Ca2+ channel inhibition induced by nitric oxide in rat insulinoma RINm5F cells

 The effect of nitric oxide (NO) donors on high-voltage-activated Ca²⁺ channels in insulin-secreting RINm5F cells was investigated using the patch-clamp technique in the whole-cell configuration. Sodium nitroprusside (SNP, 2–400 μM) induced a dose-dependent reduction in Ba²⁺ currents with maximal inhibition of 58%. The IC₅₀ for SNP was 45 μM. A different NO donor, (±)S-nitroso-N-acetylpenicillamine (SNAP, 500 μM), also produced a 50% decrease in current amplitude. When 200 μM SNP was administered together with the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidozoline-1-oxyl-3-oxide (carboxy-PTIO, 300 μM), the Ba²⁺ current inhibition was lowered to 7%. Administration of 500 μM 8-bromoguanosine 3′:5′-cyclic monophosphate sodium salt (8-Br-cGMP) mimicked the effects of SNP, causing a comparable decrease (56%) in peak-current amplitude. When soluble guanylyl cyclase was blocked by 10 μM 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ), the inhibitory effect of 200 μM SNP was reduced from 39% to 15%. The SNP-induced current decrease was 36% of controls after the blockade of L-type Ca²⁺ channels and 30% in the presence of 2.5 μM ω-conotoxin-MVIIC. These data indicate that NO inhibits both L-type and P/Q-type Ca²⁺ channels in RINm5F cells, probably by an increase in the intracellular levels of cGMP. NO may then significantly influence the Ca²⁺-dependent release of hormones from secretory cells as well as that of neurotransmitters from nerve terminals. Received: 14 April 1998 / Received after revision: 14 September 1998 / Accepted: 25 September 1998     

Clinical analyses of 75 parathyroidectomy (PTE) patients and 69 adrenalectomy (AE) patients including saliva-type amylase-secreting secondary parathyroid hyperplasia (SPTH) and insulinoma with adrenal adenoma (AA) showing primary aldosteronism

Seventy-five parathyroidectomy (PTE) and 69 adrenalectomy (AE) patients were analyzed. The 75 PTE included 56 of secondary parathyroid hyperplasia (SPTH) with chronic renal failure (CRF) and 19 of primary parathyroid hyperplasia (PPTH) without CRF. The 69 AE included 23 with Cushing’s syndrome, 30 with primary aldosteronism, four with cortical carcinoma (three virilizing and one feminizing carcinomas), seven with pheochromocytoma (two multiple endocrine neoplasia 2A), two with paraganglioma, one with schwannoma, one with non-functional adenoma, and one with hepatic cancer metastasis. The 56 SPTH showed higher levels of intact (I)-parathyroid hormone (PT) of 1,359 ± 1,036 pg/ml than the 292 ± 372 pg/ml of the 19 PPTH. Measured vitamin D of 1, 25(OH)₂D was higher in the nine PPTH (88.0 ± 34.7 pg/ml) than in the 46 SPTH (15.5 ± 13.9). High serum amylase of >350 IU/l and cyst formations were found in ten (18%) and 16 (29%) of the SPTH but none of the PPTH. At least ten (18%) of the SPTH had polycystic kidney disease (PKD). Saliva-type amylase of the SPTH resolved the high I-PTH. High levels (>6.0%) of Hb A1C (8.1%) were measured only in one SPTH case with mediastinal ectopic SPTH and PKD. High urine 17 ketosteroid (17 KS) levels of 161.5 ± 72.9 mg/l were measured in three virilizing carcinomas with metastases to the bone, liver, and/or lung. Low-grade feminizing carcinoma was observed in a 6-year-old boy. Cysts of the kidney and/or liver were found in 17 (74%) with Cushing’s syndrome, 12 (40%) with primary aldosteronism, and three (43%) with pheochromocytoma. One paraganglioma had liver and pancreatic cysts, and one schwannoma had polycystic ovary. High levels of Hb A1C were detected in six (26%) with Cushing’s syndrome, five (17%) with primary aldosteronism showing insulinoma, and two (29%) with pheochromocytoma. In all 13 patients with diabetes mellitus (DM), AE was an effective DM treatment.     

多层螺旋CT多期增强扫描及后处理对胰岛素瘤的评价

目的:探讨多层螺旋CT(MSCT)多期扫描及后处理对胰岛素瘤检出的价值。方法:13例手术证实的胰岛素瘤均行MSCT平扫及三期增强扫描,观察各期肿瘤增强程度及检出率。结果:13例CT平扫肿瘤均为等密度,动脉期及门脉期肿瘤与胰腺实质密度差为24HU与29HU,动脉期、门脉期及实质期肿瘤的检出率分别为84%、100%及62%。结论:MSCT多期成像对胰岛素瘤诊断具有重要价值,门脉期在检出肿瘤方面略优于动脉期扫描,MSCT薄层扫描及其后处理技术有助于显示肿瘤的空间位置及其与血管的关系。     

Surgical treatment of persistent hyperinsulinemic hypoglycemia (PHH) (insulinoma and nesidioblastosis)

Background The persistent hyperinsulinemic hypoglycemia is characterized by clinical symptoms that occur when the blood glucose levels drop below the normal range. Two pathological situations cause this clinical problem: The presence of a tumor of the pancreas secreting excessive amounts of insulin, known as insulinoma, and congenital beta-cell hyperplasia in the pancreas in children and noninsulinoma pancreatogenic hypoglycemia syndrome in adults. Patients and methods Clinical characteristic and surgical outcome of a group of 20 patients operated on for this hypoglycemic syndrome; 18 for insulinoma and two for nesidioblastosis in children was studied. Results eight of the insulinomas were in the head of the pancreas, two in the body, and the remaining eight in the tail. The surgical technique was enucleation in nine cases, local resection in one case because of suspicious malignancy, and distal pancreatectomy in eight cases. Both children with nesidioblastosis underwent 85% pancreatectomy with splenic preservation. There was no mortality in the study, but three patients developed a low-volume pancreatic fistula after head enucleation. Conclusions Negative results in diagnostic localization together with the small size of the insulinoma represent a poor combination for successful surgery. The intraoperative ultrasonography is the method of choice for the identification of the tumor, as it is able to identify nonpalpable lesions. This paper was presented at the 2nd Biennal Meeting of the European Society of Endocrine Surgeons (ESES), 18–20 May 2006, Krakow, Poland.     

High-dose calcium stimulation test in a case of insulinoma masquerading as hysteria

It is reported that some cases with insulinoma present with neuropsychiatric symptoms and are often misdiagnosed as psychosis. Here we report a case of insulinoma masquerading as hysteria, whose final diagnosis could be made using high-dose calcium stimulation test. A 28-yr-old woman was referred presenting with substupor, mutism, mannerism, restlessness, and incoherence. Laboratory examinations revealed hypoglycemia (33 mg/dL) and detectable insulin levels (9.7 μU/mL), suggesting the diagnosis of insulinoma. However, neither imaging studies nor selective arterial calcium injection (SACI) test with a conventional dose of calcium (0.025 mEq/kg) indicated the tumor. High-dose calcium injection (0.05 mEq/kg) evoked insulin secretion when injected into superior mesenteric artery. A solitary tumor in the head of the pancreas was resected, and her plasma glucose returned to normal. Postoperatively, iv injection of secretin resulted in a normal response of insulin, which was not found preoperatively. This case suggests the usefulness of the SACI test with high-dose of calcium in the case of insulinoma when the standard dose fails to detect such a tumor.     

Insulin and C-peptide co-localization in theβ granules of normal human pancreas and insulinomas

Summary It has been shown, by using the immunogold technique, that C-peptide and insulin are co-localized in the mature granules of human pancreatic 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 m) was smaller than that of human pancreatic cells (D=0.45 ±0.15 m). 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 granules. Thus, no topological segregation of these two antigens occurs within the granules of either normal human pancreas or insulinomas.     

Flow and image cytometric study of pancreatic neuroendocrine tumours: Frequent DNA aneuploidy and an association with the clinical outcome

Summary Eighteen pancreatic neuroendocrine (NE) tumours were analysed for nuclear DNA content by image cytometry (ICM) and flow cytometry (FCM). The DNA indices (DIs) obtained by ICM were somewhat higher than those obtained by FCM, but a major disagreement was present only in 1 case. Thirteen patients had been followed up at least for 6 years after the diagnosis or until death. At 6 years of follow-up all 4 patients with a tumour with a DI1.8 by ICM had died from their NE tumour or had metastatic disease, whereas all 9 patients with a smaller DI had no evidence of the disease (P=0.001). The DIs calculated from the FCM data also correlated well with the final outcome (P=0.01). A high incidence of DNA aneuploidy was found by both methods in histologically and clinically benign NE tumours; 12 (67%) were DNA aneuploid by FCM and 16 (89%) by ICM. It is concluded that pancreatic NE tumours are frequently DNA aneuploid, and both cytometric DNA methods give prognostic information in these tumours. The presence of DNA aneuploidy should not be considered as a sign of malignant behaviour in pancreatic NE tumours, whereas a large DI is associated with poor prognosis.     

Role of laparoscopic ultrasonography in intraoperative localization of pancreatic insulinoma

Background: A combination of digital palpation and ultrasonography plays an important role in locating insulinomas intraoperatively. Laparoscopic resection of insulinomas has been described recently, but experience in locating insulinomas during laparoscopy is lacking. Methods: From January 1998 to January 1999, three patients with pancreatic insulinomas underwent laparoscopy and laparoscopic ultrasonography aimed at intraoperative localization and potential resection. The role of laparoscopy and laparoscopic ultrasonography in locating insulinomas is evaluated. Results: Preoperative localization studies were routinely performed, and two patients had an occult tumor before laparoscopy. None of the tumors was detected by laparoscopic examination, but laparoscopic ultrasonography identified solitary tumors located at the body and tail of the pancreas. Conversion to laparotomy was performed in one patient as a planned procedure. One patient underwent laparoscopic enucleation, whereas the other had a laparoscopic distal pancreatectomy. Conclusions: Laparoscopic ultrasonography seems to be sensitive in locating insulinomas at the body and tail of the pancreas. It optimizes and facilitates resection of insulinomas through a minimally invasive approach. Received: 8 March 1999/Accepted: 10 August 1999/Online publication: 7 September 2000     

Insulinoma occurring in association with fatty replacement of unknown etiology in the pancreas: Report of a case

A 66-year-old woman with a 10-year-history of diabetes mellitus was admitted to our hospital for investigation of several recent attacks of hypoglycemia. Her fasting blood glucose level was very low, at 30–40 mg/dl, and abdominal ultrasonography and computed tomography revealed a tumor in the pancreatic tail with fatty changes. Endoscopic retrograde cholangiopancreatography revealed absence of the main pancreatic duct from the body to tail of the pancreas. Abdominal angiography showed a hypervascular tumor stain in the pancreas, and percutaneous transhepatic portal vein sampling demonstrated a step-up of immunoreactive insulin levels in the splenic vein. Based on these clinical findings, we made a preoperative diagnosis of an insulinoma accompanied by fatty changes in the pancreatic body and tail. During laparotomy for the insulinoma, fat tissue was identified in the anatomic location of the pancreatic body and tail, and resected. Pathological examination of the resected specimen revealed a number of Langerhans islets in the adipose tissue, and an islet cell tumor with fatty replacement of the pancreatic tissue around the tumor. The insulinoma was found not to have caused obstruction of the main pancreatic duct. We present herein a rare case of an insulinoma that developed in the pancreas, and was associated with fatty replacement of unknown etiology. Received: August 9, 1999 / Accepted: May 30, 2000     

胰岛素瘤的术前定性及定位诊断99例分析

目的分析不同的激素检查和影像学检查方法对胰岛素瘤术前诊断的价值。方法回顾性总结分析北京协和医院1989年12月至2005年8月入院的有明确术后病理诊断的胰岛素瘤患者的临床资料。结果本组患者的临床表现以昏迷、体重增加、大汗、定向力障碍、记忆力减退、头晕头痛为主。空腹血糖低于2.78mmol/L对于诊断胰岛素瘤的敏感性为66.6%;发作时的血清胰岛素血糖比值大于0.3的敏感性为89.7%;常用的影像学检查中胰腺灌注CT的敏感性最高,可达100.0%。结论典型的Whipple三联症和低血糖时的血清胰岛素血糖比值大于0.3是胰岛素瘤定性诊断的重要依据。目前常用的影像学检查手段中,胰腺灌注CT对于胰岛素瘤诊断的敏感性和特异性最高。