormones.

Topics: Adenoma, Islet Cell; Adult; Aged; Gastrins; Gastrointestinal Hemorrhage; Glucagon; Glucagonoma; Hormones; Humans; Insulinoma; Middle Aged; Pancreatic Neoplasms; Time Factors; Vasoactive Intestinal Peptide; Vipoma; Zollinger-Ellison Syndrome

The symptoms resulting from the hyperinsulinemia of severe refractory metastatic insulinoma were palliated using self-administered divided doses of a long-acting minisomatostatin analog, octreotide. The substance was well tolerated and the attributable side effects were minimal (primarily gastrointestinal complaints). There were significant improvements in peripheral edema, ascites, and serum electrolytes throughout therapy. Serum insulin and glucagon levels were largely unchanged. Computed tomography scans performed during therapy showed stabilization of pancreatic and hepatic disease. Severe, recurrent hypoglycemic episodes due to hyperinsulinemia were reduced both in number and severity for almost a three-month period. This allowed the elimination or reduction of other chronic, supportive medications and improved quality of life.

Topics: Adenoma, Islet Cell; Antineoplastic Agents; Drug Resistance; Female; Gastrins; Glucagon; Humans; Insulin; Insulinoma; Middle Aged; Neoplasm Metastasis; Octreotide; Pancreatic Neoplasms; Somatostatin

Topics: Adenoma, Islet Cell; Blood Glucose; Female; Gastrins; Humans; Insulinoma; Male; Octreotide; Pancreatic Neoplasms; Somatostatin; Vipoma; Zollinger-Ellison Syndrome

Topics: Adenoma, Islet Cell; Gastrectomy; Gastric Mucosa; Gastrins; Humans; Insulinoma; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Zollinger-Ellison Syndrome

One hundred twenty-seven insulinomas from 95 cases (1 malignant and 94 benign) were studied pathologically. Thirty-six tumors (35 cases) were examined by electron microscopy. Typical beta-cell secretory granules of crystalloid-form cores and/or atypical secretory granules were discerned in all tumors examined. A new type of secretory granule, with high electron-dense crystalloid-form cores and moderate electron-dense granular substance filling the space between the core and the limiting membrane, were observed in two cases. Among 68 insulinomas (67 cases) subjected to immunocytochemical investigations with ten peptide hormones (insulin, glucagon, somatostatin, pancreatic polypeptide (PP), gastrin, motilin, secretin, vasoactive intestinal polypeptide (VIP), gastric inhibitory polypeptide (GIP), and neurotensin), 42 were found to be multihormonal, varying from two to four peptides secreted. The hormones contained were insulin, glucagon, PP, somatostatin, and gastrin in different combinations. One patient had hyperinsulinemia and hypergastrinemia concurrently, and two islet tumors were excised at an interval of 10 months. Both electron microscopy and immunocytochemistry confirmed the presence of beta- and alpha-cells in the first tumor, whereas the second tumor revealed only G-cells by electron microscopy, and G- and beta-cells on immunocytochemical staining. The morphologic and immunocytochemical characteristics of the insulinomas in this series are discussed.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Cytoplasmic Granules; Female; Gastrins; Hormones; Humans; Immunoenzyme Techniques; Insulin; Insulinoma; Male; Microscopy, Electron; Middle Aged; Pancreatic Neoplasms

37 patients suffering from apudomas of the pancreas are reported (18 insulinomas, 6 isletcell-hyperplasias, 9 Zollinger-Ellison syndroms, 1 glucagonoma, 3 without hormone production). In preoperative localization computerized tomography and angiography were the best with 65% positive findings. Insulinomas were enucleated, all free of recidives. 50% of operated isletcell hyperplasias had a postoperative resisting hyperinsulinism. Either gastrectomy or tumour enucleation was performed in the Zollinger-Ellison syndrome. The five-years survival rate was 43%.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Child; Female; Follow-Up Studies; Gastrectomy; Gastrins; Glucagon; Humans; Hyperplasia; Insulin; Insulinoma; Islets of Langerhans; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Postoperative Complications; Stomach Neoplasms; Zollinger-Ellison Syndrome

Topics: APUD Cells; Apudoma; Gastric Inhibitory Polypeptide; Gastrins; Glucagon; Glucagon-Like Peptides; Humans; Insulin; Insulinoma; Motilin; Pancreatic Neoplasms; Secretin

In three families with the multiple endocrine adenomatosis type I (MEA I) trait, 51 members were investigated by measurement of circulating peptide hormones as tumor markers. Twenty-five of 51 members (49 percent) were considered to be affected by MEA I disorders. The incidence rose with age (75 percent in generation II). Both sexes were affected equally. Hyperparathyroidism was present in 20 of 25 affected members (80 percent), and pituitary tumors (prolactinomas) were found in four of 25 (16 percent). Endocrine pancreatic tumors were found in nine of 25 affected members (36 percent), but when "probable" tumors (seven) are included the frequency rises to 72 percent. Hyperparathyroidism was found in all except one member with proved lesions in other organs. Among patients with proved and possible endocrine pancreatic tumors, elevated serum levels of gastrin and pancreatic polypeptide were frequently found, 78 percent and 67 percent, respectively, and we suggest that serum gastrin and pancreatic polypeptide levels are the most useful screening markers at present for pancreatic lesions in MEA I.

Topics: Adenoma; Adolescent; Adult; Age Factors; Aged; Female; Gastrins; Humans; Hyperparathyroidism; Insulinoma; Liver Neoplasms; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Pancreatic Polypeptide; Parathyroid Neoplasms; Pedigree; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome