Case Report: Insulinoma Presenting as Excessive Daytime Somnolence.

Currently, undiagnosed insulinomas remain a difficult clinical dilemma because its symptoms in most cases can easily be misdiagnosed as other diseases. In this article, we present the case of a 14-year-old girl who presented to our hospital with recurrent episodes of excessive daytime sleepiness and abnormal behavior during sleep that had been going on for 3 months. Insulinoma is a rare neuroendocrine tumor that causes excessive release of insulin, resulting in episodes of hypoglycemia. It usually manifests as autonomic sympathetic symptoms. These symptoms resolved rapidly with the administration of glucose. After successful removal of the tumor, daytime sleepiness and abnormal nighttime behavior of the patient did not reappear.

Molecular Regulations and Functions of the Transient Receptor Potential Channels of the Islets of Langerhans and Insulinoma Cells.

Insulin secretion from the ß-cells of the islets of Langerhans is triggered mainly by nutrients such as glucose, and incretin hormones such as glucagon-like peptide-1 (GLP-1). The mechanisms of the stimulus-secretion coupling involve the participation of the key enzymes that metabolize the nutrients, and numerous ion channels that mediate the electrical activity. Several members of the transient receptor potential (TRP) channels participate in the processes that mediate the electrical activities and Ca2+ oscillations in these cells. Human ß-cells express TRPC1, TRPM2, TRPM3, TRPM4, TRPM7, TRPP1, TRPML1, and TRPML3 channels. Some of these channels have been reported to mediate background depolarizing currents, store-operated Ca2+ entry (SOCE), electrical activity, Ca2+ oscillations, gene transcription, cell-death, and insulin secretion in response to stimulation by glucose and GLP1. Different channels of the TRP family are regulated by one or more of the following mechanisms: activation of G protein-coupled receptors, the filling state of the endoplasmic reticulum Ca2+ store, heat, oxidative stress, or some second messengers. This review briefly compiles our current knowledge about the molecular mechanisms of regulations, and functions of the TRP channels in the ß-cells, the α-cells, and some insulinoma cell lines.

An observational analysis of insulinoma from a single institution.

BACKGROUND: Insulinoma is the commonest functioning pancreatic neuroendocrine tumor causing hyperinsulinemic hypoglycemia. AIM: This study is aimed to evaluate the clinical features, preoperative laboratory and imaging diagnosis and pathologic findings of insulinoma. METHODS: Data of the patients from 2001 to 2016 diagnosed as insulinoma in Tongji Hospital, China were retrospectively extracted and analyzed. RESULTS: 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%. CONCLUSION: Laboratory tests of glucose, insulin and C-peptide are reliable for preoperative diagnosis. Combination of the imaging examinations can improve the diagnosis.

Insulinoma with a History of Epilepsy: Still a Possible Misleading Factor in the Early Diagnosis of Insulinoma.

A delayed diagnosis of insulinoma remains a clinical issue. Hypoglycemic symptoms can mimic neuropsychiatric disorders such as epilepsy. A 27-year-old woman with a history of epilepsy and anti-epileptic drugs (AEDs) developed repeated seizures and neuropsychiatric symptoms after a 9-year asymptomatic interval. She had received transient treatment with AEDs before the possibility of hypoglycemia was considered. Following a clinical diagnosis of insulinoma, distal pancreatectomy was performed; her seizures didn't occur again. The early diagnosis of insulinoma requires vigilance not only for hypoglycemia in patients with neuropsychiatric symptoms but also for the possible masking effects of a history of epilepsy and preceding AED usage.

Hypoglycemia identified by a continuous glucose monitoring system in a second-trimester pregnant woman with insulinoma: a case report.

BACKGROUND: Insulinoma associated with pregnancy is a very rare condition and can be difficult to diagnose. Here, we present an interesting case of insulinoma occurring during pregnancy with special attention paid to the use of a continuous glucose monitoring system to detect hypoglycemia. CASE PRESENTATION: A 36-year-old white woman in the second trimester of pregnancy presented with recurrent episodes of hypoglycemia associated with neuroglycopenic symptoms. The use of a continuous glucose monitoring system confirmed hypoglycemia. Serum insulin, C-peptide, and proinsulin values confirmed endogenous hyperinsulinism. A tumor mass was localized at the tail of her pancreas by endoscopic ultrasound and confirmed by magnetic resonance imaging. Surgery performed at 21 weeks of gestation by distal pancreatectomy confirmed the presence of a 15 mm diameter endocrine tumor at the tail of her pancreas and led to a cure. CONCLUSIONS: Hypoglycemia during pregnancy could be due to insulinoma. Use of a continuous glucose monitoring system could help to detect hypoglycemia in these patients.

Pancreatic neuroendocrine tumors: contemporary diagnosis and management.

Pancreatic neuroendocrine tumors (PNETs) are neoplasms that arise from the hormone producing cells of the islets of Langerhans, also known as pancreatic islet cells. PNETs are considered a subgroup of neuroendocrine tumors, and have unique biology, natural history and clinical management. These tumors are classified as 'functional' or 'non-functional' depending on whether they release peptide hormones that produce specific hormone- related symptoms, usually in established patterns based on tumor subtype. This manuscript will review pancreatic neuroendocrine tumor subtypes, syndromes, diagnosis, and clinical management.

Microcystin-LR induces dysfunction of insulin secretion in rat insulinoma (INS-1) cells: Implications for diabetes mellitus.

Microcystins (MCs) are the most frequent cyanobacterial toxins observed in freshwater systems. Accumulating evidence suggests that MCs pose a serious threat to public health. However, the contributions of the exposure of MCs to the occurrence of human diseases remain largely unknown. This study provides the evidence of the effects of MC-LR on pancreatic ß-cell function through the exposure of rat insulinoma (INS-1) cells to 0, 10, 20, or 40µM MC-LR for 72h and explores the underlying molecular mechanisms. Our results demonstrate that exposure to MC-LR for 72h suppresses cell viability, disturbs glucose-stimulated insulin secretion (GSIS), and decreases the expression of insulin protein. Moreover, MC-LR disrupts the cell cycle distribution and increases cell apoptosis at 20 or 40µM for 72h, respectively, indicating that the ß-cell mass would be decreased by MC-LR exposure. A transcriptomic analysis revealed several key genes (e.g., Pdx-1, Neurod1, and Abcc8) involved in insulin secretion are significantly differentially expressed in INS-1 cells in response to MC-LR exposure. In addition, several signal transduction pathways associated with diabetes (e.g., type 1 and 2 diabetes) were also identified compared with the control cells. We recommend that MC be considered as a new environmental factor that promotes diabetes development. The identified key genes or pathways may potentially contribute to the future therapies in the environmental contaminants induced ß-cell damage.

Evolving management of insulinoma: Experience at a tertiary care centre.

BACKGROUND & OBJECTIVES: Since our previous study in 2006, several new modalities for localization of cause of endogenous hyperinsulinemic hypoglycaemia such as multiphasic computed tomography (CT), multiphasic magnetic resonance imaging (MRI), endoscopic ultrasound (EUS), intraoperative ultrasound, and intra-arterial calcium infusion with arterial stimulation venous sampling (ASVS) have become available. Therefore, to evaluate the relative usefulness of various imaging modalities to guide future management in terms of diagnosis and patient care, we analyzed presentation and management of patients of endogenous hyperinsulinemic hypoglycaemia. METHODS: In this retrospective study, medical records of patients admitted with endogenous hyperinsulinemic hypoglycaemia were retrieved. Data pertaining to clinical features, diagnosis, imaging, surgery and patient outcome were extracted. The localization of insulinoma by preoperative imaging techniques was compared with the findings at surgery to assess the accuracy of localization. RESULTS: Fasting hypoglycaemia was present in all, and post-prandial hypoglycaemia (plasma glucose ≤50 mg/dl within four hours of meal) in 25.8 per cent. Mean duration of symptoms before reaching a diagnosis of hyperinsulinemic hypoglycaemia was 3.9 years. Mean duration of provocative fast was 21.8 h (range 6-48 h). Among the currently used imaging modalities, the sensitivity of localizing tumour was 79.3 per cent for multiphasic CT, 85 per cent for multiphasic MRI and 95 per cent for EUS. EUS detected tumour missed by both CT and MRI. All, except one of the operated patients, were cured by surgery. INTERPRETATION & CONCLUSIONS: Our results suggest that patients with insulinoma have a varied presentation. Multiphasic contrast-enhanced MRI/CT scan, EUS and ASVS may be complimentary in pre-operative localization.

Safety and tolerability of diazoxide in Japanese patients with hyperinsulinemic hypoglycemia.

Diazoxide is a non-diuretic benzothiadiazine derivative, one of a group of substances introduced into clinical practice in the 1950s for the treatment of hypertension. Fajans reported the use of diazoxide for the treatment of insulinoma in 1979. Although patients with hyperinsulinemic hypoglycemia worldwide have been treated with diazoxide for more than 30 years, there are no recent reports about the adverse effects of this drug in Asian patients, including Japanese patients. Herein, we report the results of our retrospective clinical record review of 6 Japanese patients (3 females and 3 males, ranging in age from 58 to 91 years) with hyperinsulinemic hypoglycemia and inoperable insulinoma treated with diazoxide. Diazoxide improved control of hypoglycemic symptoms and maintained normoglycemia in 5 of the 6 patients, and was ineffective in one patient. Surprisingly, although all 6 patients received diazoxide according to the treatment strategy recommended in Western patients, 5 of the 6 patients developed edema and two developed congestive heart failure. Thus, when starting treatment with diazoxide in Japanese patients, the symptoms and signs of fluid retention should be evaluated carefully. Also, appropriate protocols for treatment with diazoxide should be evaluated by means of clinical trials in Japanese patients with hyperinsulinemic hypoglycemia.

Pancreatic Insulinoma Misdiagnosed as Epilepsy for Eight Years: A Case Report and Literature Review.

A 58-year-old Chinese man presented with intermittent seizure episodes after being misdiagnosed with epilepsy for eight years. MRI revealed an abnormally strong signal in the distal pancreas. The patient was subsequently diagnosed with pancreatic insulinoma based on the histological findings, and his symptoms improved following surgical removal of the tumor. The appearance of unusual manifestations of insulinoma makes it difficult to diagnose the condition. This disorder should be included in the differential diagnosis of epilepsy and mental illness.

Pathological aspects underlying pancreatogenous hyperinsulinemic hypoglycemia--report of three cases.

Pancreatogenous hyperinsulinemic hypoglycemia (PHH) is a rare disorder determined by an abnormally high secretion of insulin in the pancreas, in the absence of other medical or pharmacological factors. Either ß-cell tumors (insulinomas) or ß-cell hyperplasia (nesidioblastosis) can determine this pathology. Most publications on insulinomas or nesidioblastosis approached these subjects from a clinical point of view. This paper aims to analyze pathological aspects underlying pancreatogenous hyperinsulinemic hypoglycemia. We present two cases of insulinomas with unusual pancreatic localization and size, one of them showing amyloid deposits in the stroma. In both cases, immunohistochemistry confirmed the clinical and imagistic supposition. The third reported case refers to a 57-year-old patient with nesidioblastosis with isolated disposition of endocrine cells and areas of focal organization, both morphological aspects being extremely rare in adults. Although clinical and laboratory data are usually identical in the two forms of PHH, histopathological and immunohistochemical diagnosis is essential in differentiating insulinomas from nesidioblastosis, as the surgical management is different: enucleation for insulinomas and total or subtotal pancreatectomy for nesidioblastosis.

Insulinoma in childhood: clinical, radiological, molecular and histological aspects of nine patients.

BACKGROUND: Insulinomas are a rare cause of hyperinsulinaemic hypoglycaemia (HH) in children. The clinical features, investigations, management and histology of these rare pancreatic tumours in children have not been described in a large cohort of patients. METHODS: We conducted a retrospective review of cases diagnosed between 2000 and 2012, presenting to two referral centres in the United Kingdom. Clinical, biochemical, imaging (magnetic resonance imaging (MRI) and 6-L-¹8F-fluorodihydroxyphenylalanine (¹8F-DOPA) PET/CT scanning) and histological data were collected. RESULTS: Nine children (age range 2-14.5 years) were diagnosed during the study period at Great Ormond Street Hospital (n=5) and Royal Manchester Children's Hospital (n=4). The combination of abdominal MRI scan (7/8) and ¹8F-DOPA PET/CT scan (2/4) correctly localised the anatomical location of all insulinomas. Before surgery, diazoxide therapy was used to treat hypoglycaemia, but only four patients responded. After surgical resection of the insulinoma, hypoglycaemia resolved in all patients. The anatomical localisation of the insulinoma in each patient was head (n=4), uncinate process (n=4) and tail (n=2, one second lesion) of the pancreas. Histology confirmed the diagnosis of insulinoma with the presence of sheets and trabeculae of epithelioid and spindle cells staining strongly for insulin and proinsulin, but not for glucagon or somatostatin. Two children were positive for MEN1, one of whom had two separate insulinoma lesions within the pancreas. CONCLUSIONS: We describe a cohort of paediatric insulinoma patients. Although rare, insulinomas should be included in the differential diagnosis of HH, even in very young children. In the absence of a single imaging modality in the preoperative period, localisation of the tumour is achieved by combining imaging techniques, both conventional and functional.

Approach to the patient with spontaneous hypoglycemia.

UNLABELLED: Hypoglycemia is common in daily clinical practice and often occurs during the treatment of diabetes mellitus. However, a small minority of hypoglycemia encountered in clinical practice is spontaneous and thus not induced by glycemic lowering agents. These spontaneous hypoglycemic events confront the clinician with a diagnostic enigma. Although the trained clinician can recognize the autonomic and neuroglycopenic symptoms of hypoglycemia even in a patient not on insulin, it remains challenging to decipher the etiology of a spontaneous hypoglycemic event. A logical and stepwise approach to the spontaneous hypoglycemic event allows for a conclusive diagnosis. This diagnostic process consists of adequately diagnosing hypoglycemia by fulfilling Whipple's triad, stratifying patients according to their clinical status and analyzing a full hypoglycemic blood panel. A complete hypoglycemic blood panel should include the analysis of glucose, insulin, C-peptide, pro-insulin, insulin antibodies and the presence of oral hypoglycemic agents. For patients with episodes of hypoglycemia induced by excessive endogenous insulin, additional imaging is often required to detect the presence of an underlying insulinoma. By diagnosing the underlying cause of the spontaneous hypoglycemia, the physician also diagnosis the mechanism by which the hypoglycemic event occurs. Allowing for a problem orientated therapeutic approach. METHODOLOGY: The present review is based upon a comprehensive PubMed search between 1985 and 2013. This uses search terms of spontaneous hypoglycemia, insulinoma, nesidioblastosis, insulin auto-immunity, noninsulinoma pancreatogenous hypoglycemia syndrome, hormone deficiency, pro-IGF II, and pro-insulin growth factor II, and cross reference searching of pivotal articles in the subject.

Autocrine C-peptide mechanism underlying INS1 beta cell adaptation to oxidative stress.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

HRG regulates tumor progression, epithelial to mesenchymal transition and metastasis via platelet-induced signaling in the pre-tumorigenic microenvironment.

Mice lacking histidine-rich glycoprotein (HRG) display an accelerated angiogenic switch and larger tumors-a phenotype caused by enhanced platelet activation in the HRG-deficient mice. Here we show that platelets induce molecular changes in the pre-tumorigenic environment in HRG-deficient mice, promoting cell survival, angiogenesis and epithelial-to-mesenchymal transition (EMT) and that these effects involved signaling via TBK1, Akt2 and PDGFRß. These early events subsequently translate into an enhanced rate of spontaneous metastasis to distant organs in mice lacking HRG. Later in tumor development characteristic features of pathological angiogenesis, such as decreased perfusion and pericyte coverage, are more pronounced in HRG-deficient mice. At this stage, platelets are essential to support the larger tumor volumes formed in mice lacking HRG by keeping their tumor vasculature sufficiently functional. We conclude that HRG-deficiency promotes tumor progression via enhanced platelet activity and that platelets play a dual role in this process. During early stages of transformation, activated platelets promote tumor cell survival, the angiogenic switch and invasiveness. In the more progressed tumor, platelets support the enhanced pathological angiogenesis and hence increased tumor growth seen in the absence of HRG. Altogether, our findings strengthen the notion of HRG as a potent tumor suppressor, with capacity to attenuate the angiogenic switch, tumor growth, EMT and subsequent metastatic spread, by regulating platelet activity.

Glycated albumin causes pancreatic ß-cells dysfunction through autophagy dysfunction.

Growing evidence suggests that advanced glycation end-products (AGEs) are cytotoxic to pancreatic ß-cells. The aims of this study were to investigate whether glycated albumin (GA), an early precursor of AGEs, would induce dysfunction in pancreatic ß-cells and to determine which kinds of cellular mechanisms are activated in GA-induced ß-cell apoptosis. Decreased viability and increased apoptosis were induced in INS-1 cells treated with 2.5 mg/mL GA under 16.7mM high-glucose conditions. Insulin content and glucose-stimulated secretion from isolated rat islets were reduced in 2.5 mg/mL GA-treated cells. In response to 2.5 mg/mL GA in INS-1 cells, autophagy induction and flux decreased as assessed by green fluorescent protein-microtubule-associated protein 1 light chain 3 dots, microtubule-associated protein 1 light chain 3-II conversion, and SQSTM1/p62 in the presence and absence of bafilomycin A1. Accumulated SQSTM1/p62 through deficient autophagy activated the nuclear factor-κB (p65)-inducible nitric oxide synthase-caspase-3 cascade, which was restored by treatment with small interfering RNA against p62. Small interfering RNA treatment against autophagy-related protein 5 significantly inhibited the autophagy machinery resulting in a significant increase in iNOS-cleaved caspase-3 expression. Treatment with 500µM 4-phenyl butyric acid significantly alleviated the expression of endoplasmic reticulum stress markers and iNOS in parallel with upregulated autophagy induction. However, in the presence of bafilomycin A1, the decreased viability of INS-1 cells was not recovered. Glycated albumin, an early precursor of AGE, caused pancreatic ß-cell death by inhibiting autophagy induction and flux, resulting in nuclear factor-κB (p65)-iNOS-caspase-3 cascade activation as well as by increasing susceptibility to endoplasmic reticulum stress and oxidative stress.

Misleading features of neuroimaging and electroencephalography: insulinoma misdiagnosed as temporal lobe epilepsy.

Epilepsy is a common disorder but diagnosis remains largely clinical. Although MRI and EEG significantly aid the diagnosis of epilepsy, these techniques may also be misleading and indicate abnormalities not related to phenomenology. Consequences of erroneous diagnosis of epilepsy may lead to aggressive and escalating pharmacotherapy with potentially serious side effects. Metabolic disorders, which may mimic epilepsy, should always be considered as they are potentially curable and may be fatal if untreated. We report a case of an insulinoma, misdiagnosed as temporal lobe epilepsy. We highlight the risks associated with misinterpretation of neuroimaging and EEG and outline an approach to differentiate between symptoms of insulinoma or neuroglycopenia and temporal epileptic seizures.

Association of exercise-induced hyperinsulinaemic hypoglycaemia with MCT1-expressing insulinoma.

AIMS/HYPOTHESIS: Exercise-induced hyperinsulinism (EIHI) is a hypoglycaemic disorder characterised by inappropriate insulin secretion following anaerobic exercise or pyruvate load. Activating promoter mutations in the MCT1 gene (also known as SCLA16A1), coding for monocarboxylate transporter 1 (MCT1), were shown to associate with EIHI. Recently, transgenic Mct1 expression in pancreatic beta cells was shown to introduce EIHI symptoms in mice. To date, MCT1 has not been demonstrated in insulin-producing cells from an EIHI patient. METHODS: In vivo insulin secretion was studied during an exercise test before and after the resection of an insulinoma. The presence of MCT1 was analysed using immunohistochemistry followed by laser scanning microscopy, western blot analysis and real-time RT-PCR of MCT1. The presence of MCT1 protein was analysed in four additional insulinoma patients. RESULTS: Clinical testing revealed massive insulin secretion induced by anaerobic exercise preoperatively, but not postoperatively. MCT1 protein was not detected in the patient's normal islets. In contrast, immunoreactivity was clearly observed in the insulinoma tissue. Western blot analysis and real-time RT-PCR showed a four- to fivefold increase in MCT1 in the insulinoma tissue of the EIHI patient compared with human pancreatic islets. MCT1 protein was detected in three of four additional insulinomas. CONCLUSIONS/INTERPRETATION: We show for the first time that an MCT1-expressing insulinoma was associated with EIHI and that MCT1 might be present in most insulinomas. Our data suggest that MCT1 expression in human insulin-producing cells can lead to EIHI and warrant further studies on the role of MCT1 in human insulinoma patients.