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Introduction: Particular problems in MEN 1 syndrome come from the morphological identification of pancreatic tumors because of their are often small [<1 cm] and multiple [89% of the cases]. However intraoperatively it could be difficult to identify with palpation the tumors described by preoperative investigations and to decide the most suitable surgical treatment. The authors describe one case recently observed to underline and update the correct management., Case Report: A 34 year old woman was admitted for the surgical treatment of an insulinoma. Polimenorrea, hypercalcemia and familiarity for MEN 1 syndrome were also present. A CT scan showed the tumors in the body and tail of the pancreas [diameter 0.5-1 cm]. MRI described only a small mass in pancreatic head. A calcium angiography was positive for insulin secretion after calcium infusion in hepatic and gastroduodenal artery, and for glucagon secretion after infusion in splenic artery. An intraoperative ultrasonography discovered three nodules that were enucleated. They were one insulinoma and two glucagonomas respectively. After enucleation glycemia became immediately normal., Conclusion: To avoid wide surgical resections [es. left pancreatectomy] we suggest a conservative treatment [multiple enucletion with or without a pancreatic-jejunum side-to-side anastomosis] with a meticulous preoperative and intraoperative evaluation of all pancreatic nodules.

Background: It has been demonstrated that adrenomedullin, a newly discovered peptide, affects the release of insulin from pancreatic islets cells, suggesting a role in the insulin-regulating system., Objective: To investigate whether adrenomedullin secretion is modified in patients with insulin-secreting islet cell tumours., Design: The study was performed in nine patients with surgically treated insulinoma. Circulating adrenomedullin was assayed using a specific radioimmunoassay and its localization and distribution in the tumour were determined by means of immunohistochemistry., Results: Adrenomedullin concentrations were significantly greater in patients with insulinoma (6.6 +/- 3.2 fmol/ml) than in controls (2.1 +/- 1.1 fmol/ml). In six patients monitored before and after surgery, plasma adrenomedullin decreased from 6.3 +/- 2.9 fmol/ml to 3.0 +/- 1.6 fmol/ml. Immunoreactive adrenomedullin was localized exclusively in the tumours cells, whereas stroma, surrounding pancreas parenchyma and major ducts were negative for the peptide., Conclusions: Our findings indicate that circulating adrenomedullin is increased in insulinoma and that this increase is related to the neoplastic phenotype.

Background: To verify whether insulin levels influence PC-1 tissue content, we studied PC-1 gene expression and protein content in skeletal muscle of patients with insulinoma, a model of primary hyperinsulinemia. Data were compared with those obtained in matched insulin sensitive or resistant healthy subjects. In addition, the effect of high insulin concentration on PC-1 protein content was studied in HepG2 cells., Methods: The following measurements were performed: insulin sensitivity by euglycemic clamp; PC-1 protein content and insulin receptor autophosphorylation by specific ELISAs; PC-1 gene expression by competitive polymerase chain reaction (PCR); phosphatidyl-inositol-3 kinase by immunoprecipitation and thin layer chromatography; glycogen synthesis by (14)C-glucose incorporation., Results: Muscle PC-1 content was similar in the insulinoma patients and in insulin sensitive controls but higher (p<0.01) in insulin resistant controls (21.9+/-4.6 ng/mg protein, 23.8+/-3.9, 48.0+/-8.7, respectively). PC-1 protein content was inversely correlated with insulin sensitivity (r=-0.5, p<0.015) but with neither plasma insulin nor glucose levels. PC-1 protein content was correlated with PC-1 gene expression (r=0.53, p<0.05, n=14). Exposure to high insulin (100 nmol/l for 16 h) caused a significant (p<0.05-0.01) impairment of insulin receptor autophosphorylation, phosphatidyl-inositol-3 kinase activity and glycogen synthesis, but not of PC-1 protein content (114+/-3 vs 102+/-14 ng/mg protein) in HepG2 cells., Conclusion: These findings suggest that chronic high insulin levels do not influence PC-1 expression., (Copyright 2000 John Wiley & Sons, Ltd.)

Aim: Controversy continues to reign with regard to the need for preoperative localization of insulinomas and to which are the most sensitive and accurate diagnostic imaging modalities. Our aim was to determine the role of diagnostic procedures and suggest which of them are really useful., Methods: Over a 12-year period 34 patients underwent several preoperative diagnostic procedures to localize the insulinoma: ultrasonography (US) in 20 cases, computed tomography (CT) in 26, magnetic resonance imaging (MRI) in 28, selective angiography in 8, arterial stimulation venous sampling (ASVS) in 23 and Octreoscan in 26. All patients underwent surgical palpation and in 32 cases intraoperative ultrasonography (IOUS) was performed. Twenty-six cases underwent enucleation, six had distal pancreatic resections and two patients had only exploratory laparotomy with liver biopsies. We compared the findings of the diagnostic procedures and analyzed the surgical treatment chosen according to the pancreatic site of the tumor., Results: In 32 (94.1%) of the 34 patients with clinically suspected pancreatic insulinoma the tumor was found at surgery. Preoperative US achieved 5.2% sensitivity, CT 29.1%, selective angiography 28.5% and MRI 76.9%. ASVS achieved 91.3% sensitivity and diagnostic accuracy whereas Octreoscan achieved only 65.3% diagnostic accuracy. Surgical palpation performed before IOUS identified the tumors in 30/34 patients: in the other four cases, one was a false-positive result (a cyst in the pancreatic head), two were true negatives and one was a false negative. Surgical palpation therefore yielded 88.2% diagnostic accuracy. IOUS was performed in 32 cases and localized the tumors in 29/32 cases (sensitivity: 96.6%) with one false-negative result (diagnostic accuracy: 96.8%). The operative mortality was 2.9% and the morbidity 24.6% (30.7% in patients treated by tumor enucleation)., Conclusions: No single diagnostic imaging modality is reliable for localizing insulinoma. We therefore suggest combined MRI, ASVS and IOUS. ASVS provides particularly useful information for planning manual palpation and intraoperative ultrasonography.

Sixty-seven insulinomas were investigated by immunohistochemistry using site-directed antibodies against insulin, proinsulin, chromogranin A, HISL-19, and four proteins directly or indirectly involved in the proteolytic processing of proinsulin: the prohormone convertases PC2 and PC3, carboxypeptidase H (CPH) and 7B2. Results were expressed in a six-grade score according to the frequency of immunoreactive tumour cells. Insulin was expressed by all tumours, appearing in either a diffuse or a polarized pattern and being detected in more than 30% of tumour cells in all cases but three. Proinsulin was also expressed in all tumours, with more than 50% of tumour cells immunoreactive in all cases but 5. It was consistently localized in the Golgi apparatus. In about half the cases, moreover, it also showed diffuse cytoplasmic staining, usually with a very sparse distribution. Trabecular and solid insulinomas did not present specific, homogeneous patterns of insulin immunostaining. However, insulin immunoreactivity was much more abundant in trabecular than in solid neoplasms, being present in virtually all tumour cells (score 6) in 50% and 8% of cases, respectively. Virtually all insulinomas expressed PC2, PC3, CPH and 7B2, usually in 30-100% of tumour cells, with a frequency significantly related to that of insulin. However, detection of PC2 and 7B2 was slightly less frequent than that of PC3 and CPH. In consecutive sections these proteins were found to be mostly co-localized with insulin and chromogranin A but not with proinsulin. They were heavily expressed in all 10 tumours with more than 10% of cells showing cytoplasmic proinsulin immunoreactivity, indicating that the leakage of proinsulin from the Golgi compartment is not associated with faulty expression of converting enzymes and possibly reflects a saturated processing capacity. HISL-19 immunoreactivity was found in both Golgi apparatus and insulin stores, indicating that the relevant antigen is different from all other proteins investigated. These results do not support a defect in expression or localization of proinsulin-processing enzymes in most insulinomas.

To investigate the effects of spontaneous chronic hypoglycemia on the peripheral and central nervous system, a multimodal neurophysiological evaluation [median somatosensory (mSEP), brain stem auditory (BAEP), and visual (VEP) evoked potentials recordings] was performed in seven insulinoma patients before and 3 and 6 months after surgical removal of tumor. Before surgery, mSEP findings showed abnormal reduction in peripheral wrist-Erb conduction velocity in three patients as well as a pathological increase in Erb-N13, N13-N20, and Erb-N20 conduction times in five cases. BAEP and VEP recordings gave pathological results in two patients. Moreover, during hypoglycemia, the III-V and I-V interpeak latencies of BAEPs were significantly prolonged (P < 0.01 and P < 0.005, respectively) compared to recordings in euglycemia. After 6 months, a mSEP recovery, even if partial was noted in four patients, BAEPs were normalized in one case, and VEPs were unmodified. Compared to presurgery data, these recordings showed a significant (P < 0.05), but incomplete, shortening of BAEPs (III-V and I-V interpeak latencies) and mSEPs (Erb-N13 and Erb-N20 conduction times). Our findings demonstrate that multiple and selective neurophysiological abnormalities are present in insulinoma patients, confirm that hypoglycemia impairs suddenly brain stem function, and show that after tumor removal, long recovery times for improvement of some neurophysiological anomalies are requested.

Alternative splicing of the 36-base pair exon 11 of the human insulin receptor gene results in the synthesis of two insulin receptor isoforms with distinct functional characteristics (the isoform containing exon 11 has lower insulin binding affinity and lower internalization rate). Altered expression of these insulin receptor isoforms has been previously demonstrated in skeletal muscle of patients with non-insulin-dependent diabetes mellitus (NIDDM). However, this observation was not confirmed by other studies and is still a matter of controversy; furthermore, it is not known whether it represents a primary event or is secondary to hyperinsulinaemia and insulin resistance. In order to address this issue in patients with pure non-genetically determined hyperinsulinaemia, we examined the alternative splicing of insulin receptor mRNAs in skeletal muscle of eight patients with surgically confirmed insulinoma and insulin resistance and in eight healthy subjects, using the reverse transcriptase-polymerase chain reaction technique. The insulinoma patients displayed a significant increase in the expression of the insulin receptor isoform containing exon 11 (75.7 +/- 2.3%) when compared with normal subjects (57.9 +/- 1.5%); furthermore, this increase was positively correlated with plasma insulin concentration and negatively correlated with in vivo insulin sensitivity (glucose clamp). In conclusion, the increased expression of the insulin receptor isoform with lower insulin binding affinity in patients with primary non-genetically determined hyperinsulinaemia supports a role for insulin in the regulation of alternative splicing of insulin receptor pre-mRNA and suggests that in NIDDM an altered receptor isoform distribution might be secondary to the ambient hyperinsulinaemia rather than representing a primary defect.

We evaluated the sensitivity of 111In-Octreotide scintigraphy in the diagnosis of pancreatic insulinoma in a selected number of patients. In addition, we compared the results of scintigraphy with those of other conventional diagnostic techniques. Seven patients with surgically confirmed insulinoma (< 1.5 cm in diameter) of the pancreas were studied. Before surgery, patients underwent arteriography with Ca-gluconate, CT scan, and 111In-Octreotide scintigraphy. 111In-Octreotide scintigraphy showed a higher diagnostic specificity (85%) than selective arteriography (83%) or CT scan (57%). We conclude that 111In-Octreotide scintigraphy should always be performed before surgery in cases of pancreatic insulinoma and that a SPECT acquisition should be performed both 6 and 24 hours post-injection in order to increase the diagnostic sensitivity of the test.

Hyperinsulinemia has been assumed to contribute to the pathogenesis of atherosclerosis. To assess the reliability of such claim we planned a retrospective study on a cohort of patients with pancreatic insulin producing neoplasm. A correlation was sought between fasting insulin plasma levels and the metabolic profile emerging from those parameters known to be cardiovascular risk factors, i.e. plasma triglycerides and cholesterol, insulin resistance, hypertension. Special attention was paid to the duration of disease, because the time exposure to hyperinsulinemia could play an important role in developing cardiovascular disease. Seventy patients, 41 females and 29 males, aged 44.9 +/- 1.96 yr (range 15-80), with surgically proved insulinoma were included in the study. Chronic exposure to hyperinsulinemia was documented through the measurement of insulin plasma levels either in the fasting state or post-prandially, resulting in 44.7 +/- 3.28 and 149.9 +/- 12.22 microU/ml, respectively. Fasting glycemia in average was 45.3 +/- 1.34 mg/dl. Plasma triglycerides and cholesterol concentrations were 136.3 +/- 7.93 and 195.8 +/- 5.18 mg/dl, respectively, their distribution overlapping that anticipated for the general population. No correlation arose between the degree of hyperinsulinemia and the lipidic profile. Preoperative blood pressure was 136.9 +/- 2.87 mmHg, systolic and 81.9 +/- 1.32 mmHg, diastolic. Hypertension was present in 5 (7.1%) out of 70 patients and persisted after tumor removal. A condition of insulin resistance (M = 4.06 +/- 0.4 mg/kg min vs 7.41 +/- 0.21) was documented through the euglycemic hyperinsulinemic clamp technique in 20 patients and showed a positive and significant correlation with fasting insulinemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Ten consecutive patients with surgically proven beta-islet cell tumors, strongly suspected clinically because of positive laboratory findings, were studied by MRI at 0.5 T. Results were correlated with CT and angiography. MRI detected all 10 insulinomas, with the location confirmed at surgery. Lesion size was < 1 cm in three cases, between 1 and 2 cm in five cases, and between 2 and 3 cm in two cases. A false-negative diagnosis was obtained with CT in 6 of 10 and with angiography in 3 of 10 cases. Our results suggest that if motion artifact can be controlled or reduced, MRI can be employed to localize insulinomas in patients with positive clinical and laboratory findings.

Gastric inhibitory polypeptide (GIP) levels during an oral glucose tolerance test (OGTT) have been determined in eight patients suffering from a single benign beta-cell adenoma. GIP hypersecretion and an absent correlation between the insulin: glucose ratio and plasma GIP concentration have been observed. Our data show that the insulinotropic effect of GIP is almost abolished in insulinoma patients. This finding may help explain blood glucose levels and the inappropriate plasma insulin response to oral glucose often observed in these patients.

The diazoxide infusion test (600 mg i.v. over a 1-hour period) was performed in 12 patients bearing single benign islet B-cell adenoma and in 6 normal subjects. Blood glucose, plasma insulin and glucagon concentrations were measured every 15 min during the infusion and thereafter up to 150 min. In insulinoma patients, blood glucose levels failed to increase significantly while in the control group a significant rise starting from 30 min persisted throughout the test (p less than 0.05 or less). Plasma insulin mean levels decreased significantly in normal subjects from 30 to 60 min (p less than 0.05), while they were significantly suppressed in hypoglycemic patients from 15 to 120 min (p less than 0.02). Diazoxide administration induced in the normal group a significant decrease in glucagon levels (p less than 0.02 from 30 to 150 min) whereas no such suppression occurred in patients. In our experience, insulin response to diazoxide infusion in patients with insulinoma may provide additional information for diagnosis.