c-peptide and Insulinoma

Insulinoma is an exceedingly uncommon pancreatic islet cell neuroendocrine tumor. Its estimated incidence is approximately four cases per million individuals per year.. We report the case of sporadic insulinoma in an exceptionally very young 10-year-old boy who presented with a 1-month history of episodic tremulousness, diaphoresis, increased hunger, confusion and fainting. Initial laboratory investigations showed low blood glucose (64 mg/dL) and high blood insulin (6 μU/mL) levels. Patient was admitted in view of frequent hypoglycemic symptoms and possible pancreatic insulinoma. A 48-hour mentored fasting test was done and ceased within 3 hours due to occurrence of hypoglycemic symptoms. During the episode, blood was drawn and results showed low blood glucose level and high insulin, pro-insulin and C-peptide levels. The hypoglycemic symptoms were relieved greatly by glucose administration and Whipple's triad for insulinoma was met. An abdominal contrast-enhanced computed tomography scan showed a 10 x 12 x 17 mm, small, well-demarcated, heterogeneously enhancing lesion within the body of pancreas without dilatation of pancreatic duct. No evidence of lymphadenopathy or distant metastasis was identified. Patient underwent enucleation of pancreatic tumor. Histopathological and immunohistochemical examination of the pancreatic mass confirmed neuroendocrine tumor (insulinoma). Patient had an uneventful recovery. A post-operative 6-month follow-up showed resolution of hypoglycemic symptoms, normalized blood glucose, insulin, pro-insulin and C-peptide levels, and no evidence of recurrence.. Although rare, sporadic insulinoma should be considered in the differential diagnosis of any young individual presenting with frequent hypoglycemic symptoms (neuroglycopenic and/or autonomic nervous system symptoms). Furthermore, a literature review on insulinoma is presented.

Topics: Blood Glucose; C-Peptide; Child; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Pancreatectomy; Pancreatic Neoplasms; Recurrence; Tomography, X-Ray Computed

Studies of the biosynthesis of insulin in a human insulinoma beginning in 1965 provided the first evidence for a precursor of insulin, the first such prohormone to be identified. Further studies with isolated rat islets then confirmed that the precursor became labeled more rapidly than insulin and later was converted to insulin by a proteolytic processing system located mainly within the secretory granules of the beta cell and was then stored or secreted. The precursor was designated "proinsulin" in 1967 and was isolated and sequenced from beef and pork sources. These structural studies confirmed that the precursor was a single polypeptide chain which began with the B chain of insulin, continued through a connecting segment of 30-35 amino acids and terminated with the A chain. Paired basic residues were identified at the sites of excision of the C-peptide. Human proinsulin and C-peptide were then similarly obtained and sequenced. The human C-peptide assay was developed and provided a useful tool for measuring insulin levels indirectly in diabetics treated with insulin. The discovery of other precursor proteins for a variety of peptide hormones, neuropeptides, or plasma proteins then followed, with all having mainly dibasic cleavage sites for processing. The subsequent discovery of a similar biosynthetic pathway in yeast led to the identification of eukaryotic families of specialized processing subtilisin-like endopeptidases coupled with carboxypeptidase B-like exopeptidases. Most neuroendocrine peptides are processed by two specialized members of this family - PC2 and/or PC1/3 - followed by carboxypeptidase E (CPE). This brief report concentrates mainly on the role of insulin biosynthesis in providing a useful early paradigm of precursor processing in the secretory pathway.

Topics: Animals; C-Peptide; Carboxypeptidase H; Cattle; History, 20th Century; Humans; Insulin; Insulin-Secreting Cells; Insulinoma; Neuropeptides; Proinsulin; Proprotein Convertase 1; Proprotein Convertase 2; Protein Precursors; Protein Processing, Post-Translational; Rats; Saccharomyces cerevisiae; Swine

Topics: Biomarkers; C-Peptide; Chromatography, Gel; Diabetes Mellitus, Type 2; Diagnostic Techniques, Endocrine; Factitious Disorders; Humans; Hypoglycemia; Immunoassay; Insulin Resistance; Insulin-Secreting Cells; Insulinoma; Kidney Diseases; Pancreatic Function Tests; Pancreatic Neoplasms; Proinsulin; Reference Values; Specimen Handling

More than 90% of insulinomas are benign tumors. Insulinomas cause hypoglycemia and thereby symptoms of neuroglycopenia and catecholamine response. During symptoms, blood glucose levels should be less than 40 mg/dl (less than 2.2 mmol/l), concomitant insulin levels should be > or =6 IU/ml (> or =43 pmol/l) and concomitant C-peptide levels > or =0.2 pmol/l. Most insulinomas can be identified intraoperatively by experienced surgeons. Initial therapy consists of administration of frequent meals and/or by glucose infusion. In patients with solitary insulinomas, complete surgical removal of the tumor should be the primary goal. In patients with metastatic insulinomas, symptoms of insulin hypersecretion will only completely disappear after complete resection of all metastases.

Topics: C-Peptide; Humans; Insulin; Insulinoma; Pancreatic Neoplasms

Topics: Amino Acid Sequence; Biomarkers; C-Peptide; Diabetes Mellitus; Humans; Immunoassay; Insulin; Insulinoma; Molecular Sequence Data; Pancreatic Neoplasms; Proinsulin; Protein Precursors

Topics: Algorithms; C-Peptide; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Proinsulin

After beta-cell stimulation by carbohydrate or other secretagogues, insulin and C-peptide are secreted into the portal vein in a 1:1 molar ratio. A large fraction of endogenous insulin is cleared by the liver, whereas C-peptide, which is cleared primarily by the kidney and has a lower metabolic clearance rate than insulin, traverses the liver with essentially no extraction by hepatocytes. Hence, the molar ratio of insulin to C-peptide in peripheral venous blood (ICPR) should be less than 1.0 during fasting and feeding, unless exogenous insulin is introduced into the systemic circulation. Consequently, an ICPR in excess of 1.0 in a hypoglycemic patient argues persuasively for surreptitious or inadvertent insulin administration and against insulinoma (or sulfonylurea ingestion) as the cause of the hypoglycemia. This conclusion is supported by personal experience and by the literature.

Topics: Adult; Aged; C-Peptide; Diagnosis, Differential; Drug Overdose; Factitious Disorders; Female; Humans; Hypoglycemia; Infant; Insulin; Insulinoma; Male; Middle Aged; Osmolar Concentration; Pancreatic Neoplasms

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

Many other hypoglycemic states can be confused with an insulinoma. This article presents the diagnosis, localization, and therapy of these islet cell tumors. Also presented is a discussion of the role of nesidioblastosis in persistent hyperinsulinemic hypoglycemia in the neonate.

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

Topics: Adolescent; Animals; Base Sequence; C-Peptide; Diabetes Mellitus, Type 1; DNA, Recombinant; Drug Contamination; Female; Genes; Glucose; Humans; Insulin; Insulin Antibodies; Insulinoma; Liver; Male; Middle Aged; Pancreatic Neoplasms; Pregnancy; Pregnancy in Diabetics; Proinsulin; Protein Biosynthesis; Protein Precursors; RNA, Messenger

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

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Diabetes Mellitus; Diabetes Mellitus, Type 1; Female; Glucagon; Humans; Hypoglycemia; Infant, Newborn; Insulin; Insulinoma; Islets of Langerhans; Kidney Function Tests; Middle Aged; Peptides; Radioimmunoassay

The finding of insulin levels above a minimum threshold at the time of symptomatic hypoglycaemia is crucial in the diagnosis of endogenous hyperinsulinism. The aim of this study was to evaluate insulin levels at the time of hypoglycaemia with an insulin-specific assay in such patients.. We measured insulin levels in 15 patients with fasting hypoglycaemia related to endogenous hyperinsulinism using an insulin-specific immunoradiometric assay (IRMA) without any significant cross-reaction with intact proinsulin.. Insulin levels were below 6 mIU/l in all the samples taken at the time of symptomatic hypoglycaemia in 6/15 patients, and in some of the samples in three patients; insulin levels were below 3 mIU/l in samples from 5 patients. C-peptide levels were above 0.6 ng/ml in all these samples. The lowest proinsulin level was 35 pmol/l. Insulin levels were measured with a less specific RIA (40% cross-reaction with proinsulin) in 8/15 patients and were above 6 mIU/l in all samples in seven patients, and all but one sample in the 8th patient. Mean concomitant C-peptide and insulinoma size were lower in those patients with insulin-IRMA levels below 6 mIU/l.. Symptomatic hypoglycaemia below 0.45 g/l can result from insulin levels below 6 or even 3 mIU/l; lower insulin levels and secretion could be observed preferentially in small insulinomas. If an insulin assay devoid of any significant cross-reaction with intact proinsulin is employed, measuring C-peptide (and/or proinsulin) levels at the time of symptomatic hypoglycaemia is mandatory to make the diagnosis of endogenous hyperinsulinism.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Fasting; Female; Humans; Hyperinsulinism; Hypoglycemia; Immunoradiometric Assay; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Proinsulin

Surgical removal is the treatment of choice for insulinomas. Definitive biochemical diagnosis of organic hyperinsulinism has to be established before surgery. These tumors are sometimes undetected by preoperative imaging investigations and, in addition, surgical management may also be complicated by the absence of palpable tumors or the presence of multiple tumors. We report the value of the euglycemic clamp technique for diagnosis and surgical treatment in 21 patients with confirmed insulinomas. Data were compared with 12 controls, and nine patients were retested after surgery. During the euglycemic hyperinsulinic clamp, the mean C-peptide value was 3.6+/-2.2 ng/ml and it remained high (3.8+/-2.5 ng/ml), despite exogenous hyperinsulinemia (1762.7+/-233.2 microU/ml for the highest plateau). In contrast, the C-peptide concentration declined in 12 control patients (0.3+/-0.1 ng/ml, P < 0.001) and after successful surgery in nine retested patients (0.3+/-0.2 ng/ml, P < 0.01). During continuous glucose monitoring, successful removal of the insulin-secreting tumor was accompanied by an increase in plasma glucose concentrations and a loss of requirement for endogenous glucose within 36 min (range 28-43 min). The continuing requirement for glucose after the ablation of the tumor revealed the existence of additional and initially undetected tumors in four patients, among whom two had the multiple endocrine neoplasia type I (MEN I) syndrome. We conclude that the euglycemic hyperinsulinic clamp is a reliable and convenient diagnostic test for insulinoma, as it is both safe (no hypoglycemia) and relatively brief (3 x 90 min). Glucose monitoring and glucose clamping provide a reliable indicator of complete removal of insulin-hypersecreting tissue, especially in patients with occult or multiple tumors.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Female; Glucose Clamp Technique; Humans; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms

The amounts of immunoreactive proinsulin (IRP), immunoreactive insulin (IRI), and C-peptidelike immunoreactivity (CPR) in six insulinomas and one nesidioblastosis lesion were determined together with those in the surrounding pancreatic tissue. Four non-insulinoma and nondiabetic human pancreases were used as the control. The IRP in the seven tumors ranged from 5.85 micrograms/g to 65.45 micrograms/g (mean +/- SEM, 28.70 +/- 8.01 micrograms/g), while the IRP in the surrounding pancreatic tissue ranged from 2.08 micrograms/g to 11.71 micrograms/g (5.32 +/- 1.76 micrograms/g). Control pancreases had an IRP content of 12.01 +/- 2.36 micrograms/g. The IRI in the seven tumors ranged from 4.02 U/g to 47.97 U/g (14.40 +/- 6.35 U/g), while that in the surrounding pancreatic tissue ranged from 0.28 U/g to 3.64 U/g (2.32 +/- 0.63 U/g). Mean tumor CPR was 206.84 +/- 81.6 micrograms/g and it was 29.16 +/- 9.15 micrograms/g in the surrounding pancreatic tissue. The molar ratio of the IRP to IRI content was 6.83 +/- 1.95% for tumor tissue and 6.24 +/- 2.18% for the surrounding pancreatic tissue. These levels were similar to the ratio in the control pancreases (7.67 +/- 1.88%), in contrast to the higher serum IRP/IRI ratio in the tumor patients.

Topics: Adult; Aged; Aged, 80 and over; C-Peptide; Female; Humans; Insulin; Insulinoma; Male; Middle Aged; Pancreas; Pancreatic Diseases; Pancreatic Neoplasms; Proinsulin

This study investigated insulinoma-associated-2 autoantibody (IA-2A) and zinc transporter 8 autoantibody (ZnT8A) distribution in patients with type 1 diabetes (T1D) and latent autoimmune diabetes (LAD) and the autoantibodies' association with clinical characteristics and HLA-DR-DQ genes.. This cross-sectional study recruited 17,536 patients with diabetes from 46 hospitals across China. A total of 189 patients with T1D and 58 patients with LAD with IA-2A positivity, 126 patients with T1D and 86 patients with LAD with ZnT8A positivity, and 231 patients with type 2 diabetes (T2D) were selected to evaluate islet autoantibodies, clinical phenotypes, and HLA-DR-DQ gene frequency.. IA-2A was bimodally distributed in patients with T1D and LAD. Patients with low IA-2A titre LAD had lower fasting C-peptide (FCP) (p < 0.01), lower postprandial C-peptide (PCP) (p < 0.001), and higher haemoglobin A1c (HbA1c) levels (p < 0.05) than patients with T2D. Patients with high IA-2A titre LAD were younger than patients with low IA-2A titre LAD (p < 0.05). Patients with low IA-2A titre T1D had lower FCP (p < 0.01), lower PCP (p < 0.01), and higher HbA1c levels (p < 0.05) than patients with high IA-2A titre LAD. HLA-DR-DQ genetic analysis demonstrated that the frequency of susceptible HLA haplotypes was higher in IA-2A-positive patients (p < 0.001) than in patients with T2D. Patients with high ZnT8A titre LAD had lower FCP (p = 0.045), lower PCP (p = 0.023), and higher HbA1c levels (p = 0.009) and a higher frequency of total susceptible haplotypes (p < 0.001) than patients with low ZnT8A titre LAD.. IA-2A in patients with T1D and LAD was bimodally distributed, and the presence of IA-2A could demonstrate partial LAD clinical characteristics. ZnT8A titre had a certain predictive value for islet functions in patients with LAD.

Topics: Autoantibodies; C-Peptide; Cation Transport Proteins; Cross-Sectional Studies; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Glucose Intolerance; Glutamate Decarboxylase; Glycated Hemoglobin; HLA-DR Antigens; Humans; Insulinoma; Pancreatic Neoplasms; Zinc Transporter 8

Islet-cell associated antibodies are predictive and diagnostic markers for type 1 diabetes. We studied the differences in the early clinical course of children with type 1 diabetes with a single antibody and those with multiple antibodies against pancreatic β-cells. Sixty-seven children with type 1 diabetes aged less than 15 years diagnosed between 2010 and 2021 were included in the study and subdivided into two subgroups: children who were single positive for either glutamic acid decarboxylase (GAD) antibodies (n = 16) or insulinoma-associated antigen-2 (IA-2) antibodies (n = 13) and those positive for both antibodies (n = 38) at diagnosis. We compared the patients' clinical characteristics, pancreatic β-cell function, and glycemic control during the 5 years after diagnosis. All clinical characteristics at diagnosis were similar between the two groups. One and two years after diagnosis, children who tested positive for both antibodies showed significantly lower postprandial serum C-peptide (CPR) levels than those who tested positive for either GAD or IA-2 antibodies (p < 0.05). In other periods, there was no significant difference in CPR levels between the two groups. There was a significant improvement in glycosylated hemoglobin (HbA1c) levels after starting insulin treatment in both groups (p < 0.05), but no significant difference in HbA1c levels between the groups. Residual endogenous insulin secretion may be predicted based on the number of positive islet-cell associated antibodies at diagnosis. Although there are differences in serum CPR levels, optimal glycemic control can be achieved by individualized appropriate insulin treatment, even in children with type 1 diabetes.

Topics: Adolescent; Autoantibodies; C-Peptide; Child; Diabetes Mellitus, Type 1; Female; Glutamate Decarboxylase; Glycated Hemoglobin; Humans; Insulin; Insulinoma; Male

A 50-year-old woman was hospitalized for fainting caused by hypoglycemia. Her blood glucose level was low (40 mg/dL), immunoreactive insulin was 16.9 μU/mL, and C-peptide level was high (4.8 ng/mL). Computed tomography and magnetic resonance imaging revealed a 7-mm tumor in the uncinate process of the pancreas. A selective arterial calcium injection test indicated an increase in the superior mesenteric artery. Insulinoma of the uncinate process of the pancreas was diagnosed, and tumor enucleation was planned using an artificial pancreas for intraoperative and postoperative blood glucose control. Hypoglycemia (blood glucose, 38 mg/dL) was observed from the onset of surgery. An artificial pancreas cannot be used if the blood glucose level is ≤ 70 mg/dL; thus, continuous glucose infusion was administered. The sudden rise in blood glucose prompted insulin infusion from the device, causing hypoglycemia. Controlling blood glucose levels is challenging when introducing the artificial pancreas. However, altering the device's blood glucose control algorithm controlled the fluctuating blood glucose level, and, intraoperative average blood glucose was raised to 94.8 ± 21.1 mg/dL, thereby avoiding hypoglycemia, that is, a blood glucose level of ≤ 70 mg/dL. We report a case in which an artificial pancreas was used for glycemic control during surgery for an insulinoma.

Topics: Blood Glucose; C-Peptide; Calcium; Female; Glucose; Humans; Hypoglycemia; Insulin; Insulinoma; Middle Aged; Pancreas, Artificial; Pancreatic Neoplasms

Insulinoma, owing to the low incidence and small volume of the tumor, is often undiagnosed. The 72-h fast test is centered on diagnosing insulinoma; however, it cannot be performed on outpatients. Our aim was to evaluate the results of a 3-h oral glucose tolerance test (3-h OGTT) for insulinoma diagnosis.. Thirty-seven patients with insulinoma were enrolled for comparison with 42 control subjects. All patients underwent 3-h OGTT with measurements of insulin and C-peptide. The secretion ratios of insulin and C-peptide at 1, 2, and 3 h were calculated by comparison with their values at 0 h. We used logistic regression analysis to establish the predictive models and compared the diagnostic efficiency by receiver operating characteristic analysis.. The fasting insulin and C-peptide levels of insulinoma patients were both higher; however, the concentrations at 1 h and 2 h were both lower (P < 0.05). The levels at 3 h were not significantly different (P > 0.05). Our final logistic regression model was constructed as follows: logit (P) = 8.305 - 0.441 × insulin 2 h/0 h ratio - 1.679 × C-peptide 1 h/0 h ratio. A cutoff value of > 0.351 showed the highest diagnostic accuracy, with an area under the curve of 0.97, a sensitivity of 86.5%, and a specificity of 95.2%.. The 2-h/0-h insulin ratio, as well as the 1-h/0-h C-peptide ratio, has high diagnostic efficiency for insulinoma. The 2-h OGTT can be an alternative test for diagnosing insulinoma in outpatient settings.

Topics: Adult; Aged; Ambulatory Care; C-Peptide; Female; Glucose Tolerance Test; Humans; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Predictive Value of Tests; Reproducibility of Results; Retrospective Studies; Secretory Pathway; Time Factors

How malignant insulinomas present relative to benign insulinomas is unknown.. A single-institution retrospective study identified patients with insulinoma. Malignancy was defined by distant metastases, positive lymph node(s), T stage of 4, direct invasion into surrounding peripancreatic tissue, or presence of lymphovascular invasion. Wilcoxon Rank Sum tests and Kaplan-Meier analysis were used.. A total of 311 patients were identified: 51 malignant and 260 benign. Patients with malignant insulinoma presented with higher levels of insulin, proinsulin, and c-peptide. Malignant lesions were larger: 4.2 ± 3.2 vs 1.8 ± 0.8 cm in benign lesions, p < 0.01. Overall survival at 5 years was 66.8% vs 95.4% for malignant and benign insulinoma respectively, p < 0.01.. Larger size of insulinoma and increased serum β-cell polypeptide concentrations were associated with malignancy. Malignant insulinoma has poorer survival. Further work-up to rule out malignancy may be indicated for larger pancreatic lesions and for patients with higher pre-operative insulin and pro-insulin.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; C-Peptide; Child; Diagnosis, Differential; Female; Humans; Insulin; Insulinoma; Kaplan-Meier Estimate; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Pancreas; Pancreatic Neoplasms; Retrospective Studies; Young Adult

Topics: Adult; Blood Glucose; C-Peptide; Diagnosis, Differential; Endosonography; Female; Humans; Insulin; Insulinoma; Magnetic Resonance Imaging; Male; Pancreatic Neoplasms; Perfusion Imaging; Positron Emission Tomography Computed Tomography; Proinsulin; Sensitivity and Specificity; Tomography, X-Ray Computed

Mistletoe (Viscum album), an evergreen parasitic plant, has been widely used as an oriental phytomedicine to treat diabetes mellitus. However, it is unknown which mistletoe constituent exerts the beneficial effect against the disease. In this study, we examined the hypoglycemic activity of mistletoe and investigated whether the polypeptide viscothionin, purified from mistletoe, was responsible for the activity.. Mistletoe extracts were prepared by heating mistletoe powder made of leaves and twigs in water for 3, 6, 9, and 12 h. Rat insulinoma RINm5F cells were used to test the cytotoxicity of the extracts and their effects on the secretion of insulin and its precursor, C-peptide. The inhibitory effects of a mistletoe extract on glucose absorption were measured using an α-glucosidase inhibition assay. To determine the component of mistletoe responsible for the observed effects, the mistletoe extract was precipitated with ethanol or hydrolyzed with a protease for further testing. A potential active constituent of mistletoe was isolated by chromatography and molecular weight cut-off fractionation, and its ability to induce insulin secretion was investigated.. A 12-h heat-treated mistletoe extract, showing no cytotoxicity, significantly increased the secretion of insulin and C-peptide by RINm5F cells and enhanced the expression of glucose transporter type 4 (GLUT-4), insulin receptor substrate 1 (IRS-1), and protein kinase B (also known as AKT) in differentiated C2C12 cells. The extract also inhibited α-glucosidase activity. After ethanol precipitation, the extract showed much stronger effects on insulin- and C-peptide-secreting activities of cells, whereas the enzyme-hydrolyzed extract was less effective than the original extract, suggesting that the effect was mediated by a proteinaceous constituent of mistletoe. Subsequent analysis showed that viscothionin, a heat-stable 6-kDa polypeptide isolated from mistletoe, increased the level of insulin secretion by more than 20-fold compared to that induced by the extract.. Our study indicates that the hypoglycemic effect of mistletoe is mediated by its insulinotropic action and α-glucosidase inhibitory activity, and the effect is due to viscothionin, one of the major bioactive constituents of mistletoe.

Topics: Animals; C-Peptide; Cell Line, Tumor; Glucose; Hypoglycemic Agents; Insulin Secretion; Insulin-Secreting Cells; Insulinoma; Mice; Myoblasts; Peptides; Plant Extracts; Rats; Time Factors; Viscum album

Insulinoma is the commonest functioning pancreatic neuroendocrine tumor causing hyperinsulinemic hypoglycemia.. This study is aimed to evaluate the clinical features, preoperative laboratory and imaging diagnosis and pathologic findings of insulinoma.. Data of the patients from 2001 to 2016 diagnosed as insulinoma in Tongji Hospital, China were retrospectively extracted and analyzed.. A total of 40 patients were diagnosed as insulinoma with a male/female ratio of 0.68:1. The median onset age was 46.5 years. Nearly all the included patients presented neurological symptoms and 60% presented autonomic symptoms. More than 95% of the patients met the functional European Neuroendocrine Tumor Society criteria including glucose, insulin and C-peptide levels. The preoperative detection rates of ultrasonography, enhanced computed tomography, magnetic resonance imaging, and endoscopic ultrasonography were 60.50%, 84.95%, 80% and 83.3% respectively. The joint imaging examinations can markedly increase the detection rate. The mean tumor size was 1.89 ± 0.72 cm. Ki-67 index by histopathological diagnosis were all less than 20%. The positive rates of insulin, synaptophysin and chromogranin A were close to 100%.. Laboratory tests of glucose, insulin and C-peptide are reliable for preoperative diagnosis. Combination of the imaging examinations can improve the diagnosis.

Topics: Adult; Aged; Blood Glucose; C-Peptide; China; Endosonography; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Magnetic Resonance Imaging; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies; Tomography, X-Ray Computed; Ultrasonography; Young Adult

Insulinoma is a rare pancreatic tumor and, usually, a benign disease but can be a malignant one and, sometimes, a highly aggressive disease. The aim of this study was to determine differences between benign and malignant tumors.. Retrospective study of 103 patients with insulinoma treated in a tertiary center. It was analyzed demographic, clinical, laboratory, localization and histologic analysis of tumor and follow up data of subjects in order to identify differences between individuals benign and malignant disease.. Almost all patients (87%) had a benign tumor and survival rates of 100% following pancreatic tumor surgery. Those with malignant tumors (13%) have a poor prognosis, 77% insulinoma-related deaths over a period of 1-300 months after the diagnosis with a survival rate of 24% in five years. The following factors are associated with an increased risk of malignant disease: duration of symptoms < 24 months, fasting time for the occurrence of hypoglycemia < 8 h, blood plasma insulin concentration ≥ 28 μU/mL and C-peptide ≥ 4.0 ng/mL at the glycemic nadir and tumor size ≥ 2.5 cm.. Our data help to base the literature about these tumors, reinforcing that although insulinoma is usually a single benign and surgically treated neoplasia, the malignant one is difficult to treat. We highlight the data that help predict a malignancy behavior of tumor and suggest a long follow up after diagnosis in these cases.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cohort Studies; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Kaplan-Meier Estimate; Male; Middle Aged; Multiple Endocrine Neoplasia; Pancreatic Neoplasms; Retrospective Studies; Risk Factors; Survival Analysis; Young Adult

The 72-hour fast is used to document Whipple's triad and understand the mechanism of hypoglycemia. Although hypoglycemia develops within 24 hours in the majority of fasts, identifying possible determinants of fast duration may help to predict the need for admission. Therefore, we determined the relation between anthropometric features on fast duration and assessed end of fast parameters on maximal tumor size, extent of disease, or tumor recurrence.. A retrospective analysis of patients with insulinoma in the past 25 years who underwent a 72-hour fast was conducted. Electronic medical records were reviewed to obtain anthropometric patient data and tumor characteristics.. A total of 233 patients underwent the 72-hour fast. The mean age at diagnosis was 50 ± 16 years, with a body mass index (BMI) of 29 ± 7 kg/m. Duration of fast was not significantly related age, gender, weight, or BMI, although end-of-fast C-peptide and proinsulin may provide some information regarding tumor characteristics. Consequently, the duration of fast cannot be predicted a priori and should be allowed to run for the planned length unless hypoglycemia develops. Abbreviation: BMI = body mass index.

Topics: Adult; Aged; Anthropometry; Blood Glucose; Body Mass Index; C-Peptide; Fasting; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Proinsulin; Retrospective Studies; Time Factors; Tumor Burden

The 72-hour fast test is the current standard for the diagnosis of insulinoma. However, to conduct this test patients require hospitalization due to the chance of severe hypoglycemic episodes. Thus, it is costly and stressful for the patient. An out-patient test would serve the patient better and be more economical. Our aim was to evaluate the value of insulin to glucose and C-peptide to glucose ratios during a prolonged 5-hour oral glucose tolerance test (5-hour OGTT) in qualitative diagnosis of insulinoma, and to identify the optimal threshold for clinical screening. Initially, 15 subjects with pathological insulinoma and 12 control subjects with reactive hypoglycemia were enrolled in the study. A further 75 subjects with symptoms of hypoglycemia as a chief complaint at their initial clinic visit were subsequently screened. Serum insulin, C- peptide levels and blood glucose were quantified after a 5-hour OGTT in all participants and the ratios of serum concentrations of insulin and C-peptide to glucose were calculated. Subjects with insulinoma had significantly different insulin-to-glucose and C-peptide-to-glucose ratios from reactive hypoglycemia at the times of fasting, 4-hour post glucose load and 5-hour post glucose load. Higher specificity (73.08%) and sensitivity (82.67%) were achieved with the combined insulin-to-glucose ratio at the 5-hour post load and the C-peptide-to-glucose ratio at fasting. In combination, ratios of insulin and C-peptide release relative to blood glucose levels, measured during a 5-hour OGTT, may have important clinical value in the diagnosis of insulinoma.

Topics: Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Diagnostic Techniques, Endocrine; Female; Glucose Tolerance Test; Humans; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Time Factors

The aim of the study was to address the origin and natural history of malignant insulinoma.. Retrospective review of medical records of patients diagnosed with insulinoma at Cedars-Sinai Medical Center between 2000 and 2015 was conducted. Hormonal expression in tumor specimens was examined by immunostaining.. All the 9 patients with malignant insulinoma (35% of 26 patients with insulinoma) already had liver metastasis at hypoglycemia presentation with bulky cumulative tumor burden. Six patients had de novo diagnosis, 2 had known metastatic nonfunctioning pancreatic neuroendocrine tumor, and 1 had a known pancreatic mass. Tumor grade at presentation was G1 in 4 patients, G2 in 4, and unknown in 1. Four patients died 2 to 32 months after presentation, all with extensive liver tumor involvement. Tumor expression of proinsulin and insulin was heterogeneous and overall infrequent. The proinsulin levels and proinsulin/insulin molar ratio in patients with malignant versus benign insulinoma were 334 versus 44 pmol/L and 2.1 versus 0.9, respectively.. Malignant insulinoma seems to arise from and behave like nonfunctioning pancreatic neuroendocrine tumor oncologically but with metachronous hyperinsulinemic hypoglycemia. High proinsulin levels and proinsulin/insulin molar ratio may suggest malignant insulinoma.

Topics: Adult; Aged; C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Liver Neoplasms; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Proinsulin; Retrospective Studies

This study aimed to evaluate the usefulness of the 48-hour fasting test and insulin surrogates followed by a glucagon stimulatory test (GST) for the diagnosis of insulinoma.. Thirty-five patients with suspected insulinoma who underwent 48-hour fasting test and GST were retrospectively included in our study: 15 patients with surgically proven insulinomas and 20 patients in whom insulinoma was clinically ruled out. We determined the duration of the fasting test, plasma glucose levels, serum levels of immunoreactive insulin and C-peptide, and insulin surrogates (serum levels of β-hydroxybutyrate, free fatty acid, and response of plasma glucose to intravenous glucagon [ΔPG]) at the end of the fast.. The sensitivity and specificity of the 48-hour fasting test were 100.0% and 80.0%, respectively, for the diagnosis of insulinoma. When the 48-hour fasting test and immunoreactive insulin, C-peptide, or insulin surrogates were combined, the combination with GST showed the best results. The sensitivity, specificity, and accuracy rate were 93.3%, 95.0%, and 94.3%, respectively, with 1 false-negative case and 1 false-positive case occurring.. A more accurate and less invasive diagnosis of insulinoma was possible by combining the 48-hour fasting test with the GST, compared with the existing method.

Topics: 3-Hydroxybutyric Acid; Adult; Aged; Blood Glucose; C-Peptide; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Humans; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies; Sensitivity and Specificity; Time Factors

Most cases of insulinomas are benign. We report a case of a malignant form of insulinoma. A 46-year-old man presented with behavioural changes associated with hypoglycaemia. Diagnostic work up revealed high serum insulin, high C-peptide and low glucose levels, compatible with endogenous hyperinsulinaemic hypoglycaemia. CT imaging of the abdomen revealed a pancreatic head mass and multiple liver masses. Biopsy of the pancreatic mass revealed a grade three pancreatic neuroendocrine carcinoma. Histological analysis of a liver mass showed that it was identical to the pancreatic mass, confirming its metastatic nature. The patient underwent distal pancreatectomy with en bloc splenectomy. There was persistence of hypoglycaemic symptoms after removal of the pancreatic mass, suggesting that the liver metastases were also functioning. Symptoms were controlled by diazoxide and octreotide long-acting release. The patient is already 1 year postsurgery with no recurrence of severe hypoglycaemia, and he has good functional capacity and has returned to his office job.

Topics: Biopsy; Blood Glucose; C-Peptide; Carcinoma, Neuroendocrine; Diazoxide; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Insulinoma; Liver Neoplasms; Male; Middle Aged; Octreotide; Pancreas; Pancreatectomy; Pancreatic Neoplasms

History and admission findings | A 41year old woman presented at our internistic clinic after treatment by an emergency doctor because of confusion and amnesia accompanied by a hypoglycaemic episode while driving her car. Only by giving continuous glucose intravenously a stable clinical state could be achieved. In her medical history she took Lamotrigin for 12 years since she had seizures of unknown aetiology. 16 years ago she had similar sudden attacks with confusion and hypoglycaemia. At that time thorough diagnostics at the clinic for internal medicine did not reveal any evidence for hyperinsulinaemia. While taking Lamotrigin the patient had no seizures or similar symptoms for 12 years. Treatment and course | In the present case we detected a tumor in the pancreas and a two-fold increased insulin secretion. Histopathological work-up of the removed tissue confirmed the suspected diagnosis of insulinoma. Postoperatively, Lamotrigin treatment was terminated. Since then the patient remained asymptomatic.

Topics: Adult; Amnesia; Anticonvulsants; C-Peptide; Confusion; Endosonography; Female; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulinoma; Lamotrigine; Pancreatic Neoplasms; Recurrence; Seizures; Tomography, X-Ray Computed; Triazines

Topics: Biomarkers, Tumor; Biopsy; Blood Glucose; C-Peptide; Calcium Gluconate; Female; Humans; Immunohistochemistry; Injections, Intra-Arterial; Insulin; Insulinoma; Middle Aged; Pancreatic Neoplasms; Pancreaticoduodenectomy; Splenic Artery; Tomography, X-Ray Computed; Treatment Outcome

A 63-year-old man was diagnosed with diabetes mellitus at 42 years of age. He subsequently exhibited poor blood glucose control for a prolonged period, and his renal failure worsened. He therefore underwent hemodialysis and abdominal magnetic resonance imaging, which revealed a mass in the pancreatic tail. The immunoreactive insulin and C-peptide immunoreactivity levels were significantly elevated, and the results of a fasting test led to a diagnosis of insulinoma. The patient received treatment with oral diazoxide and continuous glucose monitoring (CGM), which resulted in the resolution of the hypoglycemia. This is a rare case of renal failure in which the CGM findings showed improvements in the blood glucose level after diazoxide administration.

Topics: Antihypertensive Agents; Biomarkers, Tumor; Blood Glucose; C-Peptide; Diabetes Mellitus, Type 2; Diazoxide; Humans; Hypoglycemia; Insulin; Insulinoma; Kidney Failure, Chronic; Male; Middle Aged; Pancreatic Neoplasms; Renal Dialysis; Treatment Outcome; Vasodilator Agents

Insulinomas are rare neuroendocrine tumours (NETs) of the pancreas, characterized clinically by neuroglycopenic symptoms during periods of substrate deficiency. The gold standard test for diagnosing an insulinoma is a 72-h fast. However, the prognostic value of parameters in the standardized 72-h fast on histopathological tumour criteria and clinical presentation has not been examined.. In thirty-three patients diagnosed with an insulinoma records, and data were investigated retrospectively. Histopathological tumour characteristics, including staging, grading and size, were reviewed. Grading was performed using Ki-67 index. Cut-off values for classical grading (G(clas)) were set at G1(clas) ≤ 2%, G2(clas) 3-20% & G3(clas) >20% and for modified grading (G(mod)) at G1(mod) <5%, G2(mod) 5-20% & G3(mod) >20%.. When G(mod) criteria were applied, the initial blood glucose was lower in GII/III(mod) patients compared to GI(mod) (2.8 ± 0.8 vs 3.8 ± 1.3 mmol/l; P = 0.046). Basal and end of fast levels of insulin (basal insulin 71 ± 61 vs 20 ± 16 mU/l; P < 0.001; end of fast insulin 77 ± 51 vs 21 ± 20 mU/l; P < 0.001) and c-peptide (basal c-peptide 5.4 ± 2.4 vs 2.7 ± 1.6 μg/l; P = 0.004; end of fast c-peptide 5.3 ± 2.4 vs 2.5 ± 1.4 μg/l; P = 0.001) were significantly higher in GII/III(mod) than in GI(mod). No differences between the groups were observed when G(clas) criteria were applied. Additionally, close correlations were observed between insulin concentration, Ki-67 index and tumour size.. This study shows an impact of histopathological tumour characteristics in patients suffering from an insulinoma on clinical presentation during a standardized 72-h fast. Lower initial blood glucose levels and higher concentrations of insulin and c-peptide are associated with worse tumour grading and larger tumour size.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cohort Studies; Fasting; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Neoplasm Grading; Neoplasm Staging; Pancreatic Neoplasms; Retrospective Studies; Tumor Burden

Recently, in vitro diagnostic tools have shifted focus toward personalized medicine by incorporating patient cells into traditional test beds. These cell-based platforms commonly utilize two-dimensional substrates that lack the ability to support three-dimensional cell structures seen in vivo. As monolayer cell cultures have previously been shown to function differently than cells in vivo, the results of such in vitro tests may not accurately reflect cell response in vivo. It is therefore of interest to determine the relationships between substrate architecture, cell structure, and cell function in 3D cell-based platforms. To investigate the effect of substrate architecture on insulinoma organization and function, insulinomas were seeded onto 2D gelatin substrates and 3D fibrous gelatin scaffolds with three distinct fiber diameters and fiber densities. Cell viability and clustering was assessed at culture days 3, 5, and 7 with baseline insulin secretion and glucose-stimulated insulin production measured at day 7. Small, closely spaced gelatin fibers promoted the formation of large, rounded insulinoma clusters, whereas monolayer organization and large fibers prevented cell clustering and reduced glucose-stimulated insulin production. Taken together, these data show that scaffold properties can be used to control the organization and function of insulin-producing cells and may be useful as a 3D test bed for diabetes drug development.

Topics: Animals; C-Peptide; Cattle; Cell Aggregation; Cell Line, Tumor; Cell Proliferation; Cell Shape; Cell Survival; Glucose; Insulin; Insulinoma; Microscopy, Electron, Scanning; Rats; Tissue Scaffolds

Excessive generation of reactive oxygen species (ROS) causing oxidative stress plays a major role in the pathogenesis of diabetes by inducing beta cell secretory dysfunction and apoptosis. Recent evidence has shown that C-peptide, produced by beta cells and co-secreted with insulin in the circulation of healthy individuals, decreases ROS and prevents apoptosis in dysfunctional vascular endothelial cells. In this study, we tested the hypothesis that an autocrine activity of C-peptide similarly decreases ROS when INS1 beta cells are exposed to stressful conditions of diabetes.. Reactive oxygen species and apoptosis were induced in INS1 beta cells pretreated with C-peptide by either 22 mM glucose or 100 μM hydrogen peroxide (H2 O2 ). To test C-peptide's autocrine activity, endogenous C-peptide secretion was inhibited by the KATP channel opener diazoxide and H2 O2 -induced ROS assayed after addition of either exogenous C-peptide or the secretagogue glibenclamide. In similar experiments, extracellular potassium, which depolarizes the membrane otherwise hyperpolarized by diazoxide, was used to induce endogenous C-peptide secretion. ROS was measured using the cell-permeant dye chloromethyl-2',7'-dichlorodihydrofluorescein diacetate (CM-H2 -DCFDA). Insulin secretion and apoptosis were assayed by enzyme-linked immunosorbent assay.. C-peptide significantly decreased high glucose-induced and H2 O2 -induced ROS and prevented apoptosis of INS1 beta cells. Diazoxide significantly increased H2 O2 -induced ROS, which was reversed by exogenous C-peptide or glibenclamide or potassium chloride.. These findings demonstrate an autocrine C-peptide mechanism in which C-peptide is bioactive on INS1 beta cells exposed to stressful conditions and might function as a natural antioxidant to limit beta cell dysfunction and loss contributing to diabetes.

Topics: Adaptation, Physiological; Animals; Apoptosis; Autocrine Communication; C-Peptide; Cell Line, Tumor; Diazoxide; Disease Models, Animal; Glucose; Glyburide; Hydrogen Peroxide; Hypoglycemic Agents; Insulin-Secreting Cells; Insulinoma; Oxidative Stress; Pancreatic Neoplasms; Potassium Chloride; Rats; Reactive Oxygen Species

The supervised 72-h fast remains the gold standard test for the diagnosis of endogenous hyperinsulinism and has recently been suggested to be shortened or even avoided.. This study aimed to evaluate whether measurement of blood glucose, insulin and C-peptide levels after a 12 h overnight fast (mini-fasting test), in at least 3 consecutive days, could allow making or ruling out diagnosis of endogenous hyperinsulinism, according to the Endocrine Society's recent guidelines.. We performed 12 h mini-fasting test in at least 3 consecutive days, dosing blood glucose, insulin and C-peptide levels in 26 inpatient patients with pathologically proven endogenous hyperinsulinism.. In our series, 100% of patients showed insulin levels of at least 3 μU/ml and C-peptide levels of at least 0.6 ng/ml concomitant with symptomatic hypoglycemia (≤ 55 mg/dl).. It leads to the conclusion that mini-fasting test might avoid, in most cases, prolonged fasting test for the diagnosis of hypoglycemia due to endogenous hyperinsulinism.

Topics: Adolescent; Adult; Biomarkers; Blood Glucose; C-Peptide; Child, Preschool; Fasting; Female; Follow-Up Studies; Humans; Hyperinsulinism; Infant; Insulin; Insulinoma; Male; Middle Aged; Predictive Value of Tests; Treatment Outcome; Young Adult

Hypoglycemia in apparently healthy adults is a rare finding in clinical practice requiring a thorough investigation of the cause. During the investigation, identification of hypoglycemia associated with inappropriately high levels of insulin and C-peptide should prompt the exclusion of rare causes of hypoglycemia, including pancreatic islet-cells disease and autoimmune hypoglycemia. In this paper, we describe two cases of hypoglycemia associated with endogenous hyperinsulinism, whose causes are uncommon in clinical practice, and review important aspects of the diagnosis and treatment of hyperinsulinemic hypoglycemia.

Topics: C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Multiple Myeloma; Pancreas; Pancreatic Neoplasms; Proinsulin; Ultrasonography

A 68-year-old man presented to the accident and emergency department with a history of central chest pain associated with exertion. He was admitted for assessment and when an acute coronary syndrome was excluded, he underwent exercise stress testing. His exercise stress testing was discontinued due to lightheadedness. His capillary glucose was checked and it showed hypoglycaemia (2.2 mmol/l). In light of this, a 72 h supervised fast was performed and it became positive within 24 h with low plasma glucose, inappropriately high insulin and C peptide levels. Sulfonylurea screen was negative. CT, MRI and endoscopic ultrasound revealed a 2 cm pancreatic tail insulinoma. He underwent successful surgical enucleation of this lesion.

Topics: Aged; Blood Glucose; C-Peptide; Exercise Test; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Pancreatic Neoplasms

The objective of the present study was to determine whether a plasma β-hydroxybutyrate (BOHB) level >2700 μmol/l during the 72-h fasting test is sufficient to rule out the diagnosis of endogenous hyperinsulinaemic hypoglycaemia (EHH).. We retrospectively studied BOHB levels in 39 patients with EHH who had undergone a 72-H fasting test to make the diagnosis of EHH, and we compared EHH patients with BOHB levels 2700 MOL/L (group 1), EHH PATIENTS with BOHB levels 2700 MOL/L (group 2) and 59 controls (median glycaemia: 3.2  mmol/l and median BOHB: 6095 μmol/l).. During a 72-h fasting test, nine patients (group 1) had BOHB levels >2700  μmol/l (median 6140 and range 2957-7824) and 30 patients (group 2) had BOHB levels <2700 μmol/l (median 542 and range 0-2607). In group 1, four patients had undergone partial pancreatectomy previously and were evaluated for the recurrence of hypoglycaemia, whereas none of the group 2 patients had been operated. The duration of the fasting test was longer in group 1 than in group 2 (P<0.0001), and at the end of the fasting test, plasma glucose concentrations were not significantly different (P=0.0617), but insulin (P=0.004), C-peptide (P=0.0015) and proinsulin (P=0.0038) levels were significantly lower in group 1 patients than in group 2 patients, suggesting lower insulin secretion and/or impaired glycaemic counter-regulation.. During a fasting test, a BOHB level >2700 μmol/l is observed in some EHH patients, suggesting that BOHB levels cannot rule out the recurrence of EHH, in particular, after partial pancreatectomy.

Topics: 3-Hydroxybutyric Acid; Adult; Aged; Aged, 80 and over; Biomarkers; Blood Glucose; C-Peptide; Diagnosis, Differential; Fasting; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulinoma; Male; Middle Aged; Multiple Endocrine Neoplasia Type 1; Pancreatectomy; Pancreatic Neoplasms; Predictive Value of Tests; Reproducibility of Results; Retrospective Studies; Sensitivity and Specificity; Time Factors; Treatment Outcome

Nesidioblastosis is a rare cause of non insulinoma pancreatogenous hypoglycemic syndrome seen in adults. It is characterized by postprandial hypoglycemia with high insulin and C-peptide levels without any detectable pancreatic lesion. The definitive diagnosis can be made only on histopathological examination of the resected specimen.. We report a case of a 50-year-old lady presenting with hypoglycemic attacks being misdiagnosed preoperatively as insulinoma and treated with enucleation leading to recurrence of symptoms after 6 months. Later medical therapy was tried which failed and patient needed subtotal pancreatectomy for resolution of symptoms.. Nesidioblastosis should be suspected in patients with endogenous hyperinsulinemic hypoglycemia without any detectable pancreatic tumor on preoperative imaging.

Topics: C-Peptide; Diagnosis, Differential; Diagnostic Errors; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Islets of Langerhans; Middle Aged; Nesidioblastosis; Pancreatectomy; Pancreatic Neoplasms

Topics: Aged, 80 and over; Blood Glucose; C-Peptide; Confusion; Diazoxide; Epilepsy, Tonic-Clonic; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Vasodilator Agents; Weight Gain

Insulinoma is a tumour of insulin-producing cells of the pancreas and is known to be one of the causes of hypoglycaemia. Usually, appropriate removal of the insulinoma results in normalization of blood glucose levels. However, we found novel cases of insulinoma, in which hyperglycaemia developed soon after resection of the insulinoma.. We encountered two patients with repeated hypoglycaemia caused by insulinoma. Following removal of the insulinoma, unanticipated hyperglycaemia was observed in both patients. Thereafter, their blood tests revealed low levels of serum C-peptide and high titres of anti-glutamic acid decarboxylase antibody, indicating concomitant Type 1 diabetes. Indeed, histological examination of the resected specimen revealed that one patient showed insulitis in non-tumorous pancreatic tissue in which β-cells had already disappeared. Moreover, inflammatory cells infiltrated the insulinoma, as if it were insulitis of Type 1 diabetes, suggesting the existence of anti-islet autoimmunity.. These are first cases of insulinoma associated with underlying Type 1 diabetes. Physicians should be aware of the possibility that insulinoma may mask Type 1 diabetes, and measurement of anti-islet autoantibodies may be helpful to find underlying Type 1 diabetes, such as in these cases. It is pathologically interesting that the immune cell infiltration into insulinoma may be suggestive of anti-islet autoimmunity.

Topics: Adult; Aged; Autoantibodies; C-Peptide; Diabetes Mellitus, Type 1; Diagnosis, Differential; Female; Humans; Hyperglycemia; Insulinoma; Islets of Langerhans; Male; Pancreatic Neoplasms

Topics: Blood Glucose; C-Peptide; Choristoma; Confusion; Diagnosis, Differential; Fasting; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Secretion; Insulinoma; Middle Aged; Nesidioblastosis; Pancreatectomy; Pancreatic Diseases; Postprandial Period; Spleen; Syncope

Recent biochemical diagnostic guidelines for insulinomas require demonstration of hypoglycemia with inappropriately elevated (nonsuppressed) insulin, C-peptide, or proinsulin, but these criteria may overlap with those in patients without insulinomas. Use of an "amended" insulin-glucose ratio that accounts for the normal variation in insulin secretion according to prevailing glycemia may improve diagnostic accuracy.. To compare the diagnostic accuracy of current diagnostic guideline criteria with the amended insulin-glucose ratio in patients with a suspected insulinoma.. Retrospective cohort study.. 2 specialized university departments in Germany.. 114 patients with suspected hypoglycemia over 10 years having diagnostic prolonged fasts.. Glucose, insulin, C-peptide, and the amended insulin-glucose ratio were measured during and at discontinuation of prolonged fasts.. Of 114 patients who were evaluated, 49 had surgical resection of histologically confirmed insulinomas. Insulinoma was excluded in 65 patients; follow-up for a mean of 10 years (range, 0 to 16 years) showed no progressively severe hypoglycemic events or diagnoses of insulinoma. Patients with insulinoma had lower glucose levels and higher insulin and C-peptide levels overall than did control patients at the end of prolonged fasts, but there was considerable overlap. The amended insulin-glucose ratio correctly identified 48 of 49 patients with insulinoma and excluded the diagnosis in 64 of 65 control patients, resulting in positive and negative predictive values of 0.98 (95% CI, 0.89 to 1.00) and 0.99 (CI, 0.92 to 1.00), respectively, compared with 0.75 (CI, 0.63 to 0.85) and 0.98 (CI, 0.89 to 1.00), respectively, for glucose, insulin, and C-peptide concentration criteria.. The study had a retrospective design, no proinsulin concentrations were available, and a nonspecific insulin immunoassay (crossreactive with proinsulin) was used.. The amended insulin-glucose ratio showed improved diagnostic accuracy over established criteria that use glucose, insulin, and C-peptide concentrations.. None.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Fasting; Female; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulin Secretion; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Practice Guidelines as Topic; Predictive Value of Tests; Radioimmunoassay; Retrospective Studies

Sulfonylurea receptor 1 (SUR1) and multidrug resistance protein 1 (MRP1) are two prominent members of multidrug resistance proteins associated with insulin secretion. The aims of this study were to investigate their expression in insulinomas and their sole and synergistic effects in modulating abnormal insulin secretion.. Fasting glucose, insulin and C-peptide were measured in 11 insulinoma patients and 11 healthy controls. Prolonged oral glucose tolerance tests were performed in 6 insulinoma patients. Insulin content, SUR1 and MRP1 were detected in 11 insulinoma patients by immunohistochemistry. SUR1 and MRP1 were also detected in 6 insulinoma patients by immunofluorescence.. Insulinoma patients presented the typical demonstrations of Whipple's triad. Fasting glucose of each insulinoma patient was lower than 2.8 mmol/L, and simultaneous insulin and C-peptide were increased in insulinoma patients. Prolonged oral glucose tolerance tests showed that insulin secretion in insulinoma patients were also stimulated by high glucose. Immunohistochemistry and immunofluorescence staining showed that SUR1 increased, but MRP1 decreased in insulinoma compared with the adjacent islets.. The hypersecretion of insulin in insulinomas might be, at least partially, due to the enrichment of SUR1. In contrast, MRP1, which is down-regulated in insulinomas, might reflect a negative feedback in insulin secretion.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP-Binding Cassette Transporters; Blood Glucose; C-Peptide; Female; Fluorescent Antibody Technique; Glucose Tolerance Test; Humans; Immunohistochemistry; Insulin; Insulin Secretion; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Potassium Channels, Inwardly Rectifying; Receptors, Drug; Sulfonylurea Receptors

The objective was to test whether chromogranin A (CgA), neuron-specific enolase (NSE), and pancreatic polypeptide (PP) are released from the pancreas during the selective arterial calcium stimulation and hepatic venous sampling test (ASVS) in patients with insulinomas.. We determined CgA, NSE, PP, insulin, C-peptide, and proinsulin in blood samples obtained during the ASVS test in 19 patients with insulinomas. Levels following calcium injection into the arteries supplying the tumor were compared with levels following calcium stimulation of arteries supplying healthy pancreatic tissue.. After calcium injection into the artery supplying the insulinoma, a significant 8-fold increase in insulin (range, 2.3-117; P < 0.001), a 3.8-fold increase in C-peptide (1.7-32.4; P < 0.001), and a 1.9-fold increase in proinsulin (0.7-5.3, P < 0.001) were detectable whereas NSE and CgA did not increase. No significant increases in insulin, C-peptide, proinsulin, CgA, and NSE concentrations were found after calcium injection into control arteries. Pancreatic polypeptide increased 1.5-fold (0.8-4.5; P = 0.017) after calcium injection into the tumor artery and 2.4-fold (0.8-7.9; P = 0.016) after injection into the control artery.. Insulin, C-peptide, and proinsulin are released by insulinoma cells in response to arterial calcium stimulation, whereas CgA and NSE are not released. Also from our study it seems that PP may be released by healthy islet cells after calcium stimulation.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor; C-Peptide; Calcium Gluconate; Chromogranin A; Female; Humans; Immunoassay; Immunohistochemistry; Injections, Intra-Arterial; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Pancreatic Polypeptide; Phosphopyruvate Hydratase; Predictive Value of Tests; Protein Precursors; Switzerland

We present the case of a 55 yr female who had recurrent severe hypoglycemic attacks with neuroglycopenic symptoms and altered sensorium including coma. The hypoglycemic episodes were not related to fasting. The hypoglycemia was hyperinsulinemic but all imaging modalities for insulinoma were negative. Selective arterial calcium stimulation test localized the lesion to splenic artery territory and distal pancreatectomy left to the splenic vein was done. The histopathology was consistent with nesidioblastosis and gradient guided pancreatectomy relieved the hypoglycemic episodes.

Topics: Blood Glucose; C-Peptide; Calcium; Female; Humans; Hyperinsulinism; Hypoglycemia; Hypoglycemic Agents; Immunohistochemistry; Injections, Intra-Arterial; Insulin; Insulinoma; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Splenectomy; Syndrome; Treatment Outcome

Fibrous tissue outgrowth and hypoxia are the major restrictions for the application of bioartificial pancreas (BAP). Accordingly, the intramedullary cavity is proposed as an implant site, and a BAP constructed of calcium phosphate cement chamber was implanted.. Mouse insulinoma cells were encapsulated in agarose gel and then enclosed in a calcium phosphate cement chamber to fabricate a BAP. BAPs were implanted in the femoral intramedullary cavity of diabetic dogs. Pre- and postprandial blood glucose levels were monitored perioperatively. Blood samples were collected for the analysis of C-peptide level, and physiological conditions were observed at predetermined intervals. BAPs were retrieved at 12 weeks postoperatively for histologic examination.. Preprandial blood glucose level of diabetic dogs decreased from 420 ± 25 to 223 ± 47 mg/dL at 1 day postoperatively and was maintained in the range of 259 ± 36 mg/dL for 12 weeks. As serum C-peptide level increased from 5.3 ± 2.8 to 105.7 ± 19.4 pmol/L, the rate of decrease of postprandial blood glucose was accelerated. Histologic examination revealed that recipient bone tissues were binding to the surfaces of BAPs directly; there was no development of fibrous tissue. Immunohistochemical stain was positive for insulin in the enclosed insulinoma cells.. This study demonstrated that BAPs implanted into the intramedullary cavity functioned well during the experimental period. Thus, the intramedullary cavity can serve as an implant site for BAPs.

Topics: Animals; Artificial Organs; Blood Glucose; C-Peptide; Diabetes Mellitus, Experimental; Dogs; Female; Humans; Insulinoma; Islets of Langerhans; Male; Mice; Pancreas Transplantation; Tissue Donors

The intramedullary cavity is a widely distributed well-vascularized microenvironment capable of sustaining grafts, and is a potential site for islet transplantation. The bone marrow offers sufficient space that may also be suitable for bioartificial pancreas (BAP) implantation.. To evaluate the feasibility of bone marrow as an implantation site for BAPs.. A calcium phosphate cement chamber satisfies the criteria for immunoisolation. Mouse insulinoma cells were suspended with agarose gel and enclosed in a calcium phosphate cement chamber to create a BAP, which was implanted in the intramuscular space in diabetic swine or the intramedullary cavity in diabetic dogs. Blood glucose and C-peptide concentrations were determined perioperatively.. In the swine, the mean ± SD blood glucose concentration decreased from 413 ± 24 mg/dL to 285 ± 47 mg/dL, and was maintained in the range of 285 to 336 mg/dL for 15 days. It increased to 368 to 450 mg/dL after the BAPs were implanted in the intramuscular space. In the dogs, the blood glucose concentration decreased from 422 ± 32 mg/dL to 247 ± 52 mg/dL, and was maintained in the range of 247 to 347 mg/dL after the BAPs were implanted in the intramedullary cavity. The C-peptide concentration increased from 6.1 ± 2.8 pmol/L to 104.7 ± 16.4 pmol/L when the BAPs were implanted in the intramedullary cavity.. This study indicates superior effectiveness of BAPs implanted in the intramedullary cavity compared with the intramuscular space. This observation may be attributed to the greater oxygen tension in the bone marrow. The BAPs in direct contact with the circulatory system receive sufficient blood flow for function and survival. This preliminary study demonstrates that the intramedullary cavity may be an implantation site for BAP transplantation.

Topics: Animals; Bioartificial Organs; Blood Glucose; Bone Cements; Bone Marrow; C-Peptide; Dogs; Insulinoma; Kidney Medulla; Mice; Pancreas Transplantation; Prostheses and Implants; Swine

We report the case of an obese 79-year-old woman who experienced postprandial hypoglycemia in the morning. The serum immunoreactive insulin (IRI) and C-peptide levels responded in parallel with her serum glucose level during a 75-g oral glucose tolerance test. A prolonged fast test lowered her serum glucose level to 30 mg/dL, but serum IRI was not fully suppressed. Abdominal computed tomography revealed a tumor in the uncinate process of the pancreas. The tumor was histologically diagnosed as benign insulinoma after surgery. Therefore, glucose-responsive insulinoma as well as reactive hypoglycemia should be considered in patients who exhibit postprandial hypoglycemia.

Topics: Aged; Blood Glucose; C-Peptide; Circadian Rhythm; Female; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Postprandial Period; Tomography, X-Ray Computed

Topics: Adult; Blood Glucose; C-Peptide; Diagnostic Errors; Dietary Carbohydrates; Female; Glucose; Humans; Hypoglycemia; Infusions, Intravenous; Insulin; Insulinoma; Pancreatic Neoplasms; Pregnancy; Pregnancy Complications, Neoplastic; Treatment Outcome

A 45-year-old woman was referred to us for hypoglycemia. The patient had been operated on for a duodenal ulcer by bilateral troncular vagotomy and pyloroplasty 20 years ago and, since then, she showed a dumping syndrome. Two months before consultation she developed repetitive episodes of symptomatic hypoglycemia. An oral glucose tolerance test showed hypoglycemia with endogenous hyperinsulinism. The continuous glucose monitoring system sensor demonstrated fasting hypoglycemia. The endoscopic ultrasound of the pancreas showed a pancreatic tumor that was confirmed in the pathologic study after surgery. Moreover, nesidiodysplasia image was found surrounding pancreatic parenchyma. We report, for the first time, both histologic lesions associated in a patient with a history of vagotomy and pyloroplasty for a duodenal ulcer and we discuss the possible pathogenic mechanisms.

Topics: C-Peptide; Duodenal Ulcer; Female; Glucose; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulinoma; Islets of Langerhans; Middle Aged; Pancreatic Diseases; Pancreatic Neoplasms; Time Factors; Vagotomy

A 67 year old female patient was admitted to our clinic with recurrent hypoglycemia in December 2006. Laboratory findings revealed an elevated insulin, and C-peptide. Imaging techniques revealed a tumor of the pancreas involving the spleen with metastases of the liver, expressing somatostatin receptors. Ultrasound-guided biopsy was performed and confirmed the suspected insulinoma. Since the hypoglycemias could not sufficiently be controlled by subcutaneous administration of octreotide and by oral glucose intake, surgical debulking was performed in a palliative intention. After resection the patient was free of hypoglycemia. In case of diagnosed insulinoma, underlying MEN (multiple endocrine neoplasia) should be considered. Excision of the tumor is recommended in patients with benign solitary insulinomas. If complete excision is impossible, there are several therapeutic options that aim at preventing hypoglycemia. Thus, in contrast to other extended tumors, surgery is reasonable in malignant insulinoma even in case of metastatic disease.

Topics: Aged; Blood Glucose; C-Peptide; Chromogranin A; Diagnosis, Differential; Disease Progression; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Liver Neoplasms; Magnetic Resonance Imaging; Palliative Care; Pancreatic Neoplasms; Recurrence; Ultrasonography

Insulinoma is the most common cause of fasting hypoglycemia resulting from autonomous insulin hypersecretion. A 59-year-old woman who had previously had an insulinoma and had undergone a partial pancreatectomy was admitted to our hospital because of recurrence of hypoglycemia after 27 years. She had two unusual endocrinological features: 1) the serum insulin response to intravenous secretin injection was not impaired, and 2) the serum C-peptide levels and ratios of serum C-peptide to insulin were relatively low. Two pancreatic tumors were readily detectable by computed tomography (CT) and magnetic resonance imaging (MRI). The selective arterial calcium injection (SACI) test showed a hyperinsulinemic response by calcium administration to the gastroduodenal artery. A partial pancreatectomy was done and her hypoglycemia disappeared. Histology revealed that the tumors were composed of monotonous, small round cells that were positive for both insulin and cathepsin B. As previous in vitro studies have shown that C-peptide can be metabolized within human insulinoma cells by proteolytic cleavage by cathepsin B, our patient's low serum C-peptide levels might have been caused by degradation of C-peptide by cathepsin B. According to the data from the literature, the molar ratio of serum C-peptide to insulin is generally decreased in patients with insulinoma than normal subjects. This case highlights the need for careful interpretation of C-peptide levels and the intravenous secretin injection test in the diagnosis of insulinoma.

Topics: Blood Glucose; C-Peptide; Female; Humans; Insulin; Insulinoma; Middle Aged; Pancreatic Neoplasms; Secretin

This study assessed the sensitivities of preoperative localisation modalities such as computed tomography (CT), magnetic resonance imaging (MRI), arteriography and arterial stimulation venous sampling (ASVS) using serum insulin and C-peptide gradients to intraoperative techniques in localising insulin-secreting tumours in our institution.. Fourteen patients with proven insulinoma, aged 20-66 years, who presented from 1997 to 2004, were studied retrospectively. All patients underwent ASVS where C-peptide and/or insulin gradients were calculated. The results were compared with the preoperative findings of CT, MRI, arteriography, as well as intraoperative ultrasound and palpation.. Intraoperative ultrasound with palpation correctly localised 10 of the 11 tumours with a sensitivity of 91%. Sensitivities of other localisation techniques were lower: 31% by CT, 50% by MRI, and 46% by arteriography. ASVS with insulin gradients alone allowed accurate localisation in 40% of patients while localisation using only C-peptide gradients of more than 2 was 43%. The insulinomas, measuring 10-30 mm, were successfully removed in 13 patients--6 from the body, 4 from the tail, 2 from the head and 1 from the junction of the body and tail. All except 1 were cured by selective surgery and remained free of hypoglycaemia over the next 2-60 months of follow-up. One patient had left lobectomy due to liver metastases from a malignant insulinoma and remained asymptomatic with medical therapy.. Intraoperative ultrasound with palpation is a highly sensitive method for the localisation of insulinoma compared with other preoperative localisation techniques.

Topics: Adult; Aged; Angiography, Digital Subtraction; C-Peptide; Calcium; Contrast Media; Female; Humans; Insulin; Insulinoma; Intraoperative Care; Magnetic Resonance Imaging; Male; Middle Aged; Palpation; Retrospective Studies; Sensitivity and Specificity; Tomography, Spiral Computed; Ultrasonography

Endoscopic ultrasonography has been accepted as a sensitive modality for preoperative tumor localization in pancreas. We have aimed to determine the performance characteristics of endoscopic ultrasonography in pancreatic insulinoma localization and evaluation of relationship between the tumor size and serum-c peptide level, lowest glucose level and insulin level.. Patients suspicious to insulinoma according to clinical and laboratory findings were included. Endoscopic ultrasonography was performed and if a tumor was identified, the patient was referred for surgery.. A total of 52 patients (24 male and 28 female) with mean age of 42.4 years underwent EUS and 43 patients underwent surgery. In one patient, a tumor was identified both by transabdominal ultrasonography and abdominal CT scan. The overall sensitivity and accuracy of endoscopic ultrasonography for detection of insulinoma was 89.5% and 83.7% respectively. The sensitivity of endoscopic ultrasonography for detection of lesions in pancreatic head, body and tail was 92.6%, 78.9%, and 40.0%, respectively. There was no relationship between c-peptide, lowest blood glucose, insulin blood levels and tumor size in surgery.. EUS is an accurate method for detection of insulinoma. The accuracy depends on the location of the tumor and is greatest for tumors in the pancreatic head.

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Endosonography; Female; Humans; Insulin; Insulinoma; Male; Middle Aged; Neoplasm Staging; Pancreatectomy; Pancreatic Neoplasms; Sensitivity and Specificity; Ultrasonography, Interventional

Insulinomas are rare tumours that originate from the islet cells of the pancreas. The aims of this study were to gain an understanding of the clinical features of insulinomas and to establish the diagnostic and therapeutic strategies.. A review was carried out in 20 patients with insulinoma surgically treated in our institution over the last 10 years. Presenting symptoms, biochemical studies, preoperative and intraoperative localization studies, operative management and complications were analysed.. The male-to-female ratio was 8:12, with a mean age of 46.4 years. Each patient suffered from significant neuroglycopenic symptoms, usually manifested by dizziness, sweating, headache and confusion. The preoperative median serum levels of glucose, insulin and C-peptide at the termination of the fast were 37.5 mg/dL, 23.5 microU/mL, 5.6 ng/mL, respectively. Preoperative tumour localization was achieved by means of ultrasonography (US), computed tomography, selective angiography or intra-arterial calcium injection with hepatic venous sampling, and sensitivities of these examinations were 81.8, 73.7, 94.1 and 100%, respectively. Intraoperative localization was carried out by a combination of manual palpation and intraoperative US with retrospective sensitivities of 80 and 100%, respectively. Enucleation was carried out in 16 patients and distal pancreatectomy in 4. The mortality and morbidity rates were 0 and 10%, respectively. One patient developed late diabetes mellitus type 1 after distal pancreatectomy.. We conclude that the diagnosis of insulinoma can be made on the basis of the results of a supervised fast, careful palpation with intraoperative US is essential for intraoperative detection of insulinomas and surgical resection is the best choice for treatment of benign insulinomas.

Topics: Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Diagnostic Imaging; Female; Humans; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Retrospective Studies

An insulinoma is a rare pancreatic endocrine tumor that is typically sporadic, solitary, and less than 2 cm in diameter. Fewer than 5% of insulinomas are larger than 3 cm. Ninety percent or more of all insulinomas are benign. Larger tumors are more likely to be malignant. We report a case of a giant pedunculated insulinoma, measuring 9 cm in diameter and weighing 100 g, with amyloid deposits accounting for 70% of the tumor volume. At the time of operation, no local invasion or metastatic disease was identified. On pathological evaluation, the tumor was classified as an insulinoma of uncertain biological behavior. In addition to describing the clinical presentation and operative findings, criteria for determining malignancy are outlined, a detailed pathological description is presented, and the 2000 World Health Organization Classification for Pancreatic Endocrine Neoplasms is reviewed.

Topics: Aged; C-Peptide; Female; Humans; Insulinoma; Ki-67 Antigen; Pancreatic Neoplasms

Traditional criteria to diagnose hyperinsulinaemic hypoglycaemia are based on insulin measurements by unspecific insulin assays. This study was performed to test whether these traditional criteria can be applied when insulin is measured by specific immunoassays.. 29 consecutive patients undergoing a prolonged fast were included; 11 patients with insulinoma and 18 healthy individuals. We determined plasma glucose, insulin, C-peptide, proinsulin, and beta-hydroxybutyrate concentrations at the termination of the fast. Insulin was measured by an unspecific radioimmunoassay (RIA) and a specific enzyme-linked immunosorbent assay (ELISA).. In 11 insulinoma patients, insulin concentrations at median plasma glucose concentration of 2.1 (range 1.3-2.5) mmol/l were 170 (76-340) pmol/l measured by RIA and 61 (11-156) pmol/l by ELISA. Insulin concentrations measured by RIA confirmed hyperinsulinaemia (i.e., >36 pmol/l, the proposed cut-off value for traditional insulin assays) in all insulinoma patients, whereas insulin concentrations measured by ELISA were <36 pmol/l in four patients. In three insulinoma patients, insulin concentrations measured by ELISA were <18 pmol/l, a proposed cut-off level to diagnose hyperinsulinaemia for specific insulin assays.. When insulin concentrations are measured by specific immunoassays in patients evaluated for fasting hypoglycaemia, traditional reference values cannot be applied.

Topics: 3-Hydroxybutyric Acid; Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Enzyme-Linked Immunosorbent Assay; Fasting; Female; Humans; Hyperinsulinism; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Proinsulin; Radioimmunoassay; Reference Values; Sensitivity and Specificity; Time Factors

Adult spontaneous hypoglycaemia is not a diagnosis per se but a manifestation of a disease. Although rare, it is important to identify spontaneous hypoglycaemia and its causes because treatment may be preventative or curative. Hypoglycaemia can occur as an epiphenomenon in many serious diseases. It is sufficient to recognise the disease's association with hypoglycaemia and then take appropriate action to prevent the recurrence of hypoglycaemia. In investigating apparently healthy individuals, common pitfalls to avoid are: failure to recognise subacute neuroglycopenia clinically; failure to document hypoglycaemia adequately during symptoms; failure to measure pancreatic hormones, counter-regulatory hormones, and ketones in hypoglycaemic samples; failure to recognise pre-analytical and analytical limitations of laboratory assays; and failure to abandon obsolete and inappropriate investigations. Providing these caveats are met, appropriate laboratory and radiological investigations will almost always uncover the cause of spontaneous hypoglycaemia.

Topics: Acute Disease; Adult; Autoantibodies; Blood Glucose; C-Peptide; Clinical Laboratory Techniques; Diagnosis, Differential; Exercise Test; Fasting; Homeostasis; Humans; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Postprandial Period; Proinsulin; Receptor, Insulin

Insulinoma is a rare, almost always benign endocrine tumor of the pancreas, clinically characterized by hyperinsulinemic, hypoglycemic episodes. Surgical excision is the therapy of choice, which may lead to postpancreatectomy diabetes mellitus in the case of extensive pancreatic resection. We present the cases and the metabolic follow up of two patients, 81 and 73 years old, with insulinoma localized close to the main duct in the pancreatic neck. Both patients underwent an 80% left pancreatectomy, avoiding a pancreatico-enteric anastomosis. In order to prevent postpancreatectomy diabetes, the islets from the tumor-free part of the resected pancreas were isolated and injected via a right colic vein into the portal system. After a follow up of 6 and 3 years respectively, both patients remained insulin-independent without any dietary restrictions. Fasting and glucagon-stimulated C-peptide-levels and glycosylated hemoglobin remained within normal range. There were no signs of recurrent insulinoma. Liver biopsy performed in one patient at 1 year after autotransplantation, showed intact, insulin-producing islets within the portal spaces. In conclusion, autologous islet transplantation can preserve the insulin secretory reserve after extended left pancreatectomy for the treatment of benign tumors in the pancreatic neck.

Topics: Aged; Aged, 80 and over; Biopsy; C-Peptide; Diabetes Mellitus; Female; Follow-Up Studies; Glucose Tolerance Test; Glycosylation; Hemoglobins; Humans; Insulinoma; Islets of Langerhans Transplantation; Liver; Male; Pancreatectomy; Time Factors; Transplantation, Autologous

The selective intra-arterial calcium stimulation test has greatly facilitated the precise regionalization of insulinomas smaller than 2 cm, which noninvasive techniques (ultrasound [US], computed tomography [CT], magnetic resonance imaging [MRI]) often fail to localize. This study examined not only the role of the test in the localization of insulinomas, but also the responsiveness of 3 beta-cell peptides (insulin, C peptide, and proinsulin) and their relationship to the degree of differentiation of the tumor cells, using percentage decrease of both proinsulin/insulin (P/I) and proinsulin/C peptide (P/C) ratios after stimulation as indices. Ten consecutive surgically proven insulinoma patients each received an injection of calcium into the arteries supplying the pancreas after standard selective angiography and beta-cell peptide levels were measured in samples taken from the right hepatic vein before and 30, 60, 90, 120, and 180 seconds after each injection prior to operation. After surgery, the expressions of the calcium sensing receptor (CaSR) on the resected tumors were assessed by immunohistochemistry. Intra-arterial calcium stimulation with sampling either for insulin or for C peptide correctly predicted the site of insulinoma in 8 of 9 patients or in 7 of 8 patients if the 2 big malignant insulinomas were excluded; thus, the detection rate of this test was 89% and 88%, respectively. Calcium administration stimulated a marked and prompt release of insulin and C peptide simultaneously. Both peaked within 30 to 60 seconds, then declined gradually thereafter, remaining above the baseline at 180 seconds. The magnitude of increase correlated well with the corresponding percentage decrease of P/I and P/C ratios. The response of proinsulin was much less. Immunohistochemistry demonstrated variable membraneous staining for CaSR in normal pancreatic islets and in about 9% of the total normal beta cells, whereas staining in tumor cells was only minimally detectable. We conclude that selective intra-arterial calcium stimulation with hepatic venous sampling either for insulin or for C peptide is a highly sensitive method for the preoperative localization of small insulinomas. Calcium injection stimulates a brisk response of insulin, C peptide, and proinsulin simultaneously and the magnitude of increase of both insulin and C peptide appears to be correlated well with the degree of differentiation of the tumor cells. The exact mechanism by which calcium provokes th

Topics: Adult; Aged; C-Peptide; Calcium; Cell Differentiation; Female; Humans; Immunohistochemistry; Injections, Intra-Arterial; Insulin; Insulinoma; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Predictive Value of Tests; Proinsulin

We report a case of insulinoma in which the diagnosis was very challenging as some of the biochemical data were consistently equivocal. In order to assess the relative reliability of the analytical tests, retrospective biochemical data on 45 other cases of histologically confirmed insulinoma were evaluated, enabling the most secure diagnostic process to be identified.. The data showed that insulin concentrations alone, although measurable, were equivocal in 17% of cases. The addition of C-peptide values clarified the diagnosis in about 50% of the borderline cases, whilst ketone (beta-hydroxybutyrate) concentrations were low during the prevailing hypoglycaemia in all cases.. The combination of these three tests is suggested as the most effective method for the biochemical diagnosis of hypoglycaemia due to insulinoma.

Topics: 3-Hydroxybutyric Acid; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Predictive Value of Tests; Reference Values; Reproducibility of Results; Retrospective Studies

Topics: Adolescent; Adult; C-Peptide; Diabetes Mellitus, Type 1; Female; Humans; Insulinoma; Islets of Langerhans; Male; Parents

It has been suggested that C-peptide is bioactive and that such bioactivity is lost when the last five amino acids are removed. In rats, C-peptide is truncated in beta-cell granules leading to the loss of these last five residues and secretion of des-[27-31]-C-peptide. The aim of this study was to determine whether this truncated form of C-peptide was also a secretory product of human islets.. Plasma from healthy subjects, patients with Type II (non-insulin-dependent) diabetes mellitus or insulinoma and cord blood was analysed by HPLC and ELISA. This method allows for separation and quantification of intact C-peptide and des-[27-31]-C-peptide. Human islets were pulse-chased and secretion stimulated by a mixture of secretagogues. Radioactive products secreted to the medium were analysed by HPLC and the relative amount of intact and truncated C-peptide measured.. The proportion of total C-peptide immunoreactivity comprised of des-[27-31]-C-peptide was 1.5% or less in all plasma samples, except for that from one patient with insulinoma where it was 4.2%. The proportion of radiolabelled des-[27-31]-C-peptide released from isolated islets was less than 1%.. In contrast to the situation in rats, des-[27-31]-C-peptide is not a major secretory product of human islets and its contribution to total circulating C-peptide is not increased in Type II diabetes or in patients with insulinoma.

Topics: Adult; C-Peptide; Chromatography, High Pressure Liquid; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Fetal Blood; Humans; Infant, Newborn; Insulinoma; Islets of Langerhans; Pancreatic Neoplasms; Peptide Fragments; Reference Values

To review patients records operated with the diagnosis of insulinoma and to discuss their clinical presentations, diagnostic and therapeutic modalities.. Retrospective study.. Ankara Numune Teaching and Research Hospital, Turkey.. Eight cases were operated in the Department of 6th Surgery, Ankara Numune Teaching and Research Hospital between 1994 and 2000. All patients had neuroglycopenic symptoms. Six patients had blood glucose levels of lower than 50 mg/dL during the admission. The other two patients had hypoglycaemia in the prolonged fasting test. Serum insulin/glucose ratio was diagnostic in all patients except one. Abdominal ultrasonography and computerised tomography could successfully localise the tumour in one case. In six patients tumours could be localised by endoscopic pancreatic ultrasonography. In one patient none of the studies could localise the tumour. Three tumours were located at the pancreatic head, one in the neck, two at the body and two at the tail. All tumours except one were palpable. Enucleation was the procedure of choice in four cases and distal pancreatectomy was the procedure of choice in four.. Post-operative course was uneventful in seven patients. One patient died due to intra-abdominal sepsis. Hypoglycaemia was controlled in all patients after the surgery.. Surgery is the mainstay of treatment of insulinoma. Enucleation should be the procedure of choice if possible. Endoscopic pancreatic ultrasonography has promising results and may replace invasive angiographic studies in the future.

Topics: Adult; Blood Glucose; C-Peptide; Confusion; Diagnosis, Differential; Dizziness; Endosonography; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Muscle Weakness; Pancreatectomy; Pancreatic Neoplasms; Retrospective Studies; Tomography, X-Ray Computed; Treatment Outcome; Turkey; Unconsciousness

A 43-year-old man presented with attacks of altered behaviour over a short period of time; they were associated with episodes of hypoglycaemia. The clinical suspicion of insulinoma prompted investigations that quickly established serum insulin and C-peptide levels to be elevated at the times when blood glucose values were low. A physical lesion was found in the head of the pancreas by means of computerised tomography and endo-duodenal ultrasound scan; an octreotide scan was negative. The patient underwent laparotomy and enucleation of a benign tumour, measuring 2.6 cm in diameter, lying within the head of the pancreas; histological examination confirmed it to be an insulinoma. Postoperatively, the patient's personality gradually became more normal and his fasting blood glucose concentrations returned to within normal limits. The diagnosis and management of insulinoma are discussed in the context of this clinical case; there is also reference to the protean clinical manifestations that may occur in this condition- and its differential diagnosis.

Topics: Adult; Blood Glucose; C-Peptide; Diagnosis, Differential; Dizziness; Endosonography; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Mental Disorders; Pancreatic Neoplasms; Personality; Tomography, X-Ray Computed

We report the case of a 69-year-old woman with insulin autoimmune syndrome first misdiagnosed as insulinoma. The case demonstrates the difficulties to correctly diagnose this rare disorder as both insulin and proinsulin levels were increased by crossreactive autoantibodies. No known triggering agent could be identified. We suggest that this diagnosis should be considered more often also in caucasian patients to avoid useless operations for such patients.

Topics: Aged; Antibody Specificity; Autoantibodies; Autoimmune Diseases; C-Peptide; Diagnosis, Differential; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Proinsulin

Characterization of metabolically inadequate insulin secretion is essential for insulinoma diagnostics. Hyperinsulinaemic, eu- and hypoglycaemic clamp procedures have been used to suppress endogenous insulin secretion in healthy subjects. The use of exogenous insulin precluded the use of insulin as a parameter to be measured. We now suggest to use exogenous insulin lispro and an insulin-specific ELISA not cross reacting with insulin lispro. Thus, determination of insulin by ELISA in this experimental setting reflects endogenous insulin. A 39-year-old man with a surgically confirmed pancreatic insulinoma was studied under hyperinsulinaemic [lispro insulin 40 mU x m(-2) body surface x min(-1)] clamp conditions. Euglycaemia was achieved (3.8 +/- 0.5 mmol/L) for 1 h and hypoglycaemia (2.36 +/- 0.49 mmol/L) was achieved for another 30 min. Insulin was evaluated by ELISA (cross-reaction with lispro insulin < 0.006%, C-peptide < 0.01%, proinsulin < 0.001%) and by a nonselective RIA (cross-reaction with proinsulin 40%). In control subjects the euglycaemic hyperinsulinaemia suppressed C-peptide to 0.36 +/- 0.03 ng/ml and hypoglycaemic hyperinsulinaemia to 0.29 +/- 0.03 ng/ml. Endogenous insulin was suppressed to 2.8 +/- 0.03 mU/L under euglycaemia and to 2.6 +/- 0.03 mU/L under hypoglycaemia in control subjects. In the insulinoma patient apparently irregular but small changes in both C-peptide (1.43 +/- 0.1 ng/ml) and more pronounced changes in endogenous insulin concentrations 4.41 +/- 0.1 mU/l under euglycaemia and 5.35 +/- 0.3 mU/l under hypoglycaemic conditions, were observed. The basal level of insulin (ELISA insulin 4.6 mU/L) and C-peptide (1.7 ng/ml) were not markedly elevated. Determination of insulin allowed better characterization of irregular pulses because of the shorter half-life of insulin relative to C-peptide. The new modification of sequential eu- and hypoglycaemic clamp procedures should also be useful in pharmacological studies of insulinotropic substances. Direct measurement of peripheral insulin may be more sensitive than C-peptide to detect low levels of autonomous insulin secretion in small insulinomas.

Topics: Adult; C-Peptide; Enzyme-Linked Immunosorbent Assay; Fasting; Glucose; Glucose Clamp Technique; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulin Lispro; Insulin Secretion; Insulinoma; Male; Pancreatic Neoplasms; Proinsulin

Previous studies have demonstrated that endogenous insulin secretion is not suppressed by exogenous insulin in patients with insulinoma. In this study we examined whether insulin secretion in insulinoma patients is suppressed by exogenous insulin during hypoglycaemia.. Sixteen insulinoma patients (5 men and 11 women) and 10 normal subjects were studied. Hyperinsulinaemic glucose clamp studies were performed at both euglycaemia (4.5 mmol/l glucose) and hypoglycaemia (2.5 mmol/l glucose).. In normal subjects, plasma C-peptide levels were suppressed by 66% during the euglycaemic hyperinsulinaemic clamps (P < 0.01). In contrast, in insulinoma patients, plasma C-peptide levels increased by 25% during the clamps (P < 0.05). In the hypoglycaemic hyperinsulinaemic clamps, plasma C-peptide levels were nearly completely (91%) suppressed in normal subjects and partially (39%) suppressed in patients with insulinoma (P < 0.01). The decrease in C-peptide levels during the hypoglycaemic clamps was > 30% in 12 (75%) of 16 insulinoma patients and > 50% in 8 (50%) patients.. This study demonstrated that in patients with insulinoma, insulin secretion was not suppressed by exogenous insulin during euglycaemia but was suppressed during hypoglycaemia, although the degree of suppression was less than that in normal subjects. Our results suggest that the feedback regulation of insulin secretion by exogenous insulin is partially retained in patients with insulinoma.

Topics: Adult; Blood Glucose; C-Peptide; Case-Control Studies; Female; Humans; Insulin; Insulin Secretion; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Predictive Value of Tests

Topics: Biopsy; Blood Glucose; C-Peptide; Female; Humans; Hypoglycemia; Insulinoma; Magnetic Resonance Imaging; Middle Aged; Pancreatic Neoplasms; Tomography, X-Ray Computed

Topics: Adult; Blood Glucose; C-Peptide; Calcium Gluconate; Chronic Disease; Female; Glucose Clamp Technique; Humans; Hypoglycemia; Infusions, Intravenous; Insulin; Insulinoma; Pancreatic Neoplasms; Portal Vein

Topics: Adult; Angiography; Blood Glucose; C-Peptide; Cognition Disorders; Diagnosis, Differential; Female; Glucose Tolerance Test; Humans; Hyperinsulinism; Hypoglycemia; Insulinoma; Male; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Splenectomy; Syncope; Tomography, X-Ray Computed

We describe a sensitive two-site sandwich enzyme-linked immunosorbent assay for the measurement of intact human proinsulin in 100 microL of serum or plasma. The assay is based on the use of two monoclonal antibodies specific for epitopes at the C-peptide/insulin A chain junction and at the insulin B chain/C-peptide junction, respectively. Cross-reactivities with insulin, C-peptide, and the four proinsulin conversion intermediates were negligible. The detection limit in buffer was 0.2 pmol/L (3 standard deviations from zero). The working range was 0.2-100 pmol/L. The mean intra- and interassay coefficients of variation were 2.4% and 8.9%, respectively. The mean recovery of added proinsulin was 103%. Dilution curves of 40 serum samples are parallel to the proinsulin calibration curve. Proinsulin concentrations in 20 fasting healthy subjects were all above the limit of detection: median (range), 2.7 pmol/L (1.1-6.9 pmol/L). Six fasting non-insulin-dependent diabetes mellitus and five insulinoma patients had proinsulin concentrations significantly higher than healthy subjects: median (range), 7.7 pmol/L (3.2-18 pmol/L) and 153 pmol/L (98-320 pmol/L), respectively.

Topics: Adult; Aged; Antibodies, Monoclonal; C-Peptide; Cross Reactions; Diabetes Mellitus, Type 2; Enzyme-Linked Immunosorbent Assay; Female; Humans; Hypoglycemia; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Proinsulin; Reproducibility of Results; Sensitivity and Specificity

A 36-year-old woman without significant medical history complained of "spells" of diplopia, fatigue, and dizziness. On formal fasting, her glucose dropped to 40 mg/dL, with simultaneous insulin levels of 15 microU/mL (normal <6 microU/mL) and C-peptide of 2.5 ng/ml (normal <2 ng/mL). An isolated plasma sulfonylurea screen done during the fast was positive for tolbutamide, suggesting the diagnosis of factitious hypoglycemia, but further workup revealed multiple pancreatic masses resulting in an eventual diagnosis of multiple insulinomas that was confirmed surgically. We discuss the approach to hypoglycemia caused by insulin excess and distinguishing clinical and biochemical features.

Topics: Adult; Blood Glucose; C-Peptide; Diagnosis, Differential; Factitious Disorders; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Sick Role

In this paper we describe for the first time late post-prandial hypoglycaemia as the sole presenting feature of an insulinoma in a patient who had previously undergone subtotal gastrectomy. The symptoms of hypoglycaemia always occurred 1-3 h after meals, not in the fasting state. Because of the history of gastrectomy and because post-prandial hypoglycaemia was reproduced by an oral glucose tolerance test, the diagnosis of reactive hypoglycaemia was made. Eighteen months later a fasting test was performed: venous plasma glucose decreased from 3.8 mmol/l to 2.7 mmol/l between 14 and 20 h of fast while plasma immunoreactive insulin did not decrease and plateaued at 185 pmol/l. Plasma C-peptide (0.9 nmol/l) and proinsulin (70 pmol/l, split 64, 65) were also elevated. All islet hormones increased in response to i.v. glucose and were suppressed after diazoxide. Although pre-operative procedures were negative in localizing an insulinoma, the patient underwent an operation and an insulinoma was detected at the body level of the pancreas. Thus, insulinoma should be considered in the differential diagnosis of reactive hypoglycaemia in gastrectomized patients. Response of islet hormones to glucose and their suppression by diazoxide are evidence of a secreting insulinoma even in the absence of preoperative localization of the pancreatic adenoma.

Topics: Blood Glucose; C-Peptide; Diagnosis, Differential; Follow-Up Studies; Gastrectomy; Glucose Tolerance Test; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Postprandial Period

Topics: Adult; C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulinoma; Pancreatic Neoplasms; Ultrasonography

To better characterize autonomous insulin secretory behaviour in insulinoma patients and to establish diagnostic criteria with high accuracy, hyper-insulinaemic, sequentially eu- and hypoglycaemic clamp tests were performed in insulinoma patients and control subjects. Ten patients with insulinoma (benign in nine, histologically proven in nine) and 10 patients with suspected episodes of hypoglycaemia, in whom thorough clinical evaluation excluded an insulinoma, were examined. Five insulinoma patients were restudied after successful extirpation of the tumour. Suppression of C-peptide during low-dose [2 pmol kg-1 min-1 (20 mU kg-1 h-1) for 90 min, plasma insulin approximately 120 pmol L-1 (20 mUL-1)] and high-dose [8 pmol kg-1 h-1 (80 mU kg-1 h-1) for 90 min, plasma insulin approximately 450 pmol L-1 (75 mU L-1)] insulin infusion under euglycaemic conditions [plasma glucose 4.4-5.0 mmol L-1 (80-90 mg dL-1)] and during high-dose insulin infusion under hypoglycaemic conditions [glucose 2-2.2 mmol L-1 (40-45 mg dL-1)] was evaluated by radioimmunoassay (RIA). Euglycaemic hyper-insulinaemia suppressed C-peptide in control subjects (P < 0.0001), whereas in insulinoma patients apparently irregular changes in C-peptide concentrations (with spontaneous or paradoxical increments, P = 0.0006 vs. controls) were observed. The combination of hyper-insulinaemia and controlled hypoglycaemia led to a nearly complete suppression of C-peptide in normal subjects (from basal, 0.76 +/- 0.08-0.06 +/- 0.01 nmol L-1; maximum observed value 0.10 nmol L-1), which was more pronounced than at the point of discontinuation of prolonged fasting (> 48 h; 0.26 +/- 0.16 nmol L-1; P = 0.005). In insulinoma patients, C-peptide remained elevated under all conditions (P = 0.51 vs. prolonged fasting). All these findings were reversible after successful surgical removal of the insulinoma. Insulinoma patients could be identified as abnormal by (a) non-suppression of C-peptide even under hyperinsulinaemic/hypoglycaemic conditions (10 out of 10 patients) and (b) irregular increments in C-peptide under conditions that led to at least partial suppression in all normal subjects (9 out of 10 patients) and/or by an apparent shift to the left of insulin secretion relative to glucose concentrations (7 out of 10 patients). Controlled exposure to hyperinsulinaemic/hypoglycaemic conditions can help to characterize autonomous secretion in insulinoma patients and may be used as a diagnostic procedure when convent

Topics: Adult; Blood Glucose; C-Peptide; Fasting; Female; Glucose Clamp Technique; Humans; Hyperinsulinism; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Insulin Secretion; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms

3 patients with recurrent, symptomatic hypoglycemia associated with increased insulin and C-peptide blood levels are described. 2 men aged 37 and 21-years had mental and social problems and although they had access to sulfonylurea drugs, both denied intake. 1 was scheduled for pancreatectomy, but as a result of the vigilance of the surgeon, the operation was canceled. By demonstrating sulfonylurea in their urine, a definitive diagnosis of factitious hypoglycemia was established, and further invasive procedures were avoided. The third was a woman aged 40-years had malignant insulinoma with liver metastases, proven by cytology. The common and differentiating clinical and laboratory characteristics of hypoglycemia due to insulinoma and factitious hypoglycemia secondary to sulfonylurea intake are discussed, and the importance of urine analysis demonstrating the presence of sulfonylurea is emphasized.

Topics: Adult; C-Peptide; Diagnosis, Differential; Factitious Disorders; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Mental Disorders; Pancreatic Neoplasms; Sulfonylurea Compounds

A mini-human insulin gene and four derivatives mutated at several regions potentially involved in the regulation of gene expression were used to generate transgenic mouse lines. The effect of these mutations on the efficiency of gene expression and cell specificity was studied using three approaches: (1) Northern blot analysis using total RNA from pancreas and other organs, (2) radioimmunoassay to detect the human C-peptide in urine samples, and (3) immunocytochemistry of pancreas sections to examine whether expression of the transgene was still specifically expressed in beta-cells. Mutation of the cis-acting elements located between -238 and -206 (GCII and CTII motifs) resulted in a strong decrease of gene expression in the pancreas of transgenic mice, but it did not lead to complete extinction of the transgene expression. This region alone (-255/-202), when linked to the minimal Herpes simplex virus thymidine kinase gene (tk) promoter, failed to activate chloramphenicol acetyltransferase (CAT) gene expression in transfected insulinoma cells, while it was activated by the equivalent region of the rat insulin I gene. On the contrary, mutation of the DNA motifs located between -109 and -75 (GCI and CTI) or between -323 and -297 (CTIII) did not significantly affect the level of the human insulin gene expression in transgenic mice. Replacement of the insulin promoter (-58/+l) by the tk promoter did not alter its level of expression in transgenic mice. In all instances, expression of the different transgenes remained localized in the islet beta-cells. Altogether, these results indicate that the GCII-CTII motif is an important regulatory element for efficient expression of the human insulin gene in vivo, although it alone does not allow gene expression as it would require the association of other elements.

Topics: Animals; C-Peptide; DNA Mutational Analysis; Enhancer Elements, Genetic; Gene Expression Regulation; Genes, Reporter; Humans; Insulin; Insulinoma; Mice; Mice, Transgenic; Mutation; Pancreas; Promoter Regions, Genetic; Regulatory Sequences, Nucleic Acid; Thymidine Kinase; Tissue Distribution; Transfection; Tumor Cells, Cultured

Topics: Aged; C-Peptide; Calcium; Female; Humans; Injections, Intra-Arterial; Insulinoma; Pancreatic Neoplasms

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; C-Peptide; Female; Glucagon; Humans; Hyperinsulinism; Insulin; Insulinoma; Islets of Langerhans; Male; Middle Aged; Pancreatic Neoplasms; Radioimmunoassay

The author describe a rare case of pancreatic beta-cell hyperplasia. The patient was referred to us because of serious hypoglycemic crises. During hospitalization, endogenous hyperinsulinism was confirmed by hematochemical and instrumental tests. AngioCT of the pancreas evidenced a small lesion of the corpus, suspected of insulinoma. The patient underwent a corpus caudalis pancreatectomy: a small nodule with histologic neuroendocrine traits was ablated. A few days after the operation, new symptomatic hypoglycemia appeared. The hormonal tests confirmed a recurrence of endogenous hyperinsulinism. The patient underwent a new operation for pancreaticoduodenectomy: histological examination confirmed a pancreatic beta-cells hyperplasia. This condition has to be taken into account in the differential diagnosis of post prandial hypoglycemia. Besides, the observation of an insulinoma doesn't exclude the presence of a diffused disorder of islet cells as in the case above described.

Topics: C-Peptide; Diagnosis, Differential; Female; Humans; Hyperinsulinism; Hyperplasia; Hypoglycemia; Insulinoma; Islets of Langerhans; Middle Aged; Pancreatectomy; Pancreatic Neoplasms; Pancreaticoduodenectomy

By means of the euglycemic three step hyperinsulinemic clamp technique, suppression of endogenous C-peptide secretion by exogenous insulin infusion was evaluated in patients with insulinoma (n = 8) and healthy controls (n = 20). Euglycemic hyperinsulinemic clamp studies were performed with an artificial pancreas (STG-22 NIKKISO, Tokyo, Japan). Insulin (Actrapid human insulin) was infused at the rate of 1.12, 3, and 10 mU/kg/min. Plasma glucose levels were clamped at 80 mg/dl, and high insulin levels were maintained in all subjects (833 +/- 78 microU/ml at the rate of 10 mU/kg/min insulin infusion). During the clamp studies, plasma C-peptide levels in normal subjects declined from 2.0 +/- 0.2 to 0.9 +/- 0.2 ng/ml, indicating suppression of endogenous insulin secretion by exogenous insulin infusion. In patients with insulinoma, plasma C-peptide levels were 3.1 +/- 1.6 ng/ml in the basal state, and were not suppressed even during exogenous hyperinsulinemia. We concluded that the feedback inhibition of insulin secretion by exogenous insulin infusion is attenuated in patients with insulinoma, and that the hyperinsulinemic clamp technique may be a useful method for the diagnosis of insulinoma.

Topics: Adult; Aged; C-Peptide; Feedback; Female; Humans; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms

An extract of a neuroendocrine tumor of the human pancreas contained a high concentration of insulin and the C-peptide of proinsulin, as determined by radioimmunoassay, together with somatostatin, calcitonin, and thymosin beta 4. Analysis of the molecular forms of the proinsulin-derived peptides by high-performance liquid chromatography demonstrated that insulin was stored in the tumor as the intact peptide. In contrast, metabolites of C-peptide, representing the (1-21), (1-23), (1-25) and (1-29) N-terminal fragments, were isolated from the extract in addition to intact C-peptide. Generation of these metabolites involves cleavage of Xaa-Leu or Leu-Xaa bonds. Previous immunohistochemical studies have identified cathepsin B in secretory granules and lysosomes of human insulinoma cells. Synthetic human C-peptide was rapidly cleaved by purified human cathepsin B, primarily at the site of leucine residues, to give several metabolites, including the (1-25) and (1-23) fragments. The data indicate that the C-peptide of proinsulin is selectively metabolized in the neoplastic B cell by a mechanism that involves proteolytic cleavages in the C-terminal region of the peptide.

Topics: Aged; Amino Acid Sequence; C-Peptide; Cathepsin B; Chromatography; Female; Humans; Immunohistochemistry; Insulinoma; Intracellular Fluid; Molecular Sequence Data; Pancreatic Neoplasms; Proinsulin; Radioimmunoassay

Insulinomas are often hard to diagnose and difficult to locate during surgery. We tested the contribution of artificial pancreas (AP) for case management of our last eight patients including two cases with multiple insulinomas. When diagnosis is uncertain, the euglycemic hyperinsulinic clamp technique under AP is a safe method to assess inappropriate insulin secretion characterized by a high plasma level of C peptide not inhibited by insulin injection. During surgery the AP provides a feed back controlled glucose infusion and thus maintains blood glucose above a predefined level. It allows a safe operation, preventing sudden hypoglycemia. By providing continuous data about intensity of glucose infusion and blood glucose, it helps to detect an occult secreting tumor (a preoperative therapeutic test with diazoxide requires stopping treatment for at least one month before surgery to avoid false negative results) and confirms the total ablation of abnormal insulin-producing cells. Peroperative monitoring curves of glucose infusion and blood glucose related to exploration and ablation procedures illustrate the contribution of this method in helping surgical treatment which can be perfectly adapted to the lesions as shown by the total recovery of our eight patients (mean follow-up: 43.2 months).

Topics: Artificial Organs; Blood Glucose; C-Peptide; Glucose Clamp Technique; Humans; Insulin; Insulin Infusion Systems; Insulinoma; Pancreatic Neoplasms; Reference Values

A 67-year-old woman was admitted in hypoglycemic coma, with fever and signs of hyperthyroidism. Diagnosis was made of both an insulinoma and subacute ("De Quervain") thyroiditis. This rare coincidence of two diseases with opposite effects on serum glucose levels, offered a rare opportunity to study glucose metabolism in this peculiar physiopathological situation. During the day abnormally high postprandial blood glucose levels were seen, pointing to the glucose intolerance usually seen in the hyperthyroid state. During the night and after prolonged fasting, however, hypoglycemia predominated, consistent with the clinical picture typical of an insulinoma. After resection of the insulinoma and spontaneous healing of hyperthyroidism, glucose metabolism reverted to normal. As shown in this case, concurrent hyperthyroidism and an insulinoma may lead to consecutive episodes of glucose intolerance and hypoglycemia within the same 24-hour period.

Topics: Aged; Blood Glucose; C-Peptide; Female; Humans; Hyperthyroidism; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Thyroiditis, Subacute

To determine the reason patients with insulinoma are unable to cease insulin secretion during hypoglycemia.. Five patients with insulinoma.. All patients fasted for up to 25 hours, during which blood was obtained serially for determination of glucose and insulin concentrations. Insulinomas were surgically removed from all patients and Glut 1 and Glut 2 transporter proteins were measured in solubilized tumor membranes by immune blotting.. In all patients, serum insulin concentrations failed to decrease to less than 30.0 pmol/L (< 5.0 microU/mL) and C-peptide concentrations to less than 0.08 nmol/L during hypoglycemia (glucose concentration, < 2.2 mmol/L) that was induced by fasting. The islet cell tumors from all five patients contained Glut 1, a low-Km glucose transporter protein, which is not normally present in beta-cells. Glut 2, a high-Km glucose transporter protein, which is normally prevalent in beta-cells, was undetectable in one patient and was present in what appeared to be low concentrations in the remaining four patients.. Our data are compatible with the concept that continued glucose transport, mediated by the low-Km Glut 1 glucose transporter, was responsible for continued insulin release during hypoglycemia in these patients.

Topics: Adult; Aged; Blood Glucose; C-Peptide; Cell Membrane; Female; Glucose Transporter Type 4; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Membrane Glycoproteins; Middle Aged; Monosaccharide Transport Proteins; Muscle Proteins; Neoplasm Proteins; Pancreatic Neoplasms

We investigated the 24-hour mean blood glucose and serum insulin (IRI), C peptide (C pep) and glucagon concentrations before (pre) and after (post) continued treatment with octreotide (100 mcg three time daily by s.c. injection) in a woman, 68 years old, affected by a nine years long benign insulinoma. The blood pool to dose 24-hour mean glucose and all hormone concentrations was obtained by equal quantities of blood samples taken every 2-hour over 24-hour. The IRI, C pep, glucagon, glucose circadian pattern and IRI/glucose ratio were determined on remaining blood portions. After continued treatment with octreotide was significantly reduced the exaggerated and inappropriate insulin (pre = 77.08 +/- 23.6 microUI/ml; post = 15.19 +/- 2.3 microUI/ml; p < 0.001) and C pep secretion (pre = 4.17 +/- 0.4 ng/ml; post--1.64 +/- 0.04; p < 0.001), while the blood glucose levels were significantly elevated (pre = 40.46 +/- 3.1 mg/dl; post = 132.46 +/- 6.9 mg/dl; p < 0.001). Also glucagon levels were significantly inhibited (pre = 73.53 +/- 12.19 pg/ml; post = 46.80 +/- 9.1 pg/ml; p < 0.05). The long-acting somatostatin analogue has improved a lot IRI/glucose ratio (pre = 1.9 +/- 0.4; post = 0.12 +/- 0.04; p < 0.001). A significant positive correlation was found between IRI and C pep before (r = 0.93; p < 0.001) as well after octreotide treatment (r = 0.85; p < 0.001). A significant positive correlation (r = 0.69; p < 0.008) between IRI and glucose was observed only after octreotide treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Aged; Blood Glucose; C-Peptide; Combined Modality Therapy; Female; Glucagon; Humans; Insulin; Insulinoma; Octreotide; Pancreatic Neoplasms

Increased thyroid hormone concentrations have been reported to have disparate effects on insulin sensitivity in man. We describe a 72-year-old lady who initially presented with episodic hypoglycemia secondary to an insulinoma that was controlled by diazoxide. She re-presented 12 months later with a recurrence of the hypoglycemia following the development of thyrotoxicosis. The diazoxide treatment was maintained and propranolol was introduced, which prevented further episodes of hypoglycemia. This appeared to be due to a direct effect of propranolol on endogenous insulin secretion, while whole body insulin sensitivity remained unchanged as assessed using the hyperinsulinemic-euglycemic clamp technique. She was later rendered biochemically euthyroid with a combination of blocking carbimazole therapy and thyroxine replacement, and this was associated with a marked decrease in insulin sensitivity. Thus, the principal effect of thyroid hormone excess in this patient was an increase in insulin sensitivity that led to the clinical relapse of the insulinoma.

Topics: Aged; C-Peptide; Diazoxide; Female; Humans; Hypoglycemia; Insulin; Insulin Resistance; Insulinoma; Pancreatic Neoplasms; Propranolol; Recurrence; Thyrotoxicosis

An insulinoma was diagnosed in a 26 year-old woman who suddenly went into hypoglycemic coma in the 38th week of an apparently uncomplicated pregnancy. On review of the history it became apparent that symptoms due to hypoglycemia had been present since the 16th week of pregnancy. Continuous intravenous infusion of glucose was administered and the patient was delivered of a healthy child 5 days later. Investigations revealed 2 insulinoma nodules in the tail of the pancreas which were successfully removed 2 weeks post partum.

Topics: Adult; Blood Glucose; C-Peptide; Diagnosis, Differential; Female; Humans; Hypoglycemia; Infant, Newborn; Insulin; Insulinoma; Pancreas; Pancreatectomy; Pancreatic Neoplasms; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Trimester, Third

RIA using anti-C-peptide antibody has been employed for determination of C-peptide in serum. However, the level by this method is a sum of the levels of C-peptide and proinsulin, because anti-C-peptide cross-reacts with proinsulin. This time we developed an improved assay for C-peptide, in which a test sample is pretreated with anti-insulin antibody to eliminate proinsulin in samples before C-peptide assay. The assay procedure is composed of 3 steps; the first is the incubation of test serum with anti-insulin antibody insolubilized with magnetic particles to form a complex of proinsulin-anti-insulin antibody, the 2nd step is the centrifugation of the mixture to eliminate the complex and the last step is the assay for C-peptide by use of RIA kit in the supernatant. The assay is simple, sensitive and reproducible. Serum C-peptide level by this method is not influenced by the presence of proinsulin in test serum, even when as high as 9 ng/ml of proinsulin is contained. This assay revealed that a patient with insulinoma had normal level of serum C-peptide in spite of the extremely high level of proinsulin.

Topics: C-Peptide; Evaluation Studies as Topic; Humans; Insulinoma; Pancreatic Neoplasms; Radioimmunoassay; Reagent Kits, Diagnostic; Reproducibility of Results; Sensitivity and Specificity

We used a newly developed immunochemiluminometric assay of proinsulin to determine its relative utility vis-à-vis C-peptide and insulin for the diagnosis of insulinoma. The evaluation was conducted in 20 consecutive patients with histologically confirmed insulinoma and 22 normal subjects who underwent a prolonged fast according to a standard protocol. Patients with insulinoma fasted to the point of demonstrating Whipple's triad; normal subjects fasted to 72 h. At the end of the prolonged fast, when the glucose value was 2.8 mmol/L or less (50 mg/dL), all three hormones had equal sensitivity (100%) in detecting insulinoma with no overlap with the values of normal subjects. When glucose levels were between 2.8 mmol/L (50 mg/dL) and 3.3 mmol/L (60 mg/dL) at the end of the prolonged fast, proinsulin was better than C-peptide and insulin in the diagnosis of insulinoma. The sensitivity was 90% for proinsulin and 85% for both C-peptide and insulin. Therefore, proinsulin not only is useful for the diagnosis of insulinoma, but it may have greater diagnostic accuracy than C-peptide and insulin.

Topics: Animals; C-Peptide; Goats; Humans; Insulin; Insulinoma; Luminescent Measurements; Pancreatic Neoplasms; Proinsulin

Universally accepted criteria for relative hyperinsulinemia have not been established for the diagnosis of insulinoma. Therefore, we sought measures of insulin action which might act as surrogates for insulin measurements and thereby contribute to the assessment of hyperinsulinemia. Since insulin is antilipolytic, antiketogenic, and glycogenic we measured plasma beta-hydroxybutyrate, FFA, and the response of plasma glucose to iv glucagon at the end of the prolonged fast in 40 patients, later confirmed histologically to have insulinoma and 25 normal persons. Plasma beta-hydroxybutyrate and FFA concentrations were significantly lower in the patients with insulinoma (median, range), (0.3, 0.1-2.7 vs. 4.5, 1.2-7.0 mmol, P < 0.0001, and 1.03, 0.17-1.75 vs. 1.79, 1.17-3.12 mmol, P < 0.001, respectively), whereas the responses of plasma glucose to glucagon were significantly greater (3.0, 1.4-5.4 vs. 0.7, 0.0-1.3 mmol, P < 0.001) than in the normals. For patients with insulinoma (20/40) and normal subjects (13/25) with plasma glucose less than or equal to 3.3 mmol and plasma insulin and C-peptide concentrations in the normal overnight fasting range, conditions in which hyperinsulinemia is most difficult to assess, a clear distinction was provided by plasma glucose response to glucagon and plasma beta-hydroxybutyrate but not by plasma FFA, plasma insulin, nor plasma C-peptide. We conclude that plasma glucose response to iv glucagon greater than or equal to 1.4 mmol and plasma beta-hydroxybutyrate less than or equal to 2.7 mmol, at the end of the prolonged fast are indicative of hyperinsulinemia of insulinoma when the plasma glucose is less than or equal to 3.3 mmol. In this plasma glucose range these insulin surrogates provide better diagnostic accuracy than plasma insulin and C-peptide.

Topics: 3-Hydroxybutyric Acid; Adolescent; Adult; Aged; Blood Glucose; C-Peptide; Fasting; Fatty Acids, Nonesterified; Female; Glucagon; Humans; Hydroxybutyrates; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms

C-Peptide, a marker for insulin secretion, is purported to be elevated in patients with insulinoma but diagnostic criteria have not been established. Thirty-seven patients with histologically confirmed insulinoma studied preoperatively, 19 normal subjects, and 2 patients who subsequently acknowledged self-administration of insulin underwent the prolonged fast (< or = 72 h) according to a standard protocol. Plasma glucose, C-peptide, and insulin were measured every 6 h until plasma glucose was less than or equal to 3.3 mmol, then hourly until Whipple's triad was demonstrated or until 72 h without symptoms was reached. At the termination of the fasts, plasma was analyzed for sulfonylurea. Statistical analysis was by rank sum test. Data are expressed as median (range). The durations of fasts were 20 (2.5-68) h for patients with insulinomas and 72 h for normal subjects. At the end of fasts plasma glucose, C-peptide, and insulin concentrations were 2.2 (1.4-2.9) vs. 3.6 (2.7-5.5) mmol, P < 0.001; 0.60 (0.20-1.92) vs. 0.13 (0.07-0.43) nmol, P < 0.001; and 126 (35-840) vs. 35 (35-126) pmol, P < 0.001, respectively, for insulinoma patients and normal subjects. All plasma samples were negative for sulfonylurea. Insulinoma patients had C-peptide values at the end of the fasts greater than or equal to 0.20 nmol whereas normal subjects and patients with insulin factitial hypoglycemia had C-peptide concentrations less than or equal to 0.10 nmol when plasma glucose was less than or equal to 2.8 mmol. Insulinoma is confirmed in a sulfonylurea negative patient with Whipple's triad during the prolonged fast and a concomitant C-peptide concentration greater than or equal to 0.20 nmol.

Topics: Adolescent; Adult; Aged; C-Peptide; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Pancreatic Neoplasms; Radioimmunoassay; Reference Values

Normal insulin secretagogues, including glucose, usually have little influence on insulin secretion from insulinomas. Therefore, insulinomas typically cause fasting hypoglycemia with relative hyperinsulinemia. This report describes a patient with hyperinsulinemia due to an islet cell adenoma with microadenomatosis, which, upon provocative in vivo testing, was found to be profoundly responsive to hypoglycemic and hyperglycemic stimuli. A 72 hr fast followed by brisk exercise resulted in a gradual reduction of serum glucose and insulin concentrations, but did not provoke symptomatic hypoglycemia. Oral glucose tolerance testing resulted in a prompt 10-fold increase in serum insulin accompanied by a mildly symptomatic and gradual fall in serum glucose to 30 mg/dl 90 minutes after glucose ingestion. An intravenous glucose challenge caused an acute increase in serum insulin to more than 1200 microU/ml with a resulting serum glucose of 11 mg/dl 25 minutes later, associated with loss of consciousness. Although a prolonged fast has proven to be the best diagnostic test for insulin secreting tumors, many other provocative tests that use normal insulin secretagogues have been somewhat useful in this regard. The patient in this report supports the concept that insulinomas vary widely in their response to a number of normal physiologic regulators of insulin secretion, including the serum glucose concentration. A variety of provocative tests may be needed to fully evaluate the rare patient in whom there is a strong clinical suspicion of insulinoma but who has a nondiagnostic prolonged fast.

Topics: Blood Glucose; C-Peptide; Female; Glucose Tolerance Test; Humans; Insulin; Insulinoma; Kinetics; Middle Aged; Pancreatic Neoplasms; Physical Exertion

We describe cases of isolated functioning insulinoma occurring in two members of the same family (father and daughter). The father had a first encapsulated insulinoma diagnosed at 14 years of age and at the age of 33 years he was operated on for a second insulinoma infiltrating the exocrine pancreas with lymph node metastases. The daughter was operated on for an encapsulated insulinoma in the tail of the pancreas when she was 6 years old. No clinical and laboratory signs of other endocrine disturbances have so far been detected in either care or in any other members of the family. Our report suggests the possibility of multiple familial insulinoma, although this is an extremely rare condition. Our data also indicate that insulinomas, even if well controlled by medical treatment, should always be removed by surgery because malignancy cannot be excluded with certainty. Moreover, patients should be closely followed up, as recurrence may develop up to 15 years after surgery.

Topics: Adolescent; Blood Glucose; C-Peptide; Child; Female; Humans; Insulin; Insulinoma; Male; Neoplasm Recurrence, Local; Pancreatic Neoplasms

To assess the effects of gender, age, and body mass index (BMI) on suppression of plasma C-peptide during insulin-induced hypoglycemia, 101 lean and obese, healthy men and women ages 20 to 80 yr underwent infusion of human regular insulin, 0.125 U/kg over 60 min after an overnight fast. Plasma glucose, insulin, and C-peptide were measured every 30 min for 120 min. C-peptide concentrations were influenced by gender at 30 min, by BMI at baseline and both BMI and age at all subsequent time points. Because of variations in baseline plasma C-peptide concentrations, percent decrease in C-peptide was evaluated. Significantly less percent decrease of C-peptide with increased age at 30, 60, and 90 min and with increased BMI at 30 and 60 min were noted with no effect of gender. From stepwise regression analysis using multiple, additional variables only the plasma glucose concentration at 30 min made a significant, albeit small (8%), contribution to the variability in percent decrease in C-peptide at 60 min. When C-peptide responses from eight histologically confirmed insulinoma patients were contrasted to values adjusted for age, gender, and BMI of normal subjects, all insulinoma patients had abnormal responses when percent decrease in C-peptide was used, whereas only four insulinoma patients had abnormal response when actual C-peptide concentrations were used.

Topics: Adult; Aged; Aged, 80 and over; Aging; Blood Glucose; Body Mass Index; C-Peptide; Female; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Middle Aged; Osmolar Concentration; Pancreatic Neoplasms; Sex Characteristics

Release of immature secretory granules rich in incompletely processed proinsulin has been proposed to explain the relative hyperproinsulinemia in type 2 diabetic and insulinoma patients because of a constant secretory drive resulting from hyperglycemia and autonomous secretion, respectively. To test this hypothesis, insulin secretion was stimulated by a combination of hyperglycemia (11 mmol/L clamp), intravenous (i.v.) tolbutamide (1 g), and i.v. glucagon (initial bolus 10 micrograms/kg body weight, maintenance infusion 2 micrograms/kg body weight per hour) for 3 h. Circulating IR-insulin and IR-C-peptide concentrations increased 89-fold and 14-fold over basal values, respectively, but IR-proinsulin concentrations increased only ninefold over basal values. Estimation of the amount of insulin secreted (based on deconvolution analysis of plasma C-peptide values) showed that approximately 76 +/- 21 U were secreted during the stimulation period. This amount is a significant proportion of pancreatic insulin content in normal humans. In molar terms, IR-proinsulin (integrated incremental response multiplied by metabolic clearance rate of proinsulin) relative to IR-C-peptide (= insulin) secretion (deconvolution analysis) was estimated to be equal or even lower than the known proportion in islets (0.22 +/- 0.05%). Thus, using a near-maximal stimulation of insulin secretion maintained long enough to cause release of amounts of insulin approaching the estimated pancreatic content, no preferential release of proinsulin was observed in normal humans. Therefore, the hyperproinsulinemia of type 2 diabetes and in insulinoma patients may be caused by additional defects in the proinsulin to insulin conversion process.

Topics: Adult; C-Peptide; Diabetes Mellitus, Type 2; Female; Glucagon; Humans; Hyperglycemia; Insulin; Insulin Secretion; Insulinoma; Male; Pancreatic Neoplasms; Proinsulin; Tolbutamide

The endocrine pancreas secretes insulin in a pulsatile fashion. This rhythm is generated at a site within the pancreas, although its precise location has not been determined. With an in vitro system, we tested the possibility that beta-cells might generate spontaneous pulsatile insulin secretion in the absence of any external influence. Human insulinoma tissue from five patients was perifused for 7-10 h with RPMI-1640 medium and constant concentrations of glucose (5.5 mM). Insulin, C-peptide, and proinsulin were measured in the effluent collected at 3.3-min intervals. All three peptides demonstrated pulsatility of secretion in a similar, synchronous fashion that was sustained throughout each study. The Clifton cycle detection program demonstrated cycling in all five tumors, with an average period for all tumors of 28, 29, and 26 min for insulin, C-peptide, and proinsulin, respectively. Spectral analysis confirmed the regularity and consistency of the hormonal secretory patterns. Mean hormone concentrations secreted by different tumors varied, but insulin and C-peptide were secreted in a nearly 1:1 ratio. This study demonstrates 1) that beta-cells are able to generate spontaneous pulsatile insulin secretory activity, which is independent of innervation or the presence of other islet cells, and 2) proinsulin secretion from the beta-cell also has an inherent pulsatility. The synchrony observed in the cycles of proinsulin and its peptide products confirms their common secretory pathway in the beta-cell. We conclude that the beta-cell may be the originator of insulin cycling.

Topics: Adenoma; Adult; C-Peptide; Female; Glucose; Humans; Insulin; Insulinoma; Islets of Langerhans; Male; Middle Aged; Pancreatic Neoplasms; Perfusion; Proinsulin; Radioimmunoassay; Time Factors

Counterregulatory hormone responses were evaluated in a 37-yr-old woman before and after removal of a benign insulin-producing islet cell tumor. Counterregulatory hormone concentrations were measured during a glucose clamp with graded reductions of plasma glucose from 5.2 to 2.6 mmol/L. In the study before surgery, the increase in plasma epinephrine concentration was markedly blunted (by greater than 90%) compared to that in the study after surgery. The peak plasma norepinephrine concentration was similarly reduced by 71%, and plasma cortisol by 63%. In addition, the glycemic thresholds for secretion of the counterregulatory hormones were lower before removal of the tumor. Peak plasma GH responses were equivalent before and after surgery, but the threshold for GH secretion was 21% lower in the first hypoglycemia study. We conclude 1) that there is evidence for abnormal glucose counterregulatory hormone secretion in this patient, which may contribute to the pathogenesis of hypoglycemia seen in patients with insulinoma; 2) the reversal of reduced counterregulatory hormone secretion after tumor resection suggests that these defective hormonal responses may be related to recurrent hypoglycemia, persistent hyperinsulinemia, or both; and 3) that abnormal glucose counterregulation may exist in the absence of type 1 diabetes.

Topics: Adult; Blood Glucose; C-Peptide; Female; Hormones; Humans; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Postoperative Period

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

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

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 direct radioimmunoassay in unextracted plasma is described. The assay has a sensitivity of 4 pmol/l (2 standard deviation from zero). The proinsulin antiserum was immuno-adsorbed against human C-peptide and insulin coupled to glass beads. Cross-reactivity of the antiserum was assessed and shown to be less than 0.01% with both peptides. In normal healthy fasting subjects the plasma proinsulin level was 6.7 +/- 1.7 pmol/l (n = 17) (mean +/- SD). Fasting proinsulin levels in non-insulin dependent diabetics were significantly elevated compared with non diabetics (14.2 +/- 2 pmol/l (n = 11) vs 6.7 +/- 1.7 (n = 17) P less than 0.005). The insulin/proinsulin ratio was 3.4:1 in the non-insulin dependent diabetic compared with 6:1 in non-diabetics. Samples from 21 insulinoma patients were assayed and mean fasting plasma proinsulin level was 255 pmol/l +/- 479 when the patients were hypoglycaemic. The range in pro-insulin levels was large (30-2300 pmol/l). Mean fasting proinsulin level in three hypoglycaemic subjects due to sulphonylurea overdose was 15.7 +/- 2.3 pmol/l. The molar ratio of proinsulin to insulin was 1:6 in healthy subjects, 1:1 in insulinoma patients and 10:1 in sulphonylurea induced hypoglycaemic patients.

Topics: C-Peptide; Diabetes Mellitus, Type 2; Humans; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Proinsulin; Radioimmunoassay; Sensitivity and Specificity

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

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

We have characterized the molecular forms of circulating insulins in patients with hyperinsulinemia of diverse etiology. We have also compared the efficacy of various chromatographic conditions using reversed-phase (RP) HPLC. Using 0.2% trifluoroacetic acid (TFA) and triethylamine (TEA) with acetonitrile as the organic modifier, at an elution rate of 0.17%/min, porcine, bovine, and human insulins could be easily separated as well as abnormal insulins in the plasma of a patient (J.R.) with hyperinsulinemia of unknown etiology. When the reversed-phase C18 column was changed and a gradient of 0.33%/min was used, the abnormal insulin in patient J.R. could not be separated. By changing the solvent system to acetonitrile and isopropanol (vol:vol, 3:1) containing 0.1% TFA, omitting the TEA, and using a gentle gradient of 0.1%/min, various semisynthetic analogues of human insulin could be easily separated and the abnormal insulin could be identified in the plasma of the patient J.R. Abnormal insulin was also found in a patient with MEN-I, but in contrast, the insulins in eight patients with benign sporadic insulinomas appeared to be normal. These results suggest that certain hyperinsulinemic states may be associated with an abnormal insulin and that RP-HPLC is useful for identification of insulin variants in the circulation. However, the conditions of RP-HPLC may be critical if the abnormalities of the insulin are subtle.

Topics: C-Peptide; Chromatography, High Pressure Liquid; Humans; Hyperinsulinism; Hypoglycemia; Insulin; Insulinoma; Pancreatic Neoplasms; Proinsulin

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

Plasma concentrations of proinsulin and C-peptide were measured in five children presenting with severe hypoglycaemia associated with elevated plasma levels of immunoreactive insulin (IRI) in order to determine whether the profile of circulating B-cell products related to the underlying pathophysiology of the pancreas. Results were compared with data from 13 normal infants. Four children, three neonates and a nine year old girl, were subjected to partial or total pancreatectomy. The neonates had nesidioblastosis, nesidioblastosis with a microadenoma, and a functional abnormality without histological derangement respectively; the older child had a localised adenoma. The remaining child, a neonate, had transient hypoglycaemia and elevated IRI levels associated with hyperlactataemia and hyperalaninaemia. All the children had markedly elevated plasma proinsulin concentrations; the highest levels were seen in the child with an isolated adenoma and in the neonate with nesidioblastosis and a microadenoma. Both of these children also had substantially elevated plasma C-peptide concentrations. The remaining three neonates had plasma C-peptide levels, which although in the normal range for normoglycaemia were inappropriately elevated during hypoglycaemia. It is concluded that elevated proinsulin and C-peptide concentrations are seen in children with hypoglycaemia associated with increased plasma IRI levels and that the profile of the concentrations does not provide a reliable marker for the nature of the underlying pancreatic abnormality.

Topics: Alanine; C-Peptide; Child; Female; Humans; Hypoglycemia; Infant, Newborn; Insulin; Insulinoma; Lactates; Male; Pancreatectomy; Pancreatic Diseases; Pancreatic Neoplasms; Proinsulin

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

Two cases of hyperinsulinism from insulin self-administration are described, both patients being admitted to hospital with a diagnosis of insulinoma. In the first case, the diagnosis was clarified after a left pancreatectomy elsewhere, thanks to the discovery of a bottle of insulin. In the second case, the diagnosis was confirmed by the measurement of C-peptide during a hypoglycemic attack. The simultaneous sharp decrease in glucose levels, an exceptional increase in insulinaemia and a reduction or disappearance of serum C-peptide is indicative of this particular type of hyperinsulinism. The two cases described here were remarkably similar. Apart from the most common features, both reported a severe hypoglycemic syndrome of recent onset; negative tolbutamide and calcium tests; a frequent relapse shortly after glucose administration.

Topics: Adult; Blood Glucose; C-Peptide; Diagnosis, Differential; Factitious Disorders; Female; Humans; Hyperinsulinism; Hypoglycemia; Insulinoma; Munchausen Syndrome; Pancreatic Neoplasms; Recurrence; Self Administration

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

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

In order to clarify the mechanism of insulin secretion, responses of insulin (IRI) and C-peptide (CPR) in plasma to various stimuli were investigated in normal subjects and patients with diabetes mellitus, liver cirrhosis, chronic nephritis or insulinoma. The response of plasma IRI and CPR to oral glucose load was less marked in the mild and moderate diabetes groups than in the normal controls. Neither IRI nor CPR in the severe diabetes group responded to oral glucose. The patients with liver cirrhosis revealed an exaggerated and delayed response of IRI and CPR, and a lowered CPR/IRI ratio, indicating a remarkable response of IRI to glucose. In contrast, the patients with chronic nephritis showed a prominent rise of CPR alone. In the insulinoma patients, both plasma IRI and CPR increased after glucose load. In the response to glucose, there was approximately 30-min lag time between the peaks of IRI and CPR in the normal controls and the patients with various diseases. Following arginine infusion, plasma IRI and CPR increased in the normal subjects and the patients with moderate diabetes. In the normal subjects, plasma IRI reached a peak at 6 min and 3 min in response to tolbutamide and glucagon, respectively, which elicit an abrupt and sharp rise of insulin from B-cells. However, diabetic patients showed a minimal change in plasma IRI and CPR, whereas there was an exaggerated response of plasma IRI and CPR in insulinoma patients. In analysis of responses of plasma IRI and CPR to tolbutamide or glucagon, there was a lag time longer than 10 min in the normal subjects. The present study confirms the concurrent release of C-peptide from the B-cells in the secretion of insulin. In addition, it was suggested that insulin and C-peptide are mainly handled in the liver and the kidney, respectively. Furthermore, a longer lag time between the peaks of IRI and CPR in response to tolbutamide or glucagon did not necessarily indicate a simultaneous release of insulin and C-peptide from the B-cell, but a delayed release of the latter.

Topics: Adult; Aged; Arginine; C-Peptide; Diabetes Mellitus; Female; Glucagon; Glucose Tolerance Test; Humans; Insulin; Insulin Secretion; Insulinoma; Islets of Langerhans; Liver Cirrhosis; Male; Middle Aged; Nephritis; Pancreatic Neoplasms; Peptides; Tolbutamide

Topics: Adult; C-Peptide; Diagnosis, Differential; Factitious Disorders; Glyburide; Humans; Hypoglycemia; Insulin; Insulinoma; Male; Pancreatic Neoplasms; Peptides

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