Pathogenesis of hypoglycemia in insulinoma patients: suppression of hepatic glucose production by insulin

To determine the mechanism by which hyperinsulinemia causes hypoglycemia in insulinoma patients, rates of glucose production and utilization, and circulating levels of insulin, glucagon, alanine, lactate, and glycerol were measured in 6 insulinoma patients during development of fasting hypoglycemia and in 8 normal volunteers studied over an identical interval. Initially, insulinoma patients had a greater plasma insulin (42 +/- 9 versus 15 +/- 1 microunits/ml) and glucagon levels (214 +/- 31 versus 158 +/- 21 pg/ml) than normal subjects, P less than 0.05, but their plasma glucose levels (81 +/- 4 mg/dl) and rates of glucose production and utilization (1.71 +/- 0.08 and 1.74 +/- 0.08 mg/kg . min, respectively) were not significantly different from those of normal subjects (93 +/- 2 mg/dl, 1.93 +/- 0.11, and 1.92 +/- 0.13 mg/kg . min, respectively). During a subsequent 8-h fast, glucose production and glucose utilization decreased in both groups, but more markedly in insulinoma patients. Since glucose utilization exceeded glucose production to a greater extent in insulinoma patients than in normal subjects, plasma glucose decreased to 44 +/- 3 mg/dl in insulinoma patients, but only to 84 +/- 1 mg/dl in normal subjects (P less than 0.001). Glucose utilization in insulinoma patients never exceeded that of normal subjects. These results demonstrate that fasting hypoglycemia in the insulinoma patients is usually due to suppression of glucose production rather than to acceleration of glucose utilization, as is widely thought. A direct effect of insulin on the liver is probably responsible, since circulating levels of gluconeogenic precursors are normal and since plasma glucagon increases during development of hypoglycemia in insulinoma patients.     

Islet Hyperplasia in Adults: Challenge to Preoperatively Diagnose Non-Insulinoma Pancreatogenic Hypoglycemia Syndrome

Background Pancreatic hyperfunctional islet hyperplasia in adults has been more and more frequently described in the literature. Postprandial neuroglycopenia, a negative normal fasting test, negative pancreatic imaging results, and positive intra-arterial calcium stimulation of serum insulin are characteristic. In affected patients the term non-insulinoma pancreatogenic hypoglycemia syndrome (NIPHS) was proposed. Materials and Methods/Patients We also encountered fasting hypoglycemia in such patients and therefore evaluated clinical and biochemical data in patients with NIPHS (n = 11), patients with insulinoma (n = 70), and patients in whom hypoglycemia was ruled out (n = 70). Results Patients with NIPHS were younger (median age: 41 years; range: 18–66) and mostly non-obese (median body mass index/BMI: 22.2 kg/m²; range: 19–39) compared with patients with an insulinoma (median age: 50 years; median: BMI 26.1 kg/m²). During an oral glucose tolerance test (OGTT) followed by a standard fasting test, neuroglycopenia was observed postprandially with a mean minimal blood glucose level of 36 ± 9 mg/dl in 7 out of 11 patients. Spontaneous hypoglycemia during the fast was 38 ± 5 mg/dl in 8 out of 11 patients. The corresponding insulin levels were 9.2 ± 9.8 mU/l (OGTT) and 6.8 ± 5.4 mU/l (fasting), significantly lower than in patients with insulinoma (P < 0.001), but not different from patients without hypoglycemia (P = 0.05). After pancreatic resection 8 patients (73%) were cured with enduring euglycemia. Pathohistological islet abnormalities with hyperplasia, hypertrophy, and microadenomatosis were confirmed in all patients. Conclusion In patients with postprandial and/or fasting neuroglycopenia NIPHS may be suspected when insulin levels are low but inadequately suppressed and localization studies failed to show a distinct pancreatic tumor.     

Rapid insulin assay for intraoperative confirmation of complete resection of insulinomas

BACKGROUND: Solitary insulinomas are usually the cause of organic hypoglycemia, whereas 13% to 24% of patients with hyperinsulinemia have multiple tumors or nesidioblastosis. Intraoperative glucose levels confirming complete excision have variable accuracy. Intraoperative insulin levels have been shown to predict operative outcome. The purpose of this study was to establish criteria for predicting operative success by using a new, rapid insulin assay as an intraoperative adjunct. METHODS: Eight consecutive patients with organic hypoglycemia underwent pancreatic exploration. With an 8-minute immunochemiluminescent insulin assay, peripheral blood levels were obtained preoperatively, during resection, and at 5-minute intervals after surgical excisions. Operative findings and outcome were compared with intraoperative insulin/glucose ratios (I/G), glucose, and insulin levels. RESULTS: By using the return of insulin levels to normal range and I/G ratios < or = 0.4 15 minutes after tumor(s) resection as criteria to predict operative success, 6 patients had their outcomes correctly predicted (5 true-positive and 1 true-negative). One patient with nesidioblastosis had a false-negative result. One could not be evaluated because of diazoxide medication. These criteria predicted postoperative absence of hypoglycemia with specificity of 100% and accuracy of 89%. CONCLUSIONS: These 8-minute insulin assay and criteria can be a useful adjunct for intraoperative assurance of complete insulinoma resection and prediction of postoperative outcome.     

"胰岛素正常"的胰岛素瘤

目的分析胰岛素瘤胰岛素水平正常的原因,以提高其诊断水平。方法对我院1982年6月至2005年10月诊断为胰岛素瘤,且胰岛素水平检测结果在正常范围内的12例进行回顾性分析。结果12例患者均出现空腹或发作性低血糖症状,连续检测血糖,至少1次血糖值<2.8 mmol/L。同期检测外周静脉血中免疫反应性胰岛素(IRI)水平均<25 mU/L。周围静脉血中免疫反应性胰岛素/血糖比值(IGR):<0.3者5例,>0.3者7例。12例中8例进行了血清C-肽检测,6例高于正常。结论少数胰岛素瘤患者的血胰岛素可在正常范围内,血胰岛素水平正常不能排除胰岛素瘤的诊断。     

Continuous monitoring and control of plasma glucose during operation for removal of insulinomas.

A glucose-controlled insulin and glucose infusion system (Biostator system, Miles Laboratories Inc., Elkhart, Ind.) was used during operation for removal of four suspected insulinomas. In two patients the Biostator system continuously monitored plasma glucose levels and, through a computer-controlled feedback mechanism, automatically infused insulin or glucose as needed. In this way plasma glucose could be kept at approximately 110 mg/dl throughout the procedure. In one patient a rise in insulin infusion rate and a fall in glucose infusion rate followed removal of the tumor. In the other, absence of these findings was consistent with the clinical suspicion that the source of hypoglycemia had not been removed. In two other patients the Biostator system continuously monitored the patient's plasma glucose, without feedback-controlled administration of insulin or glucose. This demonstrated that, in these patients, tumor manipulation and removal did not lead to severe hypoglycemia, and thus eliminated any need to prophylactically infuse large amounts of glucose. Successful tumor removal was followed by a rise in blood glucose levels in both of these individuals. The glucose-controlled insulin and glucose infusion system appears to be a useful instrument for intraoperative management of patients with suspected insulinomas.     

Islet cell hormonal responses to hypoglycemia after human islet transplantation for type 1 diabetes

Islet transplantation can eliminate severe hypoglycemic episodes in patients with type 1 diabetes; however, whether intrahepatic islets respond appropriately to hypoglycemia after transplantation has not been fully studied. We evaluated six islet transplant recipients, six type 1 diabetic subjects, and seven nondiabetic control subjects using a stepped hyperinsulinemic-hypoglycemic clamp. Also, three islet transplant recipients and the seven control subjects underwent a paired hyperinsulinemic-euglycemic clamp. In response to hypoglycemia, C-peptide was similarly suppressed in islet transplant recipients and control subjects and was not detectable in type 1 diabetic subjects. Glucagon was significantly more suppressed in type 1 diabetic subjects than in islet transplant recipients (P < 0.01), although the glucagon in islet transplant recipients failed to activate as in the control subjects (P < 0.01). Pancreatic polypeptide failed to activate in both type 1 diabetic subjects and islet transplant recipients compared with control subjects (P < 0.01). In islet transplant recipients, glucagon was suppressed normally by hyperinsulinemia during the euglycemic clamp and was significantly greater during the paired hypoglycemic clamp (P < 0.01). These results suggest that after islet transplantation and in response to insulin-induced hypoglycemia, endogenous insulin secretion is appropriately suppressed and glucagon secretion may be partially restored.     

C-peptide and glucose values in the peritransplant period after intraportal islet infusions in type 1 diabetes

BACKGROUND: Successful islet allograft transplantation has been achieved worldwide. This study aimed at evaluating the relationship between peritransplant C-peptide (CP) values and long-term allograft function. METHODS: We measured CP-to-glucose ratio (CPGR) in intraportal samples pre- and postinfusion, and in peripheral circulation at baseline pretransplant and at 1, 3, 6, 12, 72 hours, 1 week, and 15 and 30 days after first and second infusion in 13 islet allograft recipients. Peritransplant treatment included intravenous (IV) 5% dextrose in saline in all patients. We compared portal CPGR to insulin reduction (%) at 30 days after each infusion, and at 1 year after second infusion. RESULTS: CPGR peaked between the immediate postinfusion and 3 hours and decreased at 12 hours. At 1 week, CPGR was 0.76 +/- 0.45 and 1.44 +/- 0.37 after first and second infusion, respectively. CPGR at 30 days after second infusion doubled compared to first infusion (P < .001). There was no correlation between peak CPGR and insulin reduction percent at any time point. One patient experienced hypoglycemia (47 mg/dL) 1 hour after second infusion. CONCLUSIONS: There was no relationship between the CP values in the peritransplant period and long-term graft function or success rate. The early peak in the C-peptide levels is indicative of a significant insulin release after each islet infusion. For this reason, it is important to carefully monitor serum glucose levels in the peritransplant period (hourly for the first 6 hours) and to maintain an IV glucose infusion to avoid hypoglycemia.     

Enhanced, Simplified Glucose Sensors: Long-Term Clinical Application of Wearable Artificial Endocrine Pancreas

At present, 2 major problems should be solved before long-term application of the wearable artificial endocrine pancreas, the development of a reliable and stable glucose monitoring system and the development of a subcutaneous insulin infusion algorithm. With either a miniaturized extracorporeal glucose monitoring system based on microdialysis sampling method or a ferrocene-mediated needle-type glucose sensor covered with highly biocompatible membrane, poly(2-methacryloyloxyethyl phosphorylcholine- co-n -butyl methacrylate) (poly[MPC- co -BMA]) membrane, subcutaneous glucose concentrations could be monitored for 7 days without any in vivo calibrations, followed by 14 days with one point calibration. Considering the management and safety of the insulin delivery route, subcutaneous insulin infusion is obligatory. With the subcutaneous insulin infusion algorithm using a short acting insulin analogue (Insulin Lispro), near physiological glycemic control could be established in diabetic patients without showing any delayed hyperinsulinemia or hypoglycemia. The wearable artificial endocrine pancreas is now recognized as an excellent therapeutic tool for regulating blood glucose excursions physiologically in ambulatory diabetic patients on a long-term basis.     

Quality of life after islet transplant: impact of the number of islet infusions and metabolic outcome

The health-related quality of life (HRQL; Health Utilities Index Mark 2) and the fear of hypoglycemia (Hypoglycemia Fear Survey) were assessed after islet transplant; the impact of a single islet infusion and of the metabolic outcome were determined. A control group included 166 patients with type 1 diabetes. Islet transplant had no impact on overall HRQL. Prior to transplant, islet recipients had more fear of hypoglycemia than controls (P<0.000001), but this improved up to 36 months after transplant (P<0.00001, pretransplant vs. each time point). With a single islet infusion, this fear improved substantially (P<0.00001), but improved further with subsequent islet infusions (P相似文献   

Ghrelin is not necessary for adequate hormonal counterregulation of insulin-induced hypoglycemia

Ghrelin is a novel enteric hormone that stimulates growth hormone (GH), ACTH, and epinephrine; augments plasma glucose; and increases food intake by inducing the feeling of hunger. These characteristics make ghrelin a potential counterregulatory hormone. At present, it is not known whether ghrelin increases in response to insulin-induced hypoglycemia. To answer this question, we compared plasma ghrelin concentrations after a short-term insulin infusion that was allowed or not (euglycemic clamp) to cause hypoglycemia (2.7 +/- 0.2 mmol/l at 30 min) in five healthy volunteers. In both studies, plasma ghrelin concentrations decreased (P < 0.01) after insulin infusion (hypoglycemia by 14%, euglycemia by 22%), reached a nadir at 30 min, and returned to baseline at 60 min, without differences between the hypoglycemia and the euglycemia studies. Glucagon, cortisol, and GH increased in response to hypoglycemia despite the decreased ghrelin. There was a strong correlation (R(2) = 0.91, P < 0.002) between the insulin sensitivity of the subjects and the percentage suppression of ghrelin from baseline. These data demonstrate that ghrelin is not required for the hormonal defenses against insulin-induced hypoglycemia and that insulin can suppress ghrelin levels in healthy humans. These results raise the possibility that postprandial hyperinsulinemia is responsible for the reduction of plasma ghrelin that occurs during meal intake.     

Localization and surgical treatment of occult insulinomas.

Management of patients with biochemical evidence of insulinoma and negative preoperative imaging studies (occult) tumors is controversial, varying from primarily medical management to aggressive, blind nearly total pancreatectomy to extirpate the tumor. Since 1982, 12 consecutive patients with occult insulinoma underwent preoperative portal venous sampling (PVS) for insulin followed by surgical exploration with intraoperative ultrasound (IOUS). Eleven of twelve patients (92%) had insulinoma removed and were cured. Portal venous sampling correctly predicted the location of the insulinoma in 9 patients (75%) and that no tumor would be found in another patient. A fourfold insulin gradient in the pancreatic tail of one patient correctly predicted that a distal pancreatectomy would remove the insulinoma despite the fact that neither palpation nor IOUS identified any tumor. Intraoperative ultrasound was the single best method to identify occult tumors because it correctly identified 10 of 11 insulinomas that were found, including five pancreatic head tumors that were not palpable. Palpation identified five insulinomas. Of the 10 tumors that were identified during operation by palpation or ultrasound, IOUS identified significantly more (100% versus 50%, p = 0.03) and guided the successful enucleation of each. The results support the strategy of preoperative PVS and operation with IOUS to localize and remove insulinoma in patients with occult tumors. Most tumors (75%) will be correctly localized to a specific pancreatic region by preoperative PVS and identified by IOUS (83%), allowing simple enucleation and biochemical correction of hypoglycemia. Morbid blind pancreatic resections are no longer indicated and long-term medical management of hypoglycemia should be reserved for the occasional patient (8%) who fails preoperative PVS and operation guided by IOUS.     

Anesthetic management of two patients with insulinoma using propofol--in association with rapid radioimmunoassay for insulin

We experienced anesthetic management of two patients with insulinoma in whom frequent hypoglycemic episodes with blood glucose levels of 39-42 mg.dl-1 had been observed. Each patient received epidural analgesia with a catheter inserted at the T 9/10 intervertebral space. Anesthesia was induced with propofol 80-100 mg and fentanyl 200 micrograms. Tracheal intubation was facilitated with vecuronium 6 mg. Anesthesia was maintained with continuous infusion of propofol and epidural anesthesia. Rapid measurements of immunoreactive insulin (IRI) were useful for localization of insulinoma during surgery. Perioperative plasma glucose levels could be maintained within normal ranges by continuous infusion of glucose. Rebound hyperglycemic episodes were not observed, and IRI was reduced after removal of the insulinoma. General anesthesia using propofol and epidural block is a useful choice for the anesthetic management of patients undergoing an operation for removal of an insulinoma.     

胰岛素瘤的诊断和治疗：附120 例报告

目的:探讨胰岛素瘤的诊断与治疗方法。方法:回顾性分析40 年间收治的120 例胰岛素瘤患者的临床资料。结果:全组患者均有Whipple三联症的临床表现，血糖均<2.75mmol/L；75 例空腹血清胰岛素>25μU/mL，平均(65 ±6.0)μU/mL。术前B 超检查60 例，2 例发现肿瘤；CT 检查50 例，10 例发现肿瘤；术中B 超检查18 例，16 例与术中探查相符，1 例发现了未能扪及的肿瘤。良性肿瘤112例，恶性肿瘤4例，胰岛细胞增生症4例。行单纯肿瘤摘除70 例，行包括肿瘤在内的胰体尾脾切除44 例，单纯胰体尾切除4 例，活检2 例。112 例良性胰岛素瘤术后111 例低血糖症状立即消失，1 例术后仍有低血糖症状发作，通过再次手术时发现钩突部肿瘤，切除后治愈。继发胰瘘20 例，均为肿瘤摘除者，其中14 例经引流自愈，5例经手术治疗痊愈，1 例因腹腔感染死亡。结论:胰岛素瘤术前定位不易，术中探查及术中B 超是发现肿瘤的主要手段；对良性者应力争行肿瘤摘除术，对肿瘤位于胰体尾较大且深或多发肿瘤者应行胰体尾切除术。     

Peak stimulated insulin secretion is associated with specific changes in gene expression profiles in sporadic insulinomas

BACKGROUND: The molecular pathways that are responsible for pathologic insulin secretion by insulinomas have not been characterized. We studied gene expression profiles from insulinomas and determined associations between these changes and preoperative peak serum insulin levels. METHODS: Ten patients with insulinomas underwent calcium-stimulated arteriography and surgical resection. Tumor RNA was isolated; corresponding complementary DNA was hybridized to 10K human complementary DNA arrays. Pooled human islet cell complementary DNA served as the control. Cluster analysis of gene expression and analysis of expression ratios was performed. RESULTS: Nineteen genes were up-regulated at least 3-fold in insulinomas compared with controls, which included the genes for islet amyloid polypeptide and proprotein convertase type 2. Cluster analysis revealed 2 groups of patients with insulinoma and with distinct patterns of gene expression. Mean peak serum insulin values between groups were 196 and 1100 (U/mL (P<.05), which demonstrates a significant difference in insulin response to calcium stimulation between these 2 groups. CONCLUSION: We show that genes that are relevant to the pathogenesis of hyperinsulinemia are expressed preferentially in insulinomas. In addition, patients with a distinct and common pattern of gene expression had significantly higher stimulated insulin secretion levels. The study of these genes may help to identify the biochemical pathways that are responsible for pathologic insulin secretion.     

Diabetic management by insulin infusion during major surgery.

In five insulin-requiring, uremic diabetic patients undergoing renal transplantation, we infused insulin intravenously at a low rate to maintain plasma glucose levels between 100 and 200 mg/100 ml. In those patients receiving 100 mg or more of prednisone per day and 5 per cent dextrose solution, the hourly infusion rate was determined from tthe following equation: insulin (U) = plasma glucose value divided by 100. When prednisone was not given or when the patient was thin, the ratio became: plasma glucose value divided by 150. Results were compared with those of nineteen similar transplant patients treated with conventional subcutaneous insulin therapy during surgery, and significantly better glucose control was achieved with the low dosage, intravenous infusion.     

Diagnosis and minimally invasive resection of an insulinoma: report of an unusual case and review of the literature

Insulinomas are rare endocrine tumors that are usually diagnosed by inappropriate elevations in insulin and C-peptide during hypoglycemia. We report a case of a surgically confirmed insulinoma diagnosed by a mild elevation in proinsulin with suppressed insulin and C-peptide at the time of hypoglycemia during a supervised fast. A supervised fast with serial measurements of plasma glucose, insulin, and C-peptide was performed in a patient with documented hypoglycemia. Proinsulin was measured at the beginning and end of the fast. Tumor localization was accomplished with spiral CT, magnetic resonance imaging, and endoscopic ultrasound. Minimally invasive tumor resection was performed. The presence of an insulinoma was confirmed on the basis of a minimally elevated proinsulin level with a suppressed insulin level at the time of symptomatic hypoglycemia. Tumor resection was performed without complications, resulting in resolution of the hypoglycemia. This case demonstrates the importance of measuring proinsulin as a routine component of the 72-hour fast for detection of an insulinoma. Even mild elevations in circulating proinsulin can be an independent indicator of aberrant insulin secretion during hypoglycemia. Once the diagnosis of insulinoma is made and tumor localization is achieved, minimally invasive tumor resection is a safe and effective treatment modality.     

胰岛素瘤的诊断和治疗：附30例报告

目的:总结探讨胰岛素瘤的诊断和治疗方法。方法:回顾性分析近11年来治疗的30例胰岛素瘤的临床资料。结果:全组30例均表现Whipple三联征。术前B超，CT，MRI诊断的阳性率分别为34.8 %(8/23)， 58.3 %(7/12)，71.4 %(5/7)，术中B超诊断的阳性率为87.5 %(7/8)。单个肿瘤27例，多发性肿瘤3例。单发者，位于胰头8例,胰体7例,胰尾12例;多发者，1例2枚肿块均位于胰体，另2例均为2枚肿块分别位于胰体和胰尾。行肿瘤局部摘除术21例,胰体尾切除术6例，胰体尾切除术＋脾切除术2例，胰十二指肠切除术1例。良性肿瘤29例，恶性1例。术后胰瘘4例,均经充分引流后治愈。30例术后低血糖症状均消失，随访27例，良性肿瘤术后4年复发1例，再次手术切除胰体肿块后治愈，恶性肿瘤术后3年复发，因腹腔转移死亡。结论:Whipple三联征,测定IRI/G比值是定性诊断的主要依据,术中扪诊联合术中B超是最有效的肿瘤定位手段,肿瘤摘除术仍为胰岛素瘤的主要术式。     

糖尿病合并胆石症患者术前胰岛素泵强化治疗的临床观察

目的:观察并分析糖尿病合并胆石症患者腹腔镜手术前采用连续皮下胰岛素输注方法(CSII)或多次皮下注射胰岛素方法(MSII)控制血糖的效果,了解胰岛素泵在糖尿病患者手术前使用的价值。方法:162例糖尿病合并胆石症患者随机分为CSII和MSII组。CSII组患者采用经胰岛素泵连续皮下输注胰岛素的治疗方法,MSII组患者采用多次皮下注射胰岛素的治疗方法。胰岛素剂量根据血糖波动曲线调整。比较治疗前后患者的全天血糖变化、血糖达标时间、胰岛素用量及低血糖发生率。结果:两组均可有效降低血糖(P<0.01),但CSII组全天血糖值较MSII组控制更为理想,且胰岛素用量及术前调整时间均少于MSII组。CSII组低血糖发生率低于MSII组。结论:糖尿病合并胆石症患者手术前应用胰岛素治疗降糖效果显著,安全性高。     

Value of 5-hour glucose tolerance test in the diagnosis of insulinoma

We probed into the role of glucose tolerance test (GTT) in the diagnosis of insulinoma. According to the test results, 63 cases of insulinoma fell into four types. Insulinomas failed to respond normally to the stimulus of glucose and the response of insulinoma was nonspecific within 120 minutes after glucose load. The peaks of glucose tolerance curves were delayed and hypoglycemia was the rule before and 300 minutes after glucose load. GTT results of the same patient were varied from time to time. The results suggest that five-hour GTT is superior to three-hour GTT in the diagnosis of insulinoma.     

Recently experienced ten cases of insulinoma--preoperative diagnosis of localization and intraoperative simultaneous monitoring of glucose and insulin

We have experienced 10 cases of insulinoma during the last 10 years from 1977 to 1986. All cases had strong hypoglycemic symptoms such as disturbance of consciousness, and insulinoma still tended to be misdiagnosed as epilepsy. The diagnosis of insulinoma was easily available from serum IRI (immunoreactive insulin)/plasma glucose ratio in all of the ten cases. As preoperative procedures for the diagnosis of localization, arteriography, computed tomography and portal blood sampling were positive in 6 of 8, 4 of 6 and 2 of 2 patients, respectively. At operation, all insulinomas could be identified by digital palpation. We performed simple excision of the tumor in 6 patients and distal pancreatectomy in 4 patients. The tumors were solitary and benign in all patients, ranging in size from 1.0 cm to 4.5 cm. Three cases were presented as case reports. In these cases, portal blood sampling and/or intraoperative monitoring of plasma glucose and serum IRI were performed. Portal blood sampling was effective even for a case which was negative in image diagnostic procedures. Furthermore, simultaneous monitoring of plasma glucose and serum IRI by quick radioimmunoassay seemed to be a good guide to the completeness of resection of insulin producing tumors.