c-peptide and Adenoma--Islet-Cell

A 76-year-old man, a known case of insulinoma, was well controlled for 11 days on 50 micrograms SMS 201-995 every 12 h; clinical recovery was immediate with normalization of blood sugars and C-peptide levels. The potential value of this new drug in the management of insulinomas is illustrated by this case and by 11 additional case reports which are reviewed. A rise in C-peptide levels during treatment without concomitant hypoglycaemia might be the first indication of a loss of control.

Topics: Adenoma, Islet Cell; Aged; Antineoplastic Agents; Blood Glucose; C-Peptide; Humans; Insulinoma; Male; Octreotide; Pancreatic Neoplasms

Gut peptide secreting tumours originate most commonly from the pancreatic Islets of Langerhans. Tumours at a variety of other sites have also been shown to synthesize and release these peptides, reflecting the wide distribution of the peptide secreting cells of the diffuse neuroendocrine system. Tumours such as the glucagonomas, insulinomas, VIPomas and gastrinomas are associated with characteristic clinical syndromes resulting from the effects of the peptide they secrete. The majority of the islet cell tumours in fact secrete a number of different peptides and many of these are present in several molecular forms, some of which may not be biologically active. This may explain the lack of clinical sequelae in association with tumours such as the somatostatinomas. The clinical features, methods of diagnosis, localisation and treatment of these tumours will be discussed.

Topics: Adenoma, Islet Cell; Bombesin; Bronchial Neoplasms; C-Peptide; Carcinoma, Small Cell; Diagnosis, Differential; Endocrine System Diseases; Erythema; Gastrointestinal Hormones; Glucagon; Glucagonoma; Humans; Insulin; Insulin Secretion; Insulinoma; Male; Neoplasms; Neurotensin; Pancreatic Hormones; Pancreatic Neoplasms; Pancreatic Polypeptide; Somatostatinoma; Vasoactive Intestinal Peptide; Zollinger-Ellison Syndrome

About 8%-15% of the patients with organic hyperinsulinism have an islet cell carcinoma (13% in our series). In addition to a history of complaints of relatively recent onset, the patients present clinically the typical intermittent neurologic-psychiatric symptoms concurrently associated with hypoglycemia. The diagnosis is established biochemically on the basis of hypoglycemia, with inadequate incrementation of the insulin concentration subsequent to suppression and provocation tests. Elevated serum proinsulin and, in most patients, an increased insulin secretion rate are usually found after administration of agents such as glucose or leucine. Localization of the tumors is achieved by selective coeliacography as well as abdominal computerized axial tomography. The islet cell carcinoma is found most frequently in the tail of the pancreas, less frequently in the body and head of the pancreas. Metastatic spread is seen early into adjacent lymph nodes and especially in the liver. The treatment of choice is surgical resection of the tumor. Even in cases with advanced metastatic involvement, surgical intervention appears indicated. Medical treatment includes the administration of diazoxide, long-acting glucagon as well as the cytostatic agent streptozotocin. The average survival time is 30-40 months after diagnosis (in our series 79 months). Thus, the prognosis of patients with islet cell carcinoma appears relatively favorable, especially when compared with adenocarcinoma of the pancreas.

Topics: Adenoma; Adenoma, Islet Cell; C-Peptide; Diagnosis, Differential; Diazoxide; Female; Glucagon; Humans; Hyperinsulinism; Liver Neoplasms; Lymphatic Metastasis; Male; Pancreatic Neoplasms; Prognosis; Proinsulin; Streptozocin

Topics: Adenoma, Islet Cell; Angiography; Antineoplastic Agents; Benzothiadiazines; Blood Glucose; C-Peptide; Catheterization; Diagnosis, Differential; Diazoxide; Epinephrine; Hypoglycemia; Pancreas; Pancreatic Neoplasms; Portal Vein; Proinsulin; Somatostatin; Splenic Vein; Tomography, X-Ray Computed

Topics: Adenoma, Islet Cell; C-Peptide; Humans; Hypoglycemia; Insulin; Pancreatic Neoplasms; Proinsulin

Topics: Adenoma, Islet Cell; Amino Acid Sequence; C-Peptide; Diabetes Mellitus; Humans; Hypokalemia; Immunoassay; Insulin; Insulin Antibodies; Kidney; Pancreatic Neoplasms; Peptides; Proinsulin

The most common cause of organic fasting hypoglycemia in adults is the presence of an insulin-producing pancreatic adenoma, but when high insulin levels are not found, the differential diagnosis is challenging. Misdiagnosis can lead to an unnecessary pancreatectomy. Insulin concentrations may be low in some cases despite a clinical history suggestive of insulinoma. In these cases, a proinsulinoma should be suspected, although the rarity of this condition requires an extensive workup before reaching a final diagnosis. We describe an unusual case of a 38-year-old man with a severe hypoglycemic syndrome due to a proinsulin-secreting pancreatic adenoma. Insulin was measured by the specific assay and suppressed under the lower detection limit during fasting hypoglycemia. Serum proinsulin and C-peptide levels were abnormally elevated, and further tests revealed an islet cell tumor. The tumor was surgically removed, relieving the fasting hypoglycemia. Histopathological study showed a conventional well-differentiated neuroendocrine tumor with high immunoreactivity against proinsulin and with lesser intensity against insulin. Interestingly, GS-9A8 antibody clone used for immunostaining proinsulin did not cross-react with human insulin or C-peptide, providing an unbiased picture of proinsulin secretion. The resolution of symptoms, the fall of proinsulin concentrations after tumor removal and the histopathology study confirmed the diagnosis of proinsulinoma.

Topics: Adenoma, Islet Cell; Adult; C-Peptide; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Male; Pancreatic Neoplasms; Proinsulin; Syndrome

The work-up of fasting hypoglycemia may be difficult but is crucially important because a wrong diagnosis can lead to either unnecessary pancreatectomy or a missed pancreatic tumor. We describe a patient with severe fasting hypoglycemia [22-32 mg/dl (1.2-1.8 mmol/liter) after 6-10 h of fasting] in which the diagnosis of a secretory islet-cell tumor was obscured, rather than facilitated, by use of a new, highly specific serum insulin assay. Insulin measured by the specific assay suppressed normally during fasting hypoglycemia [undetectable at < 2.0-3.8 micro IU/ml (26.4 pmol/liter)], whereas insulin measured by older, less specific assays was diagnostically elevated [34, 73 micro IU/ml (236.1, 507.0 pmol/liter)]. Serum proinsulin and C-peptide levels were abnormal, and further work-up revealed an islet-cell tumor that secreted predominantly proinsulin. The tumor was surgically removed, relieving the fasting hypoglycemia. We conclude that insulin levels as measured by new, highly specific insulin assays may obscure the diagnosis of a functional, proinsulin-secreting islet-cell tumor. Because proinsulin cross-reacts with insulin in older insulin assays, C-peptide or proinsulin should be measured to rule out a proinsulin-secreting islet-cell tumor. Normative values for new insulin assays must be established during prolonged fasting.

Topics: Adenoma, Islet Cell; Adult; Anemia, Sickle Cell; Biopsy, Needle; C-Peptide; Fasting; Humans; Hypoglycemia; Insulin; Male; Pancreatectomy; Pancreatic Neoplasms; Proinsulin; Sensitivity and Specificity; Ultrasonography

To evaluate the C-peptide suppression test as a screening test in patients with symptoms of hypoglycemia as compared to the standard fasting test.. Retrospective discriminant analysis of data from C-peptide suppression tests.. Clinical study.. Patients with insulinomas and patients without insulinomas but having symptoms compatible with hypoglycemia.. The results from C-peptide suppression tests of 26 patients with insulinomas and 100 patients without insulinomas were compared.. A classification plot which introduces two discriminant parameters for the C-peptide suppression test: the ratio of [blood glucose]/[C-peptide] at the lowest C-peptide concentration and mean glycemia during insulin infusion.. In patients with insulinomas, minimal serum C-peptide levels were higher (1.81+/- 0.87 ng/mL; median 1.83 ng/mL; maximal suppression 37 +/- 24% of basal C-peptide levels) as compared to patients without insulinoma (0.40 +/- 0.15 ng/mL; median 0.30 ng/mL; maximal suppression of 75 +/- 9%; P<0.001). Mean glycemia during the test was lower in patients with insulinomas (30.8 +/- 3.3 vs. 47.5 +/- 8.3 mg/dL; P<0.001) as was the [blood glucose]/[C-peptide] ratio (21.9 +/- 14.6 vs. 139.2 +/- 43.8; P<0.001). Discriminant analysis revealed a specificity of 96% to rule out the diagnosis of 'insulinoma' at a 1% probability threshold with a sensitivity of 100%.. We developed a new classification plot for the C-peptide suppression test in order to accurately identify those patients whose symptoms of hypoglycemia are not due to endogenous hyperinsulinemia/insulinomas. Thus, the need for fasting tests and hospitalization costs can be reduced.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Aged, 80 and over; C-Peptide; Female; Humans; Hypoglycemia; Insulin; Insulin Antagonists; Insulin Secretion; Male; Middle Aged; Pancreatic Neoplasms

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

Inhibition of C-Peptide secretion by exogenous insulin was studied during euglycemic clamp in 13 patients with histologically verified causes of organic hyperinsulinaemia (10 with beta cell adenoma; 2 with beta cell carcinoma and 1 with beta cell hyperplasia) and in 10 healthy controls. Euglycemic clamps were performed using artificial endocrine pancreas (Clamp Mode 9:1) while insulin infusion (Humulin Normal-Lilly) rate was 0.1 U/kg BW/h. Blood samples for serum insulin (RIA INEP) and C-Peptide (RIA-Biodata) were taken at 0; 30; 60; 90 and 120 min. Statistical analysis was done using SPSS on IBM-PC with Wilcoxon sum rank test and one way ANOVA. All the patients were studied before the operation and in four of them clamp studies were repeated after the operation. Statistically significant suppression of C-Peptide values in 120 min was established in the control group (p less than 0.05) while there was no significant suppression in insulinoma group (p greater than 0.05), except in one patient with beta cell hyperplasia. Various types of responses (suppression, no change, paradoxical increase) were observed after the operation in the insulinoma group. Possible mechanisms and the meanings of the absence of insulin induced C-Peptide suppression in insulinoma group are discussed. It is concluded that euglycemic hyperinsulinemic clamp study could be useful and a complementary test to other established tests for the confirmation of the diagnosis of insulinoma. Further work on beta cell response after the operation in patients with insulinoma is necessary.

Topics: Adenoma; Adenoma, Islet Cell; Adult; Aged; Analysis of Variance; Body Mass Index; C-Peptide; Carcinoma; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Hyperplasia; Insulin; Insulin Secretion; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms

After an acute episode of pancreatitis, a 63-year-old man was found to have a pancreatic glucagonoma. The tumor was resected without evidence of metastases. Three years later he had symptoms of uncontrolled diabetes, no skin lesions, and diarrhea and was found to have a pancreatic pseudocyst and multiple hepatic metastases. Glucagon concentrations were raised but were suppressible by glucose and somatostatin and responded to arginine stimulation. He was treated for 6 months with octreotide (Sandostatin), which reduced his symptoms; the pseudocyst resolved, but liver metastases continued to grow. Although spontaneous resolution of the pseudocyst is possible, this case appears to illustrate differences in sensitivity of endocrine and exocrine tissues to suppression by Sandostatin.

Topics: Adenoma, Islet Cell; Arginine; Blood Glucose; C-Peptide; Eosinophilia; Follow-Up Studies; Glucagon; Glucagonoma; Humans; Male; Middle Aged; Octreotide; Pancreatic Cyst; Pancreatic Neoplasms; Pancreatic Pseudocyst

Topics: Adenoma, Islet Cell; Adult; C-Peptide; Female; Humans; Insulinoma; Pancreatic Neoplasms; Remission Induction; Reoperation

Topics: Adenoma, Islet Cell; Adult; Blood Glucose; C-Peptide; Diagnosis, Differential; Humans; Hyperinsulinism; Hypoglycemia; Infant, Newborn; Insulin; Insulinoma; Pancreatic Neoplasms

Recently somatostatin analogues were successfully used to control insulin-induced hypoglycemia in patients with insulinoma. We observed a transient decrease in glucose levels and symptomatic hypoglycemia after administration of the long-acting somatostatin-analogue octreotide (Sandostatin) in two insulinoma patients. We studied the acute effects of octreotide (administered before breakfast) on blood glucose and gluco-regulatory hormones in these patients. In one patient, we studied the effects of glucagon replacement and changing the time of breakfast (relative to octreotide administration) on octreotide-associated changes in blood glucose and glucoregulatory hormones. Compared with control levels, octreotide therapy reduced insulin levels. During hypoglycemia glucagon and growth hormone levels were suppressed, but cortisol levels appropriately increased. The increase in catecholamine levels was normal in one patient, but markedly attenuated in the other. A transient decrease in serum glucose after octreotide was absent after glucagon replacement, but present when breakfast was taken before administration of octreotide. We conclude that in patients with insulinoma, octreotide therapy may be associated with clinically important hypoglycemia, during which counterregulatory hormone secretion may be attenuated.

Topics: Adenoma, Islet Cell; Aged; C-Peptide; Female; Glucagon; Humans; Hypoglycemia; Insulin; Insulinoma; Octreotide; Pancreatic Neoplasms

It has been shown, by using the immunogold technique, that C-peptide and insulin are co-localized in the mature granules of human pancreatic beta cells and insulinomas with typical granules. The mean gold bead densities of both C-peptide and insulin were at least twice as high in the normal pancreas when compared with the insulinomas. The mean granule diameter of the insulinoma cells (D = 0.30 +/- 0.12 micron) was smaller than that of human pancreatic cells (D = 0.45 +/- 0.15 micron). The morphometric data indicate that each of the antigens (C-peptide and insulin) is distributed similarly in the halos and the dense cores of the beta granules. Thus, no topological segregation of these two antigens occurs within the beta granules of either normal human pancreas or insulinomas.

Topics: Adenoma, Islet Cell; C-Peptide; Cytoplasmic Granules; Humans; Immunohistochemistry; Insulin; Insulinoma; Islets of Langerhans; Pancreatic Neoplasms

A peptide was extracted and purified from rat insulinoma tissue which, although similar, was not identical to normal rat C peptides. The purity of the peptide, called rat insulinoma peptide (RIP), was investigated using polyacrylamide gel electrophoresis, isoelectric focusing and high-performance liquid chromatography. It appears to contain two peptides similar to each other but differing in their isoelectric points. The peptides as assessed by fast atom bombardment mass spectrometry have molecular masses in the region of 1982 Da, given a chain length of approx. 22 amino-acid residues. Evidence obtained using an established rat C peptides radioimmunoassay suggests that RIP shares a common C-terminus with rat C peptides. The antiserum produced to RIP was used to develop a radioimmunoassay using a tracer prepared by iodinating purified tyrosylated RIP.

Topics: Adenoma, Islet Cell; Animals; C-Peptide; Chromatography, High Pressure Liquid; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Insulin; Insulinoma; Isoelectric Focusing; Isoelectric Point; Male; Molecular Weight; Neoplasm Proteins; Pancreatic Neoplasms; Radioimmunoassay; Rats; Rats, Inbred Strains

Dissociated human insulinoma cells were plated onto plastic multiwell dishes. Cells were maintained for 1 mo on plastic with three passages. Cultures consisted of small colonies with some areas of stratification and few intercellular spaces. Ultrastructural studies indicated that cultured cells had epithelial features with desmosomes at cell-to-cell contacts and intermediate filaments in addition to secretory granules in the cytoplasm. Insulin and C-peptide were released in equimolar amounts in culture media. When challenged for 30 min with 16.7 mM glucose, 1 mM 3-isobutyl-1-methylxanthine, 4 mM tolbutamide, or 10(-6) M glucagon, insulinoma cells responded by a 1.5-, 1.5-, 2-, or 3-fold increase, respectively, in insulin release above baseline levels. A 15-min challenge with 10(-5) M isoproterenol increased insulin secretion by 1.85-fold. By indirect immunofluorescence, an anti-insulin antibody reacted positively with cell cytoplasm, whereas anti-somatostatin and anti-glucagon antibodies did not. Insulinoma cell surface expressed class I MHC molecules but not class II molecules. Immediately after isolation, crude insulinoma cells were contaminated by 2% of DR+ cells from nonislet components that disappeared after several weeks in culture. The ability of insulinoma cells to stimulate allogenic T-lymphocyte proliferation was assessed by [3H]thymidine incorporation in mixed culture combinations. Crude insulinoma cells elicited a strong lymphoproliferative response with a stimulation index ranging between 3.5 and 7, whereas no stimulation was found after 1 mo in culture. It is postulated that absence of class II-positive cells in the stimulatory cell preparation conditioned this immune tolerance across the major histocompatibility barrier.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: 1-Methyl-3-isobutylxanthine; Adenoma, Islet Cell; Adult; C-Peptide; Fluorescent Antibody Technique; Glucagon; Glucose; Humans; Insulin; Insulin Secretion; Insulinoma; Lymphocyte Culture Test, Mixed; Lymphocytes; Microscopy, Electron; Pancreatic Neoplasms; Tolbutamide; Tumor Cells, Cultured

In two female patients of 62 and 76 years of age, respectively, who had insulinomas subsequently confirmed by histology, the secretion pattern of insulin-producing tumours was studied. In the 62-year old patient complete reproducible suppression of insulinoma secretion was achieved by means of large exogenous doses of insulin, whereas this was not possible in the 76-year old patient. A modified hypoglycaemic clamping technique was used in the study. It is concluded that, depending on plasma insulin levels, relative suppression of insulinoma is possible, and it is recommended to use the described differentiated clamping procedure to investigate the secretion pattern of autonomous insulin-producing tumours.

Topics: Adenoma, Islet Cell; Aged; Blood Glucose; C-Peptide; Female; Glucose; Humans; Infusions, Intravenous; Insulin; Insulin Secretion; Insulinoma; Middle Aged; Pancreatic Neoplasms

We previously found that patients with hypoglycemia due to chronic renal and liver disease had anomalous metabolic responses to glucose and glucagon stimulation. In this study we evaluated the use of glucagon (2 mg, iv) tests in the diagnosis of spontaneous hypoglycemia secondary to hepatocellular carcinoma (HCC) and insulinoma. Twenty-one normal subjects, 45 patients with HCC (11 with hypoglycemia), and 14 patients with insulinoma (all with hypoglycemia) were studied. The fasting blood glucose level was low in all patients with hypoglycemia. The fasting plasma insulin and C-peptide concentrations were high in patients with insulinoma and low in patients with HCC and hypoglycemia. The blood glucose responses to glucagon administration were less than normal in patients with HCC and hypoglycemia and within normal limits in patients with insulinoma. The insulinoma patients had increased plasma insulin and C-peptide responses to glucagon despite having low blood glucose levels. Compared with the HCC patients without hypoglycemia, HCC patients with hypoglycemia had impaired plasma insulin and C-peptide responses. The fasting hypoglycemia, hypoinsulinemia, and impaired insulin/C-peptide responses to glucagon in patients with hepatoma and hypoglycemia presumably reflect the production of insulin-like substances by the hepatoma. We conclude that glucagon administration results in characteristic responses in these groups of patients and can be of use in the diagnosis of spontaneous hypoglycemia secondary to hepatoma or insulinoma.

Topics: Adenoma, Islet Cell; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Carcinoma, Hepatocellular; Female; Glucagon; Humans; Hypoglycemia; Insulin; Insulinoma; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms

The pluripotent rat islet tumor cell line MSL-G2 expresses primarily glucagon or cholecystokinin and not insulin in vitro but changes phenotype completely after prolonged in vivo cultivation to yield small-sized hypoglycemic tumors composed almost entirely of insulin-producing beta cells. When a genomic DNA fragment containing the coding and upstream regulatory regions of the human insulin gene was stably transfected into MSL-G2 cells no measurable amounts of insulin or insulin mRNA were detected in vitro. However, successive transplantation of two transfected clones resulted in hypoglycemic tumors that efficiently coexpressed human and rat insulin as determined by human C-peptide-specific immunoreagents. These results demonstrate that cis-acting tissue-specific insulin gene enhancer elements are conserved between rat and human insulin genes. We propose that the in vivo differentiation of MSL-G2 cells and transfected subclones into insulin-producing cells reflects processes of natural beta-cell ontogeny leading to insulin gene expression.

Topics: Adenoma, Islet Cell; Animals; C-Peptide; Cell Differentiation; Cells, Cultured; Clone Cells; DNA Restriction Enzymes; Gene Expression Regulation; Humans; Immunohistochemistry; Insulin; Insulinoma; Pancreatic Neoplasms; Rats; Transfection

Topics: Adenoma, Islet Cell; Adolescent; Adult; Blood Glucose; C-Peptide; Female; Glucagon; Humans; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Hormones; Pancreatic Neoplasms; Predictive Value of Tests

Acute effects of somatostatin analog (SMS 201-995) on pancreatic hormones were studied in two patients with malignant islet-cell carcinoma. Before and after subcutaneous injection of somatostatin with a doses of 50 micrograms, blood glucose (BG), serum growth hormone (hGH), C-peptide immunoreactivity (CPR), plasma immunoreactive glucagon (IRG) and gastrin were assayed, and changes in elution patterns of IRG and gastrin were also analyzed on Bio-Gel P-30 column chromatography. In Patient 1 with glucagonoma syndrome and hypergastrinemia, a prompt and remarkable decrease in plasma IRG and gastrin was observed after the injection of SMS 201-995 in association with a decrease in blood glucose, and then IRG and gastrin increased gradually. The suppressive effect continued for at least 6 hours. On gel filtration of the plasma obtained before the injection of the analog, three major peaks, greater than 20000, 9000 and 3500 molecular-weight (mol wt) fractions, were seen in IRG fraction. The decrease in plasma IRG observed at 1 hour after the injection was mainly due to a marked decrease in the 3500 molecular weight fraction. In addition, a slight decrease in the 9000 mol wt fraction was seen. At 4 hours after the injection, the 3500 mol wt peak returned to the previous level, while the 9000 mol wt peak decreased further. On the other hand, the gastrin elution pattern of plasma obtained before the injection revealed three major gastrin peaks, greater than 20000, 7000 and 5000 mol wt fraction. The changes in the gastrin elution pattern after the injection were similar to those of the IRG elution pattern. In Patient 2 with Zollinger-Ellison's syndrome, the plasma gastrin level decreased gradually for 5 hours after the injection. On gel filtration of the plasma obtained before the injection, two major gastrin peaks, 7000 and 5000 mol wt fraction, of which the large-molecular fraction was more prominent than the small-molecular fraction, were observed. After the injection, a marked decrease in the small-molecular fraction and a gradual decrease in the large-molecular fraction were observed for 4 hours, accompanied by a decrease in plasma gastrin. At 7 hours after the injection, the smaller fraction was augmented again. The serum CPR and hGH was slightly suppressed after the injection in both patients. The adverse effects of slight nausea and vomiting were noticed only in Patient 1.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adenoma, Islet Cell; Adult; Blood Glucose; C-Peptide; Depression, Chemical; Female; Gastrins; Glucagon; Growth Hormone; Humans; Middle Aged; Octreotide; Pancreatic Hormones; Pancreatic Neoplasms

Subtotal pancreatectomy specimens from one case of nesidioblastosis, one case of focal adenomatosis, and two cases of insulin-producing islet-cell tumours were studied with special reference to their production of pro-insulin, C-peptide and insulin, and their contents of argyrophil parenchymal cells. Specific immunostaining revealed the presence of abundant cells reacting with pro-insulin, C-peptide, and insulin antiserum; at least the great majority of them were obviously non-argyrophil cells. The content of extractable immunoreactive insulin (IRI) was higher in the cases of nesidioblastosis and focal adenomatosis than in the two insulomas. Molar ratios of IRI to C-peptide immunoreactivity (CPR) varied between 7 and 100. Gel filtration analysis of the extracts revealed two peaks of CPR, corresponding to 3,000 and 10,000 daltons, respectively. Ultrastructurally, the insulin cells in cases of nesidioblastosis and focal adenomatosis contained numerous typical beta granules. In the islet-cell neoplasms some "polycrine" islet cells were also found, containing typical as well as atypical granules with electron dense or pale cores. Some cells even showed a mixture of apparent beta and alpha granules. Despite structural differences and variable contents of IRI and CPR, the predominance of cells reactive with antibodies to pro-insulin, C-peptide, and insulin, and the absence of argyrophil pro-insulin cells in adenomatosis and insulomas indicates that the hormonal products of these parenchymal cells are not any chemically modified insulin or any other member of the insulin family.

Topics: Adenoma; Adenoma, Islet Cell; Adolescent; Adult; Antibodies, Monoclonal; C-Peptide; Child; Child, Preschool; Female; Humans; Immunoenzyme Techniques; Infant; Insulin; Insulinoma; Islets of Langerhans; Male; Microscopy, Electron; Pancreatic Diseases; Pancreatic Neoplasms; Proinsulin; Radioimmunoassay

A case of multiple nonfunctional pancreatic islet cell tumor in multiple endocrine neoplasia type I (MEN I) is reported. The patient was a 41-year-old woman who had a past history of thyroid cancer (papillary carcinoma) and hyperparathyroidism due to parathyroid adenoma. Later, a nonfunctional pituitary tumor and five nonfunctional pancreatic tumors were found simultaneously and the patient was finally diagnosed as having MEN I. Following surgical enucleation, the pancreatic tumors were histopathologically diagnosed as benign islet cell tumors. One of them (tumor 3) exhibited a solid nodular pattern while the others showed gyriform patterns. They were divided histochemically and immunohistochemically into three types: two (tumors 1 and 2) produced a single hormone (glucagon), one (tumor 3) produced five (insulin, glucagon, somatostatin, gastrin and pancreatic polypeptide) and the remaining two (tumors 4 and 5) produced two (glucagon and pancreatic polypeptide). Electron microscopically, three types of endosecretory granules were found in the tumor cells of tumor 3 but only one type was found in tumor 4. However, in the tumor 4 extract, glucagon, pancreatic polypeptide, C-peptide, somatostatin, vasoactive intestinal peptide and growth hormone releasing factor were detected by radioimmunoassay. These findings suggest that these pancreatic tumors were both multicellular and multihormonal.

Topics: Adenoma, Islet Cell; Adult; C-Peptide; Female; Gastrins; Glucagon; Growth Hormone-Releasing Hormone; Humans; Immunohistochemistry; Insulin; Microscopy, Electron; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Pancreatic Polypeptide; Radioimmunoassay; Somatostatin; Vasoactive Intestinal Peptide

Topics: Adenoma, Islet Cell; Blood Glucose; C-Peptide; Female; Humans; Insulin; Insulinoma; Middle Aged; Pancreatic Neoplasms

The results of various tests for the diagnosis and localization of insulinoma in ten patients were reviewed. The diagnostic criteria IRI X 100/(BS-30)greater than 50 and IRI/BS greater than 0.30 in the fast were most reliable in establishing a diagnosis of insulinoma. If a diagnosis of insulinoma is in doubt after several overnight fasts, C-peptide suppression test should be carried out since the test is safe and convenient. As insulin stimulation tests often lead to false-negative results and sometimes cause dangerous levels of hypoglycemia in patients with insulinoma, they are not widely recommended now. However they may be useful, if positive, in some patients with insulinoma who exhibit no abnormality in insulin-glucose ratio or C-peptide suppression test. Percutaneous transhepatic portal catheterization with measurements of radioimmunoreactive insulin concentration, supported by the clear theoretical grounds for interpretation of its results, was the most reliable method for preoperative localization of an insulinoma. Therefore the method, together with pancreatic angiography, should be attempted in all the patients with insulinoma. Insulinoma is an endocrine tumor curable by surgical removal, but there still remain a few unfortunate patients who have brain damages due to severe hypoglycemia or are blindly treated by pancreatectomy. Such cases should be eliminated by the early diagnosis and correct preoperative localization of the tumor.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Female; Glucagon; Humans; Insulin; Insulin Secretion; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Tolbutamide

The diagnosis of insulinoma on the basis of persistent hypoglycemia requires further confirmation. The insulin suppression test has been used to support this diagnosis prior to surgical intervention. In this study the euglycemic clamp technique was used to compare five control volunteers with four hypoglycemic patients with suspected insulinoma. Insulin was infused over successive two-hour periods at 2, 4, and 8 mU/kg/min. Plasma glucose levels were clamped at 80 mg/dL (4.4 mmol/L) using an artificial pancreas. High insulin levels were measured in all subjects, ranging from 225 +/- 30 microU/mL (1614 +/- 215 pmol/L) to 1018 +/- 239 microU/mL (7304 +/- 1714 pmol/L). Levels of C peptide fell to 0.1 ng/mL (0.028 nmol/L) in control subjects but remained at high levels in the patients. Insulinoma was confirmed on laparotomy in all four patients. In two patients tested after removal of the tumor the results were found to have returned to normal.

Topics: Adenoma, Islet Cell; Blood Glucose; C-Peptide; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Infusion Systems; Insulinoma; Pancreatic Neoplasms

To determine the mechanism responsible for deficient carbohydrate metabolism in patients with insulinoma, we studied three affected patients and seven normal controls using the hyperglycaemic clamp method (8.4 mmol/l) with the BIOSTATOR (GCIIS). In insulinoma patients, the amount of glucose necessary to reach the hyperglycaemic clamp was less than that required in normal controls (6.19 +/- 1.19 mg/min/kg vs. 9.95 +/- 0.53 mg/min/kg) (p less than 0.05). There was no significant difference in metabolized glucose (M) in the stable phase of the hyperglycaemic clamp; however, the M/IRI in this phase was less in those with insulinoma (7.9 +/- 0.50) than in controls (22.26 +/- 4.14) (p less than 0.05). There was no difference in beta cell secretory response to hyperglycaemic stimulus (defined as the increase in the concentration of C-peptide from the basal state to the stable phase of the hyperglycaemic clamp) between the two groups. Hepatic insulin extraction was significantly lower in patients with insulinoma than in normal controls (+0.72 +/- 0.07 vs. +0.85 +/- 0.01). Finally, the ratios of fractional turnover of glucose (K/IRI); glucose clearance/IRI and total rate of elimination of glucose from the extracellular pool/IRI were also all lower in patients with insulinoma than in controls (p less than 0.05). These data support the conclusion that deficient glucose metabolism seen in these patients is not related to a lack of response to glucose on the part of normal or neoplastic islet tissue.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenoma, Islet Cell; Adult; Blood Glucose; C-Peptide; Female; Glucose; Humans; Insulin; Insulinoma; Islets of Langerhans; Liver; Middle Aged; Pancreatic Neoplasms

Topics: Adenoma, Islet Cell; Angiography; Blood Glucose; C-Peptide; Humans; Insulin; Insulinoma; Islets of Langerhans; Multiple Endocrine Neoplasia; Pancreatectomy; Pancreatic Neoplasms; Prognosis; Tomography, X-Ray Computed; Ultrasonography

This report describes a 78-year-old woman with insulinoma, treated with a combination of diphenylhydantoin and a calcium antagonist. The effectiveness of 200 mg of diphenylhydantoin and 180 mg of diltiazem was evaluated by measuring the levels of plasma glucose, immunoreactive insulin and immunoreactive insulin/plasma glucose after fasting or by the oral glucose tolerance test, and by the appearance of hypoglycemic symptoms. The mean concentration of fasting plasma glucose increased significantly during the treatment. The levels of immunoreactive insulin/plasma glucose and C-peptide immunoreactivity/plasma glucose significantly decreased. Symptomatically, no episode of hypoglycemia was noted during the combined treatment.

Topics: Adenoma, Islet Cell; Aged; Benzazepines; Blood Glucose; C-Peptide; Celiac Artery; Diltiazem; Female; Humans; Insulin; Insulinoma; Pancreatic Neoplasms; Phenytoin; Propranolol; Radiography; Verapamil

Specific binding of the C-peptide of proinsulin was evaluated using a transplantable NEDH rat islet cell tumour predominantly composed of insulin-secreting B-cells. Cultured tumour B-cells exhibited greater than 90% viability assessed by trypan blue exclusion, and retained the ability to form tumours with accompanying hypoglycaemia and hyperinsulinaemia after reimplantation. During binding experiments with synthetic rat C-peptide I and iodinated tyrosylated rat C-peptide I, tumour B-cells exhibited 54 +/- 6% specific binding. Displacement of tracer increased with increasing concentrations of unlabelled rat C-peptide I (0.25-1,000 ng/ml), and the specificity of binding was substantiated by reduced displacement with human C-peptide. Scatchard analysis of specific C-peptide binding revealed a curvilinear plot with upward concavity. The demonstration of specific C-peptide binding to insulin-secreting B-cells provides evidence for a physiological role of proinsulin C-peptide.

Topics: Adenoma, Islet Cell; Animals; C-Peptide; Cells, Cultured; Humans; Islets of Langerhans; Kinetics; Male; Neoplasm Transplantation; Rats; Rats, Inbred Strains; Receptor, Insulin

The regulation of insulin secretion in patients with insulinoma is known to be abnormal. For example, physiological and pharmacological stimuli often fail to stimulate insulin in such patients. Recently, insulin has been found to inhibit its own secretion in normal subjects. To determine if insulin has this effect in patients with insulinoma, we infused insulin at rates of 1 and 10 mU/kg X min in such a patient and in eight normal subjects. Euglycemia was maintained by the euglycemic glucose clamp technique, and endogenous insulin secretion was estimated by measuring plasma C-peptide levels. In the normal subjects, plasma C-peptide declined from 1.60 +/- 0.22 (+/- SEM) to 1.16 +/- 0.17 and 0.82 +/- 0.11 ng/ml during the low and high dose insulin infusions, respectively, indicating 27% (P less than 0.01) and 48% (P less than 0.001) decreases in endogenous insulin secretion at moderately elevated and extremely elevated insulin levels, respectively. In the insulinoma patient, plasma C-peptide was 2.6 ng/ml basally, did not change during the low dose insulin infusion, and rose to 3.4 ng/ml during the high dose insulin infusion. We conclude that the feedback regulation of insulin secretion by insulin that occurs in normal subjects is absent in insulinoma patients. This finding could have pathophysiological and possibly diagnostic significance.

Topics: Adenoma, Islet Cell; Adult; Blood Glucose; C-Peptide; Feedback; Female; Humans; Insulin; Insulin Secretion; Insulinoma; Male; Pancreatic Neoplasms

Two new radioimmunoassays for human proinsulin (hPI) have been developed and used to study patients with islet cell tumors and familial hyperproinsulinemia. Both antisera were adsorbed against human C-peptide conjugated to Sepharose, following which cross-reactivity to insulin and C-peptide was less than 0.001%. Antiserum 18D recognized the junction between the insulin B-chain and C-peptide and provided fivefold greater sensitivity than our previously reported hPI assay. Antiserum 11E recognized a determinant which includes or is adjacent to the A-chain-C-peptide junction or which is specified by the tertiary structure. In all 20 patients studied with surgically confirmed islet cell tumors, fasting plasma proinsulinlike material (PLM) was abnormal (greater than 3 SD from the mean measured in either lean or obese subjects) in both assays. This provided better discrimination than has been reported for PLM measured by gel filtration (abnormal in 13 of 14 of the present samples) with a considerably less laborious procedure. Samples from two families in which a mutant proinsulin is present in the circulation have immunoreactivity in the two assays consistent with previous identification of the molecule as an A-chain-C-peptide-linked intermediate of proinsulin conversion. The immunoreactivity of a sample from another family in which large amounts of proinsulin circulate are consistent with an intact molecule being the predominant form. This assay will be useful for confirming the diagnosis of insulin-secreting tumor in patients suspected of recurrent fasting hypoglycemia and in physiologic studies of proinsulin secretion.

Topics: Adenoma, Islet Cell; Adult; Amino Acid Sequence; C-Peptide; Chromatography, High Pressure Liquid; Cross Reactions; Glucose Tolerance Test; Humans; Insulinoma; Pancreatic Neoplasms; Proinsulin; Radioimmunoassay

Topics: Adenoma, Islet Cell; Aged; Blood Glucose; C-Peptide; Female; Growth Hormone; Half-Life; Hormones; Humans; Insulin; Insulinoma; Octreotide; Pancreatic Neoplasms; Somatostatin

Topics: Adenoma, Islet Cell; Blood Glucose; C-Peptide; Humans; Insulin; Insulinoma; Pancreatic Neoplasms

A woman with a multiple-hormone-producing pancreatic islet cell tumor with hepatic metastases and with recurrent hypoglycemic attacks, was treated with streptozotocin. After this treatment, the elevated serum levels of insulin, C-peptide, glucagon and serotonin fell markedly and the low level of fasting blood glucose returned to normal. In accordance with these hormonal changes, scintiscan and CT scan revealed marked regression of the metastatic tumors in the liver. She is alive at this writing, five years after the streptozotocin treatment. Streptozotocin should thus be considered for treatment of malignant islet cell carcinoma with liver metastases and which is not amenable to surgery.

Topics: Adenoma, Islet Cell; Blood Glucose; C-Peptide; Female; Glucagon; Humans; Insulin; Insulinoma; Liver Neoplasms; Middle Aged; Pancreatic Neoplasms; Serotonin; Streptozocin

We evaluated the possibility to diagnose the case of insulinoma using the combination of portal blood sampling and gel filtration techniques. The portal blood sampling showed 52 muU/ml of immunoreactive insulin (IRI) level at the closest splenic vein to the tumor, but the level should not be high enough to reasonalize the being of the tumor. The gel filtration pattern of IRI from the blood at the same point was clearly different from the other samples. Therefore, it could be useful for the diagnosis of insulinoma to combine percutaneous transhepatic portal blood sampling and gel filtration in such a case.

Topics: Adenoma, Islet Cell; C-Peptide; Chromatography, Gel; Female; Hepatic Veins; Humans; Hypoglycemia; Insulin; Insulinoma; Middle Aged; Pancreatic Neoplasms; Portal Vein; Splenic Vein

The diagnosis of an insulin producing tumour can be confirmed by a minimum of biochemical investigations. Its preoperative localisation is more difficult. Sonogram, Computertomogram, selective angiography and percutaneous transhepatic collecting of blood samples for insulin analysis from the portal system were preoperative measured to localize the tumours in 32 of 37 patients of our series. In 2 patients intraoperative tumour localisation by measurement of incorporated p32 proved to be effective. In B-cell-carinomas pancreas resection is the adequate therapy. With regard to the therapeutic effects a high risk is involved in the 'blind' left or right sited resection of non-localized tumours.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Blood Glucose; C-Peptide; Child; Child, Preschool; Female; Follow-Up Studies; Humans; Hyperinsulinism; Infant; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Postoperative Complications

The usefulness and the limits of the artificial endocrine pancreas in the surgical management of insulinoma has been evaluated in three male patients who underwent pancreatic resection because of previously detected adenoma. In particular, blood glucose and contemporary levels of insulin and C-peptide were continuously monitored before, during and after surgery, to record the temporal relationship between the removal of insulinomas and the variations of these parameters. In the pre-resection phase, only two cases revealed hypoglycemia and required dextrose infusion to correct hypoglycemia and reach euglycemic levels, whereas all the patients showed elevated insulin and C-peptide levels. After anesthesia and surgical incision, the pancreas was observed and manipulated in search of adenoma. In all patients this manoeuvre caused an increase of insulin and C-peptide levels and in two cases a slight decrease of blood glucose levels. After adenoma resection, a prompt increase of glycemia was observed only in one patient, in the other two the time which elapsed before significant blood glucose changes was more prolonged (55 and 80 min. respectively). On the contrary, a rapid fall in insulin and C-peptide levels was observed in all cases. We conclude that artificial endocrine pancreas has the advantage of maintaining the normoglycemia before and during surgery, preventing the risk of dangerous hypoglycemia in basal conditions and following manipulation of pancreas while localizing adenoma. However, the prolonged interval elapsed before significant blood glucose variations limits the usefulness of the artificial endocrine pancreas in localizing intraoperatively previously undetected adenomas.

Topics: Adenoma, Islet Cell; Blood Glucose; C-Peptide; Humans; Insulin; Insulin Infusion Systems; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms

Insulin, C-peptide and proinsulin were measured in peripheral blood of 11 patients suffering from different types of hormone-producing pancreatic B-cell tumours. While proinsulin was elevated in 10/11 patients during prolonged fasting, C-peptide and insulin levels were found within the reference range in 5/11 and 3/5 cases respectively. A rapid insulin assay performed during surgery was helpful for localisation and identification of the respective tumours.

Topics: Adenoma, Islet Cell; Adult; Aged; C-Peptide; Female; Humans; Infant, Newborn; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Proinsulin

The difficulty of clinical and biochemical diagnosis of insulinoma lies in the extreme variability of both clinical symptoms and glycaemia/insulinaemia levels, so that neither parameter is a totally reliable diagnostic indicator. The possibility of introducing a third parameter, the non-esterified fatty acid (FFA) level, to enhance the reliability of insulinoma diagnosis was therefore investigated. The behaviour of glucose, insulin and plasmatic FFA levels and the correlation of the three parameters were studied in 4 patients whose suspected insulinomas were later surgically confirmed. The tests applied were as follows: 24 hour fast followed by endovenous glucose, oral glucose administration, tolbutamide stimulus test, adrenaline and glucagon tests. The results revealed anomalies in insulinaemia and glycaemia behaviour such as have already, in part, been described in organic hyperinsulinism, e.g. the discrepancy between insulin and glucose levels after prolonged fasting. It was also clear that the parameters examined still leave much room for uncertainly in the biochemical diagnosis of insulinomas. Numerous anomalies were also observed in the behaviour of plasmatic FFA. For example lipid mobilisation was often reduced in conditions that normally stimulate it (fasting, the administration of catecholamines). Equally the prolonged blockage of lipid mobilisation was encountered in the presence of factors that normally reduce lipolysis (endovenous glucose). On the basis of these results it is suggested that a combined assessment of glucose and plasmatic FFA levels may be a more sensitive diagnostic indicator of insulinoma than the insulin/glucose ratio commonly reported in the literature. The mechanism behind the lipid mobilisation anomalies of insulinomas is also discussed in the light of its apparent connection with the glucose/insulin interaction characteristic of the condition.

Topics: Adenoma, Islet Cell; Adult; Aged; Blood Glucose; C-Peptide; Epinephrine; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Glucose Tolerance Test; Humans; Insulin; Insulinoma; Male; Middle Aged; Tolbutamide

In order to study the suppression of C-peptide secretion in 5 patients with insulin-producing tumours or beta cell hyperplasia, we raised and maintained plasma insulin at a high physiological level and kept plasma glucose unchanged for 2 h with combined infusions of glucose and insulin (insulin clamp technique). No suppression of C-peptide secretion was seen in any of the patients, in contrast with a 35-65% decline seen in each of 17 healthy control subjects. In 3 patients surgical removal of beta cell adenoma normalized the response, whereas it remained unchanged in a patient with beta cell hyperplasia after partial pancreatectomy and in another with inoperable carcinoma. These results indicate that insulin secretion by insulinomas is characterized by lack of suppression by insulin. Measurement of the insulin-insulin feedback loop by the clamp technique may provide a rapid test to reveal autonomous insulin secretion without the risk of hypoglycaemia.

Topics: Adenoma, Islet Cell; Adult; Blood Glucose; C-Peptide; Female; Humans; Insulin; Insulinoma; Male; Methods; Middle Aged

The mean age of the 13 patients studied (9 women, 7 men) was 50.5 +/- 15.7 years. The disease was discovered on account of malaise (3 cases), behavioural disorders (4 cases), coma (3 cases), syncope (1 case) or right hemiparesis (1 case) or in the course of systematic examination (1 case). Eleven patients consulted for evaluation of hypoglycaemia and 2 for behavioural disorders. The history was characteristic, with malaise, loss of consciousness, severe neurological disorders (seizures, hemiparesis, hemiplegia or coma) and psychiatric disorders. These symptoms typically occurred in the morning before breakfast or between meals in 9 patients, and atypically at any point of time or after meals in 4 patients. Their hypoglycaemic nature was demonstrated by blood glucose determination in 11/13 cases and by response to ingestion of sugar in 12/13 cases. The mean period elapsed between the initial symptoms and the final diagnosis was 20.3 +/- 17.3 months. Inappropriate insulin secretion was elicited a.m. before breakfast, during Conn's diet or fasting test, or by calculating the blood insulin/glucose ratio or Turner's coefficient. Prior to surgery, the insulinoma was located by ultrasonography in 3/8 cases, by computerized tomography in 2/6 cases, by selective arteriography in 6/11 cases, and by phlebography with spleno-portal catheterization and staged sampling for insulin and C-peptide assays in 8/9 cases. Histological examination after surgery (11 cases) or necropsy (1 case) showed an adenoma without evidence of malignancy.

Topics: Adenoma, Islet Cell; Adult; Aged; Blood Glucose; C-Peptide; Fasting; Female; Humans; Hypoglycemia; Insulin; Insulin Secretion; Insulinoma; Male; Middle Aged; Neurologic Manifestations; Pancreatic Neoplasms; Portography; Tomography, X-Ray Computed; Ultrasonography

Topics: Adenoma, Islet Cell; Aged; C-Peptide; Female; Humans; Insulin; Insulinoma; Pancreatic Neoplasms

Topics: Adenoma, Islet Cell; Adult; Blood Glucose; C-Peptide; Computers; Female; Humans; Insulin; Insulinoma; Pancreatic Neoplasms

Insulin secretion by a transplantable rat islet B-cell tumour is accompanied by the release of two putative proinsulin cleavage intermediates, four peptides of Mr 9000-12 000 (excluding proinsulin) and peptides of Mr 21 000, 34 000 and 60 000. Granule-enriched subcellular preparations contain major peptides of identical Mr values. Of these peptides seven at least coincide in molecular weight with peptides secreted by isolated rat islets and thus may be constituents of the normal insulin secretory granule.

Topics: Adenoma, Islet Cell; Animals; C-Peptide; Cells, Cultured; Cytoplasmic Granules; Electrophoresis, Polyacrylamide Gel; Insulin; Insulin Secretion; Insulinoma; Molecular Weight; Pancreatic Neoplasms; Peptide Fragments; Proinsulin; Rats

Two cases of glucagonoma, one benign and the other malignant, was presented. Benign glucagonoma in a 29-year-old man with multiple endocrine neoplasia type 1 was composed largely of tumor cells with secretory granules ranging from 139 to 417 nm in diameter identical to A cell granules. There were a few tumor cells which contained no A cell granules but smaller granules of approximately 166 nm diameter similar to those of pancreatic polypeptide containing cells. Radioimmunoassay of the tumor extract showed 319 micrograms/g wet weight of glucagon and 0.72 microgram/g wet weight of pancreatic polypeptide. Malignant glucagonoma in a 34-year-old man was a massive tumor of 7 X 6 X 5 cm replacing the tail and body of the pancreas with multiple metastases. The tumor contained 0.2 microgram/g wet weight of glucagon and 0.065 microgram/g wet weight of vasoactive intestinal peptide. The electron microscopic examination revealed that the tumor cells had variable numbers of atypical secretory granules measuring 110 to 200 nm in diameter different from A cell granules. An analysis of plasma glucagon by the gel filtration technique showed the heterogeneity of glucagon molecules indicating the presence of large glucagon. Atypical secretory granules in malignant glucagonoma were considered to represent immature granules containing the precursor or intermediate of glucagon.

Topics: Adenoma, Islet Cell; Adult; C-Peptide; Cytoplasmic Granules; Glucagon; Glucagonoma; Humans; Insulinoma; Male; Neoplasm Metastasis; Neoplasms, Multiple Primary; Pancreatic Neoplasms; Radioimmunoassay

A case of somatostatinoma syndrome in a 30-year-old woman is presented. Basal levels of growth hormone and of pancreatic and gastric hormones were reduced and the response of growth hormone, insulin and C-peptide to stimuli such as arginine, glucose, glibenclamide and calcium was virtually abolished. Similarly, gastric acid secretion, pancreatic exocrine function and intestinal absorption were significantly reduced. On the other hand, basal and stimulated levels of adrenocorticotropic hormone (ACTH), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and thyroid-stimulating hormone (TSH) were within the normal range. Plasma somatostatin-like immunoreactivity was increased to 600-2,000 pg/ml (normal: 88-140 pg/ml). Immunocytochemical studies demonstrated the presence of somatostatin immunoreactive material in the primary tumour in the head of the pancreas and in the liver metastases. In spite of two courses of chemotherapy with streptozotocin and 5-fluorouracil the patient died due to liver failure 5 months after the first admission to hospital.

Topics: Adenoma, Islet Cell; Adult; C-Peptide; Female; Humans; Insulin; Liver Neoplasms; Pancreatic Neoplasms; Pancreatic Polypeptide; Pituitary Hormones; Somatostatin; Somatostatinoma; Streptozocin; Xylose

Topics: Adenoma, Islet Cell; Adult; Aged; Blood Glucose; C-Peptide; Chromatography, Gel; Fasting; Female; Glucagon; Glucose Tolerance Test; Humans; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Peptides

Using the artificial pancreas, blood glucose levels were maintained at 80 mg/dl in nine hypoglycemic patients (four with histologically proven insulinomas and five with nontumoral hypoglycemia) and in four normal subjects during a 24-h fast. The amount of glucose used, serum insulin levels, and glucose clearance were higher in patients with nontumoral hypoglycemia than in normal subjects and highest in the patients with an insulinoma. Surgical or pharmacological treatment resulted in normalization of all parameters. In contrast to the 72-h fast, the 24-h glucose clamp technique allowed the study of hypoglycemic patients without inducing hazardous hypoglycemia.

Topics: Adenoma, Islet Cell; Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Female; Glucose; Humans; Hypoglycemia; Insulin; Insulin Infusion Systems; Insulinoma; Male; Metabolic Clearance Rate; Middle Aged; Pancreatic Neoplasms

Percutaneous transhepatic portal vein catheterisation with blood sampling from the various areas of drainage, especially the pancreatic veins, was undertaken in seven patients with insulinoma to diagnose its site. In six patients measurement of serum-insulin levels revealed an abrupt rise in the vascular area later found to drain the area of the insulinoma. Insulin measurement in one patient with insulinoma in the head of the pancreas falsely indicated an islet-cell tumour in the region of the tail of the pancreas. C-peptide concentration in serum followed the concentration of insulin, but did not show such a marked rise. The method of percutaneous transhepatic portal vein catheterisation with selective blood sampling for the measurement of hormonal concentration was superior to ultrasound, computer tomography or coeliacography for determining the site of the tumour.

Topics: Adenoma, Islet Cell; C-Peptide; Humans; Insulin; Insulinoma; Methods; Pancreas; Pancreatic Neoplasms; Veins

One of the main problems encountered in the surgical treatment of insulinoma is that of locating them within the pancreas, since about 10% of these tumors are occult. Modern pre- and intraoperative methods of identifying of hormone-producing pancreatic tumors remove the need for 'blind resection'. Complete exploration of the pancreas, biopsy, intraoperative toluidin-blue-0 staining, glucose monitoring, and especially selective pancreatic venous blood sampling with insulin radioimmunoassay make it possible to locate nearly all tumors. Percutaneous transhepatic portal venography and selective portal blood sample collection for insulin analyses should be done routinely before planning a reintervention when organic hyperinsulinism persists.

Topics: Adenoma, Islet Cell; Blood Glucose; C-Peptide; Female; Humans; Insulin; Insulinoma; Intraoperative Period; Male; Pancreatectomy; Reoperation

Diabetic ketoacidosis is an extremely rare manifestation of glucagonoma. We report such a case in a 72-year-old woman known to be diabetic for seven years. The patient was admitted with diabetic ketoacidosis and associated necrolytic migratory erythrema which suggested the diagnosis of glucagonoma. Plasma glucagon levels were increased (569 to 2298 pg/ml). A vascular tumor of the head of the pancreas without obvious hepatic metastases was visualised by angiography. Duodeno-pancreatectomy including the head of the pancreas led to complete recovery of the mucocutaneous lesions and the plasma glucagon level fell (229 pg/ml). The tumor had several histological characteristics suggesting malignancy and a high glucagon content on extraction. Electron microscopy showed multiple A cells and a few isolated B cells. Most of the cells showed immunoreactivity with anti-glucagon and anti-glicentine antibodies. Three months after surgery, the diabetes was again required treatment with insulin. Plasma glucagon level was again increased and chemotherapy with dimethyltriazenimidazolecarboxamide was undertaken.

Topics: Adenoma, Islet Cell; Aged; Blood Glucose; C-Peptide; Diabetic Ketoacidosis; Female; Glucagon; Glucagonoma; Humans; Pancreatic Neoplasms

We have established somatic cell hybrids by fusing cells from two human insulinomas with an established murine cell line LMTK- Cl1D. After selection of the hybrids, the media were analyzed and found to contain insulin and human C-peptide immunoreactive material. The newly synthesized material was further characterized by pulse labeling and immunoprecipitation, and shown in five hybrid lines on Sephadex G-50 chromatography to have a size similar to proinsulin. The hybrids produced the apparent proinsulin-like material for up to 7 mo. Chromosome composition of the hybrids was determined by isozyme analysis and banding techniques. Chromosome 11, which previously has been assigned the insulin gene using cDNA probes, was identified in the hybrids producing proinsulin-like material. However, the retention of this chromosome did not always assure the production of hormone. This independent technique has confirmed the localization of the insulin gene to chromosome 11 and offers the opportunity of studying insulin processing and developing continuous insulin-producing cell lines.

Topics: Adenoma, Islet Cell; Animals; C-Peptide; Cell Line; Chromosomes, Human, 6-12 and X; Humans; Hybrid Cells; Insulin; Insulinoma; Karyotyping; Mice; Pancreatic Neoplasms; Proinsulin

The results of clinical endocrine and metabolic studies on a 57-year-old female with surgically and autopsy verified glucagonoma syndrome were presented. All of the clinical manifestations of glucagonoma syndrome so far reported in the literature were noted but there was no evidence indicating the presence of multiple endocrine adenomatosis. The plasma IRG level was always more than 20 times above the normal, and the IRG response to insulin and tolbutamide injection was abnormal and the results of the other endocrinological studies revealed less remarkable features, if any. The surgically removed metastatic tumor of the liver contained an enormous amount of IRG and an appreciable amount of IRI, indicating that the elevated plasma IRG was mainly of tumor origin. These results clearly indicate that in glucagonoma there is some abnormality in glucagon release from the tumor. In addition to these findings, hypocalcemia, cardiac left ventricular hypertrophy and gastrointestinal dysfunction reportedly due to hyperglucagonemia were also seen in this patient.

Topics: Adenoma, Islet Cell; C-Peptide; Endocrine Glands; Female; Glucagon; Glucagonoma; Glucose Tolerance Test; Humans; Insulin; Liver Neoplasms; Middle Aged; Pancreatic Neoplasms; Tolbutamide

Topics: Adenoma, Islet Cell; Adult; Aged; Blood Glucose; C-Peptide; Female; Humans; Hyperinsulinism; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Paraneoplastic Endocrine Syndromes; Peptides

Topics: Adenoma, Islet Cell; Adult; C-Peptide; Female; Humans; Hyperinsulinism; Insulin; Insulinoma; Male; Middle Aged; Peptides; Proinsulin

Of 29 patients examined operation revealed a malignant tumor in 9 and a benign insulinoma in 18, 2 insulinomas were not found. The problems of preoperative tumor localization were limited to small insulinomas (size 7-35 mm). Ultrasound detected all of 3 insulinomas as low echogenic structures (size 7, 8, 17 mm). Computed tomography demonstrated 4 of 5 insulinomas (size 7, 8, 15, 17 mm) due to contrast enhancement following bolus injection. Arteriography localized 12 of 18 insulinomas preoperatively and 14 of 18 retrospectively. Selective transhepatic venous sampling for insulin assay identified 7 of 8 tumors. Real-time ultrasound and dynamic CT are promising in the diagnostics of insulinomas over 7 mm and should precede arteriography. Selective transhepatic venous sampling as the last diagnostic step is a major procedure and most specific, but not always without problems in interpretation.

Topics: Adenoma, Islet Cell; Angiography; C-Peptide; Humans; Insulin; Insulinoma; Pancreatic Neoplasms; Portal Vein; Tomography, X-Ray Computed; Ultrasonography

ERCP was performed in three patients with insulinoma. One had a large malignant tumor, while the remaining two had small tumours. In two of these patients pancreatic juice was collected for C-peptide determination. Pancreatography was performed and pancreatic juice was obtained in seven other subjects comprising: five control subjects and two patients in whom insulinoma was suspected because of symptoms suggestive of hypoglycaemia. Pancreatography was normal in all subjects except the patient with a large insulinoma in whom an obstruction of the main pancreatic duct was found. The maximal C-peptide concentrations in pancreatic juice of patients with insulinoma were found to be several-fold higher than in the control subjects and in one of the patients in whom insulinoma was suspected but unproven. The remaining patient with suspected insulinoma had a maximal C-peptide concentration comparable with those found in patients with proven insulinoma. Thus remarkable differences in maximal C-peptide concentrations obtained in patients with and without insulinoma were found. However, the clinical significance of the findings needs further evaluation. The value of ERP in patients with suspected insulinoma may be twofold: an obstruction of the main pancreatic duct may indicate a large, hardly resectable tumour; in patients in whom the duct is unaffected the relation between the tumour as visualized by angiography, and the duct, is of value for the surgeon when planning the operation.

Topics: Adenoma, Islet Cell; C-Peptide; Cholangiopancreatography, Endoscopic Retrograde; Humans; Insulinoma; Pancreatic Juice; Pancreatic Neoplasms; Peptides

A synthetic human C-peptide analogue has been used as a common standard for the comparison of insulin C-peptide measurements in seven assay systems in six laboratories. Even in terms of this common standard there was statistically significant numerical heterogeneity between laboratories for estimates of the C-peptide content of the same plasma samples. However, the consistency in ranking order of estimates of C-peptide in the plasma samples between laboratories suggests that laboratories are in most cases measuring at least similar immunoreactive constituents and that a reference plasma might prove useful in comparing results between laboratories. Until a more suitable reference material is available, the synthetic analogue, 64 formyllysine C-peptide, in ampoules coded 76/561, will be made available for research purposes.

Topics: Adenoma, Islet Cell; C-Peptide; Diabetes Mellitus; Humans; Pancreatic Neoplasms; Peptides; Proinsulin; Quality Control; Radioimmunoassay

Topics: Adenoma, Islet Cell; Blood Glucose; C-Peptide; Food; Food Deprivation; Glucose Tolerance Test; Humans; Hypoglycemia; Infant, Newborn; Infant, Newborn, Diseases; Insulin; Radioimmunoassay; Tolbutamide

Twenty five cases of insulin autoimmune syndrome including this case has been reported so far without having the pathogenesis clarified. This paper describes a case which suggests one aspect of pathogenesis. The patient, a housewife concurrently had insulinoma and severe rheumatoid arthritis, complaining of hypoglycemic syncope attacks. During the attacks her blood sugar levels ranged from 19 to 22 mg%. Her serum extractable immunoreactive insulin (IRI) and insulin binding antibody levels were 557 microunits/ml and 0.390 mU/ml, respectively. gamma-Globulin-bound insulin was also measured electrophoretically. Bio-Gel P 10 column chromatography eluted almost all IRI at the void volume at pH 7.4 and a smaller but significant IRI peak also at pH 3.0. Selective angiography revealed a tumor-like staining in the pancreas body. Pancreatectomy relieved her of hypoglycemic attacks. Histology disclosed two small insulinomas. Insulinoma, rheumatoid arthritis and insulin autoimmune syndrome coexisted in this case, suggesting some causal relationship among them.

Topics: Adenoma, Islet Cell; Arginine; Arthritis, Rheumatoid; Autoimmune Diseases; C-Peptide; Female; Glucose Tolerance Test; Humans; Insulin; Insulin Antibodies; Middle Aged; Pancreatectomy; Pancreatic Neoplasms

Topics: Adenoma, Islet Cell; Blood Glucose; C-Peptide; Calcium; Humans; Hypoglycemia; Pancreatic Neoplasms; Proinsulin

The contents of insulin and C-peptide extractable with acid alcohol from the tail of the pancreas and insulinoma were investigated, using gel filtration in seven nondiabetics including two patients with insulinoma and eight diabetics. The gel filtration patterns of both C-peptide and insulin in pancreatic extract were fairly stable even after the pancreas had been left for 14 hrs in the room temperature. In nondiabetics except cases of insulinoma the content of insulin in pancreas ranged from 1.42 to 4.56 U per gram and that of C-peptide from 8.76 to 25.63 microgram per gram wet pancreas. The proportion of proinsulinlike components (PLC) ranged from 0.01 to 2.04% of insulin plus PLC. In diabetics insulin content was low and ranged from 0 to 1.68 U per gram and that of C-peptide from 0 to 14.48 microgram per gram wet pancreas. In insulinoma, both insulin and C-peptide increased and PLC occupied 5.48 and 5.96%, respectively.

Topics: Adenoma, Islet Cell; Adult; Aged; C-Peptide; Chromatography, Gel; Diabetes Mellitus; Female; Humans; Insulin; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Peptides; Proinsulin

A simple diagnostic strategy in the diagnosis of insulinoma in adult subjects is proposed based upon the literature and own experiences. It comprises measurement of plasma proinsulin, insulin and C-peptide as well as blood glucose after an overnight fast. When a low or normal proinsulin concentration is found, organic hyperinsulinaemia is very unlikely, while elevated proinsulin, after exclusion of uremia, hepatic cirrhosis, thyreotoxicosis and surreptitious administration of insulin or sulfonylurea drugs, strongly indicates this condition.

Topics: Adenoma, Islet Cell; Adult; Blood Glucose; C-Peptide; Fasting; Female; Humans; Insulin; Insulin Secretion; Male; Pancreatic Neoplasms; Proinsulin; Radioimmunoassay

Calcium gluconate (10 mg Ca(++)/kg) was administered intravenously over a 2-hour period to 16 adult patients who were evaluated for hypoglycemia. In nine of ten patients with benign or malignant insulinomas (eight proven at operation, and two with positive chemical tests and angiographic localization awaiting operation), significant hypoglycemia and hyperinsulinemia occurred within 60 to 90 minutes after the start of the calcium infusion. Serum proinsulin and Cpeptide concentrations increased at the time of the calciuminduced hyperinsulinemia in several patients in whom these parameters were studied. The one individual who did not respond to the calcium infusion was found to have a benign insulinoma. His basal glucose/insulin ratio of 0.64 was the lowest of the insulinoma group and thus his failure to respond to calcium may indicate that his tumor was secreting maximally at the time of the infusion. Following successful removal of the insulinoma, calcium infusion did not result in changes in serum glucose or insulin concentrations (tested in five patients). In contrast, neither a patient with pathologically documented islet cell hyperplasia, five others with reactive, fupctional or drug-induced hypoglycemia, nor four healthy volunteers showed any changes in circulating glucose or insulin levels while receiving calcium intravenously. Calcium infusion is a safe, rapid and effective provocative test for the diagnosis of insulin-secreting, islet cell tumors of the pancreas.

Topics: Adenoma, Islet Cell; Adult; Blood Glucose; C-Peptide; Calcium; Child; Humans; Infusions, Parenteral; Insulin; Male; Pancreatic Neoplasms; Proinsulin

Topics: Adenoma, Islet Cell; Arginine; Blood Glucose; C-Peptide; Glucagon; Glucose Tolerance Test; Humans; Insulin; Liver Neoplasms; Male; Middle Aged; Somatostatin; Streptozocin

Computerized tomographic localization of insulinomas utilises the differences in radiodensity between the tumor and the adjacent pancreatic tissue. With the aid of this new technique four insulinomas have been localized preoperatively. All of the tumors had the same radiodensity. Firm, well encapsulated beta-islet-cell tumors were detected with the same ease as an insulinoma, which was soft and almost without encapsulation. The smallest tumor detected was 1.0 cm in diameter. Of the four insulinomas, localized by computer tomography of the body, only one was also detected angiographically and only two were detected sonographically.

Topics: Adenoma, Islet Cell; Adult; Angiography; Blood Glucose; C-Peptide; Fasting; Female; Humans; Insulin; Male; Middle Aged; Tomography, X-Ray Computed; Ultrasonography

The glucose-controlled insulin infusion system (GCIIS), the socalled artificial beta-cell, is an important and useful device for detecting and treating hypoglycemic reactions. The dangers of several diagnostic tests such as the tolbutamide or the insulin response test may successfully be avoided. Patients suffering from severe hypoglycemia are kept in normoglycemia by the feedback-controlled dextrose infusion before and during operation.

Topics: Adenoma, Islet Cell; Adult; Artificial Organs; Blood Glucose; C-Peptide; Feedback; Female; Humans; Insulin; Islets of Langerhans; Male; Middle Aged; Monitoring, Physiologic; Pancreatic Neoplasms; Tolbutamide

Proinsulin is converted to insulin and C-peptide in the pancreatic in the pancreatic beta cells: the latter two peptides are secreted in equimolar concentrations. Thus, measurements of serum C-peptide provide a means of assessing pancreatic beta cell function in addition to that of insulin. This technique has proved particularly useful in insulin treated diabetic patients in whom the development of circulating insulin antibodies interferes with the radioimmunoassay of the hormone. The C-peptide assay has also been used to facilitate the diagnosis of various hypoglycemic conditions, including islet cell tumors and factitious injection of insulin. The extraction of C-peptide in the urine reflects average serum values over a period of time and urine C-peptide measurements are especially useful in children or individuals in whom repeated blood sampling is difficult.

Topics: Adenoma, Islet Cell; C-Peptide; Diabetes Mellitus; Humans; Hypoglycemia; Insulin Antibodies; Islets of Langerhans; Pancreas; Pancreatic Neoplasms; Peptides; Proinsulin

Topics: Adenoma, Islet Cell; Adult; Aged; Blood Glucose; C-Peptide; Female; Humans; Male; Middle Aged; Pancreatic Neoplasms; Peptides

During hypoglycemia induced by an infusion of porcine insulin, impaired suppression of endogenous insulin secretion as measured by C-peptide was demonstrated in 11 of 12 patients with insulinoma. During hypoglycemia (plasma glucose less than or equal to 40 mg/dl) the mean C-peptide immunoreactivity (CPR) of normal subjects was less than or equal to 1.2 ng/ml, whereas 11 of 12 insulinoma patients had a mean CPR of larger than or equal to 1.9 ng/ml. One patient showed normal CPR suppression by these criteria but may have shown impaired CPR suppression for glucose less than or equal to 30 mg/dl. Impaired CPR suppression during insulin-induced hypoglycemia may prove to be a useful test for insulinoma.

Topics: Adenoma, Islet Cell; Adult; Aged; Blood Glucose; C-Peptide; Feedback; Female; Humans; Insulin; Insulin Secretion; Male; Middle Aged; Pancreatic Neoplasms; Peptides; Proinsulin; Time Factors

In seven patients with factitious hypoglycemia due to the surreptitious injection of insulin, we made the diagnosis by measurements of plasma insulin and C-peptide immunoreactivity (in seven patients), facilitated by the finding of circulating insulin-binding antibodies (in two patients). The simultaneous demonstration of low plasma glucose, high immunoreactive insulin and suppressed C-peptide immunoreactivity represents a triad of results pathognomonic of exogenous insulin administration. Determination of plasma free C-peptide and free insulin permitted patients with high titers of insulin antibodies, including those with a history of insulin-treated diabetes, to be studied and diagnosed in a way similar to that in subjects who had no circulating insulin antibodies.

Topics: Adenoma, Islet Cell; Adolescent; Adult; C-Peptide; Child, Preschool; Diabetes Complications; Female; Humans; Hypoglycemia; Insulin; Insulin Antibodies; Male; Pancreatic Neoplasms; Peptides; Self Medication; Substance-Related Disorders

Topics: Adenoma, Islet Cell; Animals; Blood Glucose; C-Peptide; Fasting; Fishes; Humans; Insulin; Peptides; Proinsulin; Radioimmunoassay

Topics: Adenoma, Islet Cell; C-Peptide; Glucagon; Humans; Insulin; Insulin Secretion; Pancreatic Neoplasms; Peptides; Stimulation, Chemical

Topics: Adenoma, Islet Cell; Adult; Aged; C-Peptide; Child; Diabetes Mellitus; Glucose Tolerance Test; Humans; Male; Middle Aged; Pancreatic Neoplasms; Peptides

Topics: Adenoma, Islet Cell; C-Peptide; Diabetes Mellitus; Humans; Insulin; Peptides