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PubMed - Insulinoma (40 unread)

An unusual cause of reversible axonal neuropathy and hypertension in a 10-year-old girl.

Fetched: May 24th, 2012, 11:00pm MDT

An unusual cause of reversible axonal neuropathy and hypertension in a 10-year-old girl.

J Clin Neurosci. 2012 May 19;

Authors: Kaul B, Kaur P, Tripathi M, Khadgawat R, Ammini AC, Agarwala S, Kaushal S, Dattagupta S

Abstract
A 10-year-old girl, who was referred with refractory epilepsy, had 1.5years of episodic abnormal behavior. On examination, she also had hypertension and peripheral neuropathy. Hypoglycemia with correspondingly high insulin levels was documented during a confusional episode. MRI of the abdomen revealed an islet cell tumor in the body of the pancreas. One year after tumor excision, both the neuropathy and hypertension showed remarkable improvement. A final diagnosis of insulinoma with hypoglycemic axonal neuropathy and hypertension (reversed with tumor excision) was made. Insulinoma is the commonest cause of hyperinsulinemic hypoglycemia in adults, but is rare in childhood. To our knowledge, distal symmetrical motor-sensory axonal neuropathy has been described in only 40 patients, and hypertension has not been reported with insulinoma.

PMID: 22613486 [PubMed - as supplied by publisher]
Blockade of β-cell K(ATP) channels by the endocannabinoid, 2-arachidonoylglycerol.

Fetched: May 24th, 2012, 11:00pm MDT

Blockade of β-cell K(ATP) channels by the endocannabinoid, 2-arachidonoylglycerol.

Biochem Biophys Res Commun. 2012 May 15;

Authors: Spivak CE, Kim W, Liu QR, Lupica CR, Doyle ME

Abstract
The endocannabinoid system has been demonstrated to be active in the pancreatic β-cell. However the effects of the endocannabinoids (ECs) on insulin secretion are not well defined and may vary depending on the metabolic state of the β-cell. Specifically it is not known whether the effects of the ECs occur by activation of the cannabinoid receptors or via their direct interaction with the ion channels of the β-cell. To begin to delineate the effects of ECs on β-cell function, we examined how the EC, 2-AG influences β-cell ion channels in the absence of glucose stimulation. The mouse insulinoma cell line R7T1 was used to survey the effects of 2-AG on the high voltage activated (HVA) calcium, the delayed rectifier (K(v)), and the ATP-sensitive K (K(ATP)) channels by whole cell patch clamp recording. At 2 mM glucose, 2-AG inhibited the HVA calcium (the majority of which are L-type channels), K(v), and K(ATP) channels. The channel exhibiting the most sensitivity to 2-AG blockade was the K(ATP) channel, where the IC(50) for 2-AG was 1μM. Pharmacological agents revealed that the blockade of all these channels was independent of cannabinoid receptors. Our results provide a mechanism for the previous observations that CB1R agonists increase insulin secretion at low glucose concentrations through CB1R independent blockade of the K(ATP) channel.

PMID: 22609205 [PubMed - as supplied by publisher]
Concentration-dependent transitions govern the subcellular localization of islet amyloid polypeptide.

Fetched: May 24th, 2012, 11:00pm MDT

Concentration-dependent transitions govern the subcellular localization of islet amyloid polypeptide.

FASEB J. 2012 Mar;26(3):1228-38

Authors: Magzoub M, Miranker AD

Abstract
Islet amyloid polypeptide (IAPP) is a peptide hormone cosecreted with insulin by pancreatic β-cells. In type II diabetes, IAPP aggregates in a process that is associated with β-cell dysfunction and loss of β-cell mass. The relationship between IAPP's conformational landscape and its capacity to mediate cell death remains poorly understood. We have addressed these unknowns by comparing the cytotoxic effects of sequence variants with differing α-helical and amyloid propensities. IAPP was previously shown to oligomerize cooperatively on binding to lipid bilayers. Here, comparable transitions are evident in cell culture and are associated with a change in subcellular localization to the mitochondria under toxic conditions. Notably, we find that this toxic gain of function maps to IAPP's capacity to adopt aggregated membrane-bound α-helical, and not β-sheet, states. Our findings suggest that upon α-helical mediated oligomerization, IAPP acquires cell-penetrating peptide (CPP) properties, facilitating access to the mitochondrial compartment, resulting in its dysfunction.

PMID: 22183778 [PubMed - indexed for MEDLINE]
Akt signals upstream of L-type calcium channels to optimize insulin secretion.

Fetched: May 24th, 2012, 11:00pm MDT

Akt signals upstream of L-type calcium channels to optimize insulin secretion.

Pancreas. 2012 Jan;41(1):15-21

Authors: Cui X, Yang G, Pan M, Zhang XN, Yang SN

Abstract
OBJECTIVES: Both the serine/threonine protein kinase Akt and the voltage-gated L-type calcium channel act as important players in glucose-stimulated insulin secretion. Akt recruits the L-type calcium channel to and maintains them in the plasma membrane. This study aimed to characterize the role of L-type calcium channels in mediation of Akt signaling in glucose-stimulated insulin secretion.
METHODS: Insulin secretion was evaluated in rat pancreatic islets and INS-1 pancreatic β cells by a standard insulin radioimmunoassay.
RESULTS: Akt inhibition effectively abrogates not only glucose-stimulated but also potassium depolarization-stimulated insulin secretion from rat islets, the latter critically relying on the voltage-gated calcium channel-mediated Ca(2+) influx without involvement of glucose metabolism. Likewise, Akt inhibition also reduces both glucose-stimulated and potassium depolarization-stimulated insulin secretion from INS-1 cells. Importantly, pharmacological ablation of L-type calcium channels partially blocks Akt inhibition-induced reduction in glucose-stimulated insulin secretion but completely prevents that in potassium depolarization-evoked insulin release from INS-1 cells. Furthermore, Akt inhibition does not influence calcium ionophore A23187-induced insulin secretion from INS-1 cells, which occurred without involvement of L-type calcium channels.
CONCLUSIONS: Akt signals upstream of L-type calcium channels to optimize glucose-stimulated insulin secretion.

PMID: 21792084 [PubMed - indexed for MEDLINE]
Antiaging Gene Klotho Enhances Glucose-Induced Insulin Secretion by Up-Regulating Plasma Membrane Levels of TRPV2 in MIN6 β-Cells.

Fetched: May 20th, 2012, 11:01pm MDT

Antiaging Gene Klotho Enhances Glucose-Induced Insulin Secretion by Up-Regulating Plasma Membrane Levels of TRPV2 in MIN6 β-Cells.

Endocrinology. 2012 May 17;

Authors: Lin Y, Sun Z

Abstract
Klotho is a recently discovered antiaging gene. Klotho is expressed in mouse pancreatic islets and in insulinoma β-cells (MIN6 β-cells). The purpose of this study was to investigate whether Klotho plays a role in the regulation of insulin secretion in MIN6 β-cells by overexpression and silencing of Klotho. It is interesting that overexpression of Klotho increased glucose-induced insulin secretion in MIN6 β-cells. Overexpression of mouse Klotho protein also significantly increased plasma membrane levels of transient receptor potential V2 (TRPV2), calcium entry, and the glucose-induced increase in intracellular calcium. On the other hand, knockdown of Klotho by siRNA significantly decreased plasma membrane levels of TRPV2 and attenuated glucose-induced calcium entry and insulin secretion. Tranilast, a selective inhibitor of TRPV2, abolished the promoting effects of overexpression of Klotho on glucose-induced calcium entry and insulin secretion in MIN6 cells. Thus, TRPV2 lies in the downstream of Klotho in the regulation of glucose-induced insulin secretion. This study demonstrated, for the first time, that Klotho may enhance glucose-induced insulin secretion by up-regulating plasma membrane levels of TRPV2 and thus glucose-induced calcium responses. These findings reveal a previously unidentified role of Klotho in the regulation of glucose-induced insulin secretion in MIN6 β-cells.

PMID: 22597535 [PubMed - as supplied by publisher]
Critical Role of Egr Transcription Factors in Regulating Insulin Biosynthesis, Blood Glucose Homeostasis, and Islet Size.

Fetched: May 20th, 2012, 11:01pm MDT

Critical Role of Egr Transcription Factors in Regulating Insulin Biosynthesis, Blood Glucose Homeostasis, and Islet Size.

Endocrinology. 2012 May 17;

Authors: Müller I, Rössler OG, Wittig C, Menger MD, Thiel G

Abstract
Expression of early growth response protein (Egr)-1, a protein of the Egr family of zinc finger transcription factors, is stimulated in glucose-treated pancreatic β-cells and insulinoma cells. The purpose of this study was to elucidate the role of Egr transcription factors in pancreatic β-cells in vivo. To overcome the problem associated with redundancy of functions between Egr proteins, conditional transgenic mice were generated expressing a dominant-negative mutant of Egr-1 in pancreatic β-cells. The Egr-1 mutant interferes with DNA binding of all Egr proteins and thus impairs the biological functions of the entire Egr family. Expression of the Egr-1 mutant reduced expression of TGFβ and basic fibroblast growth factor, known target genes of Egr-1, whereas the expression of Egr-1, Egr-3, Ets-like gene-1, and specificity protein-3 was not changed in the presence of the Egr-1 mutant. Expression of the homeobox protein pancreas duodenum homeobox-1, a major regulator of insulin biosynthesis, was reduced in islets expressing the Egr-1 mutant. Accordingly, insulin mRNA and protein levels were reduced by 75 or 25%, respectively, whereas expression of glucagon and somatostatin was not altered after expression of the Egr-1 mutant in β-cells. Glucose tolerance tests revealed that transgenic mice expressing the Egr-1 mutant in pancreatic β-cells displayed impaired glucose tolerance. In addition, increased caspase-3/7 activity was detected as a result of transgene expression, leading to a 20% decrease of the size of the islets. These results show that Egr proteins play an important role in controlling insulin biosynthesis, glucose homeostasis, and islet size of pancreatic β-cells in vivo.

PMID: 22597533 [PubMed - as supplied by publisher]
Hypoglycaemia related to inherited metabolic diseases in adults.

Fetched: May 18th, 2012, 11:00pm MDT

Hypoglycaemia related to inherited metabolic diseases in adults.

Orphanet J Rare Dis. 2012 May 15;7(1):26

Authors: Douillard C, Mention K, Dobbelaere D, Wemeau JL, Saudubray JM, Vantyghem MC

Abstract
ABSTRACT: In non-diabetic adult patients, hypoglycaemia may be related to drugs, critical illness, cortisol or glucagon insufficiency, non-islet cell tumour, insulinoma, or it may be surreptitious. Nevertheless, some hypoglycaemic episodes remain unexplained, and inborn errors of metabolism (IEM) should be considered, particularly in cases of multisystemic involvement. In children, IEM are considered a differential diagnosis in cases of hypoglycaemia. In adulthood, IEM-related hypoglycaemia can persist in a previously diagnosed childhood disease. Hypoglycaemia may sometimes be a presenting sign of the IEM. Short stature, hepatomegaly, hypogonadism, dysmorphia or muscular symptoms are signs suggestive of IEM-related hypoglycaemia. In both adults and children, hypoglycaemia can be clinically classified according to its timing. Postprandial hypoglycaemia can be an indicator of either endogenous hyperinsulinism linked to non-insulinoma pancreatogenic hypoglycaemia syndrome (NIPHS, unknown incidence in adults) or very rarely, inherited fructose intolerance. Glucokinase-activating mutations (one family) are the only genetic disorder responsible for NIPH in adults that has been clearly identified so far. Exercise-induced hyperinsulinism is linked to an activating mutation of the monocarboxylate transporter 1 (one family). Fasting hypoglycaemia may be caused by IEM that were already diagnosed in childhood and persist into adulthood: glycogen storage disease (GSD) type I, III, 0, VI and IX; glucose transporter 2 deficiency; fatty acid oxidation; ketogenesis disorders; and gluconeogenesis disorders. Fasting hypoglycaemia in adulthood can also be a rare presenting sign of an IEM, especially in GSD type III, fatty acid oxidation [medium-chain acyl-CoA dehydrogenase (MCAD), ketogenesis disorders (3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) lyase deficiency, and gluconeogenesis disorders (fructose-1,6-biphosphatase deficiency)].

PMID: 22587661 [PubMed - as supplied by publisher]
Single agent- and combination treatment with two targeted suicide gene therapy systems is effective in chemo-resistant small cell lung cancer (SCLC) cells.

Fetched: May 15th, 2012, 11:00pm MDT

Single agent- and combination treatment with two targeted suicide gene therapy systems is effective in chemo-resistant small cell lung cancer (SCLC) cells.

J Gene Med. 2012 May 11;

Authors: Michaelsen SR, Christensen CL, Sehested M, Cramer F, Poulsen TT, Patterson AV, Poulsen HS

Abstract
BACKGROUND: Transcriptional targeted suicide gene (SG) therapy driven by the Insulinoma-associated 1 (INSM1) promoter makes it possible to target suicide toxin production and cytotoxicity exclusively to SCLC cells and tumors. It remains, however, to be investigated if acquired chemo-resistance, observed in the majority of SCLC patients, desensitizes SCLC cells to INSM1 promoter-driven SG therapy. METHODS: A panel of SCLC cell lines resistant to clinically relevant chemotherapeutics was characterized regarding expression of proteins involved in response to chemotherapy and regarding INSM1 promoter activity. Sensitivity towards INSM1 promoter-driven SG therapy was tested using different systems: Yeast cytosine deaminase-uracil phosphoribosyl transferase (YCD-YUPRT) in combination with the prodrug 5-fluorocytosine (5-FC) or E.coli nitroreductase (NTR) together with the bromomustard prodrug SN27686. RESULTS: The chemo-resistant cell lines displayed heterogeneous expression profiles of molecules involved in multi-drug resistance (MDR), apoptosis and survival pathways. Despite this, the INSM1 promoter activity was found to be unchanged or increased in SCLC chemo-resistant cells and xenografts compared to chemo-sensitive variants. INSM1 promoter-driven SG therapy with YCD-YUPRT/5-FC or NTR/SN27686, was found to induce high levels of cytotoxicity in both chemo-sensitive and -resistant SCLC cells. Moreover, the combination of INSM1 promoter-driven YCD-YUPRT/5-FC therapy and chemotherapy and the combination of INSM1 promoter-driven YCD-YUPRT/5-FC and NTR/SN27686 therapy were observed to be superior to single agent therapy in chemo-resistant SCLC cells. CONCLUSIONS: Collectively, this study demonstrates that targeted SG therapy is a potent therapeutic approach for chemo-resistant SCLC patients with highest efficacy achieved when applied as combination SG therapy or in combination with standard chemotherapy. Copyright © 2012 John Wiley & Sons, Ltd.

PMID: 22576955 [PubMed - as supplied by publisher]
Tumor enucleation with preoperative endoscopic transpapillary stenting for pediatric insulinoma.

Fetched: May 15th, 2012, 11:00pm MDT

Tumor enucleation with preoperative endoscopic transpapillary stenting for pediatric insulinoma.

Pediatr Surg Int. 2012 May 11;

Authors: Ide S, Uchida K, Inoue M, Koike Y, Otake K, Matsushita K, Hashimoto K, Nagano Y, Inoue H, Isaji S, Kusunoki M

Abstract
The 13-year-old boy underwent tumor enucleation for pancreatic head insulinoma close to the pancreatic main duct after a preoperative endoscopic pancreatic stent placed by endoscopic retrograde cholangiopancreatography. The tumor was safely excised by identifying the indwelled pancreatic stent during the surgical procedure without pancreatic duct injury or postoperative complications.

PMID: 22576843 [PubMed - as supplied by publisher]
Comparison of cell membrane water permeability in monolayers and suspensions.

Fetched: May 15th, 2012, 11:00pm MDT

Comparison of cell membrane water permeability in monolayers and suspensions.

Cryo Letters. 2012 Mar-Apr;33(2):95-106

Authors: Higgins AZ, Karlsson JO

Abstract
We previously measured the membrane water permeability of monolayers and suspensions of MIN6 mouse insulinoma cells at room temperature, and found that water transport was faster in monolayers. Here, we compare water transport kinetics in monolayers and suspensions over a range of temperatures for two different cell types, MIN6 cells and bovine pulmonary artery endothelial cells (BPAEC). At room temperature the results for BPAEC and MIN6 cells were similar, with approximately 2-fold faster water transport in monolayers than suspensions. The activation energy for water transport (Ea) was estimated from Arrhenius plots of the water permeability data. The values of Ea for monolayers and suspensions of MIN6 cells were not significantly different. However, the activation energy was significantly lower for BPAEC monolayers (Ea = 49 +/- 2 kJ per mol) than suspensions (Ea = 70 +/- 4 kJ per mol). Predictions of water transport during cryopreservation revealed substantial differences in supercooling between monolayers and suspensions.

PMID: 22576122 [PubMed - in process]
Inhibition of Glucose-Stimulated Insulin Secretion by KCNJ15, a Newly Identified Susceptibility Gene for Type 2 Diabetes.

Fetched: May 10th, 2012, 11:00pm MDT

Inhibition of Glucose-Stimulated Insulin Secretion by KCNJ15, a Newly Identified Susceptibility Gene for Type 2 Diabetes.

Diabetes. 2012 May 7;

Authors: Okamoto K, Iwasaki N, Doi K, Noiri E, Iwamoto Y, Uchigata Y, Fujita T, Tokunaga K

Abstract
Potassium inwardly rectifying channel, subfamily J, member 15 (KCNJ15) is a type 2 diabetes-associated risk gene, and Kcnj15 overexpression suppresses insulin secretion in rat insulinoma (INS1) cells. The aim of the current study was to characterize the role of Kcnj15 by knockdown of this gene in vitro and in vivo. Human islet cells were used to determine the expression of KCNJ15. Expression of KCNJ15 mRNA in islets was higher in subjects with type 2 diabetes. In INS1 cells, Kcnj15 expression was induced by high glucose-containing medium. Regulation of Kcnj15 by glucose and its effect on insulin secretion were analyzed in INS1 cells and in normal mice and diabetic mice by the inactivation of Kcnj15 using small interfering RNA. Knockdown of Kcnj15 increased the insulin secretion in vitro and in vivo. KCNJ15 and Ca(2+)-sensing receptor (CsR) interact in the kidney. Binding of Kcnj15 with CsR was also detected in INS1 cells. In conclusion, downregulation of Kcnj15 leads to increased insulin secretion in vitro and in vivo. The mechanism to regulate insulin secretion involves KCNJ15 and CsR.

PMID: 22566534 [PubMed - as supplied by publisher]
Repression of malignant tumor progression upon pharmacological IGF-1R blockade in a mouse model of insulinoma.

Fetched: May 10th, 2012, 11:00pm MDT

Repression of malignant tumor progression upon pharmacological IGF-1R blockade in a mouse model of insulinoma.

Mol Cancer Res. 2012 May 4;

Authors: Zumsteg A, Caviezel C, Pisarsky L, Strittmatter K, Garcia-Echeverría C, Hofmann F, Christofori G

Abstract
NVP-AEW541, a specific ATP-competitive inhibitor of the insulin-like growth factor-1 receptor (IGF1R) tyrosine kinase, has been reported to interfere with tumor growth in various tumor transplantation models. We have assessed the efficacy of NVP-AEW541 in repressing tumor growth and tumor progression in the Rip1Tag2 transgenic mouse model of pancreatic β-cell carcinogenesis. In addition, we have tested NVP-AEW541 in Rip1Tag2;RipIGF1R double-transgenic mice which show accelerated tumor growth and increased tumor malignancy compared to Rip1Tag2 single-transgenic mice. Previously, we have shown that high levels of IGF-II, a high-affinity ligand for IGF1R, are required for Rip1Tag2 tumor cell survival and tumor growth. Unexpectedly, treatment of Rip1Tag2 mice with NVP-AEW541 in prevention and intervention trials did neither affect tumor growth nor tumor cell proliferation and apoptosis. Yet, it significantly repressed progression to tumor malignancy, i.e. the rate of the transition from differentiated adenoma to invasive carcinoma. Treatment of Rip1Tag2;RipIGF1R double-transgenic mice resulted in moderately reduced tumor volumes and increased rates of tumor cell apoptosis. Sustained expression of IGF-II and of the IGF-II-binding form of insulin receptor (IR-A) in tumor cells suggests a compensatory role of IR-A upon IGF1R blockade. The results indicate that inhibition of IGF1R alone is not sufficient to efficiently block insulinoma growth and imply an overlapping role of IGF1R and insulin receptor in executing mitogenic and survival stimuli elicited by IGF-II. The reduction of tumor invasion upon IGF1R blockade on the other hand indicates a critical function of IGF1R signaling for the acquisition of a malignant phenotype.

PMID: 22562956 [PubMed - as supplied by publisher]
Effect of Sanguis draconis (a dragon's blood resin) on streptozotocin- and cytokine-induced β-cell damage, in vitro and in vivo.

Fetched: May 10th, 2012, 11:00pm MDT

Effect of Sanguis draconis (a dragon's blood resin) on streptozotocin- and cytokine-induced β-cell damage, in vitro and in vivo.

Diabetes Res Clin Pract. 2011 Dec;94(3):417-25

Authors: Hu CM, Li JS, Cheah KP, Lin CW, Yu WY, Chang ML, Yeh GC, Chen SH, Cheng HW, Choy CS

Abstract
The study was to examine the effects of Sanguis draconis ethanol extract (SDEE) on streptozotocin (STZ)- and cytokine-induced β-cell damage. In vitro, SDEE did not cause cytotoxicity below 200 μg/ml, and can prevent STZ (5mM)-induced cell death and apoptosis below 100 μg/ml on RIN-m5F cells. SDEE inhibits IL-1β/IFN-γ-stimulated NO, TNF-α release, and iNOS expression. Furthermore, SDEE suppressed the IL-1β/IFN-γ- or STZ-induced p65 expression of NF-κB, which is associated with inhibition of IκB-α degradation. In vivo, treatment of ICR mice with STZ (100 mg/kg, i.p. single injection) resulted in hyperglycemia and hypoinsulinemia, which was further evidenced by blood glucose and plasma insulin. The diabetogenic effects of STZ were completely prevented when mice were orally administered with SDEE for 3 weeks, however, the blood glucose and plasma insulin showed no significant change after SDEE administration alone. In addition, SDEE also can inhibit STZ-induced iNOS protein expression, pancreatic injury and lipid peroxidation. In conclusions, the molecular mechanism by which SDEE inhibits iNOS gene expression appears to involve the inhibition of NF-κB activation. These results suggest the possible therapeutic value of S. draconis and could be potentially developed into a novel drug for preventing the progression of diabetes mellitus.

PMID: 21899910 [PubMed - indexed for MEDLINE]
Surgical management of insulinomas: short- and long-term outcomes after enucleations and pancreatic resections.

Fetched: May 8th, 2012, 11:00pm MDT

Surgical management of insulinomas: short- and long-term outcomes after enucleations and pancreatic resections.

Arch Surg. 2012 Mar;147(3):261-6

Authors: Crippa S, Zerbi A, Boninsegna L, Capitanio V, Partelli S, Balzano G, Pederzoli P, Di Carlo V, Falconi M

Abstract
OBJECTIVE: To analyze the characteristics and outcomes following enucleation and pancreatic resections of insulinomas.
DESIGN: Retrospective cohort study; prospective database.
SETTINGS: Academic, tertiary, and referral centers.
PATIENTS: Consecutive patients with insulinomas (symptoms of hyperinsulinism and positive fasting glucose test) who underwent surgical treatment between January 1990 and December 2009.
MAIN OUTCOME MEASURES: Operative morbidity, tumor recurrence, and survival after treatment.
RESULTS: A total of 198 patients (58.5% women; median age, 48 years) were identified. There were 175 (88%) neuroendocrine tumors grade G1 and 23 (12%) neuroendocrine tumors grade G2. Malignant insulinomas defined by lymph node/liver metastases were found in 7 patients (3.5%). Multiple insulinomas were found in 8% of patients, and 5.5% of patients had multiple endocrine neoplasia type 1. Surgical procedures included 106 enucleations (54%) and 92 pancreatic resections (46%). Mortality was nil. Rate of clinically significant pancreatic fistula was 18%. Enucleations had a higher reoperation rate compared with pancreatic resections (8.5% vs 1%; P = .02). Multiple endocrine neoplasia type 1 was significantly associated with younger age at onset (P < .005) and higher rates of malignancies and multiple lesions. Median follow-up was 65 months. Six patients (3%; 5 patients had neuroendocrine tumors grade G2) developed tumor recurrence. Four patients (2%) died of disease. New exocrine (1.5%) and endocrine (4%) insufficiencies were associated only with pancreatic resections.
CONCLUSIONS: Outcomes following surgical resection of insulinomas are satisfactory, with no mortality and good functional results. Recurrence is uncommon (3%), and it is more likely associated with neuroendocrine tumors grade G2. Insulinomas in multiple endocrine neoplasia type 1 are at higher risk for being malignant and multifocal, requiring pancreatic resections.

PMID: 22430908 [PubMed - indexed for MEDLINE]
Hyperinsulinism Presenting In Childhood and Treatment By Conservative Pancreatectomy.

Fetched: May 4th, 2012, 11:00pm MDT

Hyperinsulinism Presenting In Childhood and Treatment By Conservative Pancreatectomy.

Endocr Pract. 2012 May 1;:1-14

Authors: Patterson ME, Mao CS, Yeh MW, Ipp E, Cortina G, Barank D, Vasinrapee P, Pawlikowska-Haddal A, Lee WN, Yee JK

Abstract
Objective: The objective of this case report is to describe the uncommon presentation of hyperinsulinism in an 8 year old male, and the patient's evaluation, treatment, and outcome. Methods: The patient's clinical findings, biochemical and imaging studies, surgical approach, and outcome are reported. The discussion encompasses a review of literature that provided the basis for the patient's diagnostic and surgical approach. Results: Biochemical analysis indicated hyperinsulinism. Endoscopic ultrasound showed no pancreatic lesions suspicious for insulinoma. Genetic studies showed no known mutations of ABCC8, KCNJ11, GCK, and GLUD1 present. Selective arterial calcium stimulation and hepatic vein sampling did not show a focal source for hyperinsulinism in the pancreas, and 18F-DOPA imaging showed diffusely increased uptake in the pancreas. The patient ultimately required partial pancreatectomy due to continued hypoglycemia on diazoxide and octreotide. Intraoperative glucose monitoring directed the extent of surgical resection. A 45% pancreatectomy was performed which resolved the hypoglycemia, but led to impaired glucose tolerance after surgery. Conclusion: The unusual presentation of hyperinsulinism in childhood required an individualized approach to diagnosis, and surgical management using intraoperative glucose monitoring, resulting in a conservative pancreatectomy.

PMID: 22548943 [PubMed - as supplied by publisher]
AMPA receptors regulate exocytosis and insulin release in pancreatic beta cells.

Fetched: May 4th, 2012, 11:00pm MDT

AMPA receptors regulate exocytosis and insulin release in pancreatic beta cells.

Traffic. 2012 Apr 27;

Authors: Wu ZY, Zhu LJ, Zou N, Križančicá Bombek L, Shao CY, Wang N, Wang XX, Liang L, Xia J, Rupnik M, Shen Y

Abstract
Ionotropic glutamate receptors (iGluRs) are expressed in islets and insulinoma cells and involved in insulin secretion. However, the exact roles that iGluRs play in β cells remain unclear. Here, we demonstrated that GluR2-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) were expressed in mouse β cells. Glutamate application increased both cytosolic calcium and the number of docked insulin-containing granules, which resulted in augmentation of depolarization-induced exocytosis and high-glucose-stimulated insulin release. While glutamate application directly depolarized β cells, it also induced an enormous depolarization when K(ATP) channels were available. Glutamate application reduced the conductance of K(ATP) channels and increased voltage oscillations. Moreover, actions of AMPARs were absent in Kir6.2 knock-out mice. The effects of AMPARs on K(ATP) channels were mediated by cytosolic cGMP. Taken together, our experiments uncovered a novel mechanism by which AMPARs participate in insulin release.

PMID: 22540213 [PubMed - as supplied by publisher]
US-guided ethanol ablation of insulinomas: a new treatment option.

Fetched: May 4th, 2012, 11:00pm MDT

US-guided ethanol ablation of insulinomas: a new treatment option.

Gastrointest Endosc. 2012 Jan;75(1):200-6

Authors: Levy MJ, Thompson GB, Topazian MD, Callstrom MR, Grant CS, Vella A

PMID: 22078104 [PubMed - indexed for MEDLINE]
Regulation of microRNA-375 by cAMP in Pancreatic β-Cells.

Fetched: April 29th, 2012, 11:00pm MDT

Regulation of microRNA-375 by cAMP in Pancreatic β-Cells.

Mol Endocrinol. 2012 Apr 25;

Authors: Keller DM, Clark EA, Goodman RH

Abstract
MicroRNA-375 (miR-375) is necessary for proper formation of pancreatic islets in vertebrates and is necessary for the development of β-cells in mice, but regulation of miR-375 in these cells is poorly understood. Here, we show that miR-375 is transcriptionally repressed by the cAMP-protein kinase A (PKA) pathway and that this repression is mediated through a block in RNA polymerase II binding to the miR-375 promoter. cAMP analogs that are PKA selective repress miR-375, as do cAMP agonists and the glucagon-like peptide-1 receptor agonist, exendin-4. Repression of the miR-375 precursor occurs rapidly in rat insulinoma INS-1 832/13 cells, within 15 min after cAMP stimulation, although the mature microRNA declines more slowly due to the kinetics of RNA processing. Repression of miR-375 in isolated rat islets by exendin-4 also occurs slowly, after several hours of stimulation. Glucose is another reported antagonist of miR-375 expression, although we demonstrate here that glucose does not target the microRNA through the PKA pathway. As reported previously, miR-375 negatively regulates insulin secretion, and attenuation of miR-375 through the cAMP-PKA pathway may boost the insulin response in pancreatic β-cells.

PMID: 22539037 [PubMed - as supplied by publisher]
Additional resection of the pancreas body prevents postoperative pancreas fistula in patients with portal annular pancreas who undergo pancreaticoduodenectomy.

Fetched: April 27th, 2012, 11:00pm MDT

Additional resection of the pancreas body prevents postoperative pancreas fistula in patients with portal annular pancreas who undergo pancreaticoduodenectomy.

Case Rep Gastroenterol. 2012 Jan;6(1):131-4

Authors: Muto J, Mano Y, Harada N, Uchiyama H, Yoshizumi T, Taketomi A, Shirabe K, Maehara Y

Abstract
Portal annular pancreas (PAP) is a rare variant in which the uncinate process of the pancreas extends to the dorsal surface of the pancreas body and surrounds the portal vein or superior mesenteric vein. Upon pancreaticoduodenectomy (PD), when the pancreas is cut at the neck, two cut surfaces are created. Thus, the cut surface of the pancreas becomes larger than usual and the dorsal cut surface is behind the portal vein, therefore pancreatic fistula after PD has been reported frequently. We planned subtotal stomach-preserving PD in a 45-year-old woman with underlying insulinoma of the pancreas head. When the pancreas head was dissected, the uncinate process was extended and fused to the dorsal surface of the pancreas body. Additional resection of the pancreas body 1 cm distal to the pancreas tail to the left side of the original resection line was performed. The new cut surface became one and pancreaticojejunostomy was performed as usual. No postoperative complications such as pancreatic fistula occurred. Additional resection of the pancreas body may be a standardized procedure in patients with PAP in cases of pancreas cut surface reconstruction.

PMID: 22532811 [PubMed - in process]
A novel dual-color reporter for identifying insulin-producing Beta- cells and classifying heterogeneity of insulinoma cell lines.

Fetched: April 27th, 2012, 11:00pm MDT

A novel dual-color reporter for identifying insulin-producing Beta- cells and classifying heterogeneity of insulinoma cell lines.

PLoS One. 2012;7(4):e35521

Authors: Lee NS, Rohan JG, Zitting M, Kamath S, Weitz A, Sipos A, Salvaterra PM, Hasegawa K, Pera M, Chow RH

Abstract
Many research studies use immortalized cell lines as surrogates for primary beta- cells. We describe the production and use of a novel "indirect" dual-fluorescent reporter system that leads to mutually exclusive expression of EGFP in insulin-producing (INS(+)) beta-cells or mCherry in non-beta-cells. Our system uses the human insulin promoter to initiate a Cre-mediated shift in reporter color within a single transgene construct and is useful for FACS selection of cells from single cultures for further analysis. Application of our reporter to presumably clonal HIT-T15 insulinoma cells, as well as other presumably clonal lines, indicates that these cultures are in fact heterogeneous with respect to INS(+) phenotype. Our strategy could be easily applied to other cell- or tissue-specific promoters. We anticipate its utility for FACS purification of INS(+) and glucose-responsive beta-like-cells from primary human islet cell isolates or in vitro differentiated pluripotent stem cells.

PMID: 22530041 [PubMed - in process]
Reduced expression of the LRP16 gene in mouse insulinoma (MIN6) cells exerts multiple effects on insulin content, proliferation and apoptosis.

Fetched: April 27th, 2012, 11:00pm MDT

Reduced expression of the LRP16 gene in mouse insulinoma (MIN6) cells exerts multiple effects on insulin content, proliferation and apoptosis.

J Huazhong Univ Sci Technolog Med Sci. 2012 Apr;32(2):190-8

Authors: Li X, Xue B, Wang X, Sun L, Zhang T, Qu L, Zou X, Mu Y

Abstract
This study assessed the effects of leukemia-related protein 16 (LRP16) on the regulation of pancreatic functions in mouse insulinoma (MIN6) cells. Cells with down-regulated expression of LRP16 were obtained by a shRNA interference strategy. Insulin content and glucose-stimulated insulin secretion (GSIS) were examined by radioimmunoassay. Western blotting was applied to detect protein expression. Glucose-stimulated sub-cellular localization of PDX-1 was immunocytochemically determined. Cell proliferation and apoptosis were detected by flow cytometry. Our results showed that LRP16 regulated insulin content in MIN6 cells by controlling expression of insulin and insulin transcription factors. LRP16 gene silence in MIN6 cells led to reduced cell proliferation and increased apoptosis. The observation of phosphorylation of serine-473 Akt and the localization of PDX-1 to the nucleus under glucose-stimulation exhibited that LRP16 was a component mediating Akt signaling in MIN6 cells. These results suggest that LRP16 plays a key role in maintaining pancreatic β-cell functions and may help us to understand the protective effects of estrogen on the functions of pancreatic β-cells.

PMID: 22528219 [PubMed - in process]
Rate of Clinically Significant Postoperative Pancreatic Fistula in Pancreatic Neuroendocrine Tumors.

Fetched: April 27th, 2012, 11:00pm MDT

Rate of Clinically Significant Postoperative Pancreatic Fistula in Pancreatic Neuroendocrine Tumors.

World J Surg. 2012 Apr 24;

Authors: Inchauste SM, Lanier BJ, Libutti SK, Phan GQ, Nilubol N, Steinberg SM, Kebebew E, Hughes MS

Abstract
BACKGROUND: In 2005, the International Study Group of Pancreatic Fistula (ISGPF) developed a definition and grading system for postoperative pancreatic fistula (POPF). The authors sought to determine the rate of POPF after enucleation and/or resection of pancreatic neuroendocrine tumors (PNET) and to identify clinical, surgical, or pathologic factors associated with POPF. METHODS: A retrospective analysis of pancreatic enucleations and resections performed from March 1998 to April 2010. We defined a clinically significant POPF as a grade B that required nonoperative intervention and grade C. RESULTS: One hundred twenty-two patients were identified; 62 patients had enucleations and 60 patients had resections of PNET. The rate of clinically significant POPF was 23.7 % (29/122). For pancreatic enucleation, the POPF rate was 27.4 % (17/62, 14 grade B, 3 grade C). The pancreatic resection group had a POPF rate of 20 % (12/60, 10 grade B, 2 grade C). This difference was not significant (p = 0.4). In univariate analyses, patients in the enucleation group with hereditary syndromes (p = 0.02) and non-insulinoma tumors (p = 0.02) had a higher POPF rate. Patients in the resection group with body mass index (BMI) > 25 (p < 0.01), multiple endocrine neoplasia type 1 (MEN-1; p < 0.01) and those who underwent simultaneous multiple procedures (p = 0.02) had a higher POPF rate. Multivariate analyses revealed that hereditary syndromes were able to predict POPF in the enucleation group, while having BMI > 25 and increasing lesion size were also associated with POPF in the group undergoing resection. CONCLUSIONS: We found a clinically significant POPF rate after surgery in PNET to be 23.7 % with no difference by the type of operation. Our POPF rate is comparable to that reported in the literature for pancreatic resection for other types of tumors. Certain inherited genetic diseases-von Hippel-Lindau disease (VHL) and MEN-1-were associated with higher POPF rates.

PMID: 22526042 [PubMed - as supplied by publisher]
Successful Control of Intractable Hypoglycemia Using Radiopharmaceutical Therapy with Strontium-89 in a Case with Malignant Insulinoma and Bone Metastases.

Fetched: April 27th, 2012, 11:00pm MDT

Successful Control of Intractable Hypoglycemia Using Radiopharmaceutical Therapy with Strontium-89 in a Case with Malignant Insulinoma and Bone Metastases.

Jpn J Clin Oncol. 2012 Apr 23;

Authors: Naganuma A, Mayahara H, Morizane C, Ito Y, Hagihara A, Kondo S, Ueno H, Itami J, Okusaka T

Abstract
This report describes the case of a 57-year-old woman with liver and bone metastases from malignant insulinoma, who was afflicted with severe hypoglycemia. Treatment of the liver metastases using octreotide, diazoxide and transarterial embolization failed to raise her blood glucose level and she required constant glucose infusion (about 1000 kcal/day) and oral feeding (about 2200 kcal/day) to avoid a hypoglycemic attack. Subsequently, 110 MBq (2.0 MBq/kg) of strontium-89 were administered by intravenous injection. Three weeks after the strontium-89 injection, we could reduce the dose of constant glucose infusion while maintaining a euglycemic status. Six weeks after the injection, the constant glucose infusion was discontinued. Although strontium-89 therapy is indicated for patients with multiple painful bone metastases, it was also useful as a means of inhibiting tumor activity and controlling hypoglycemia in this case. To our knowledge, this is the first report to provide evidence that strontium-89 can be useful in controlling intractable hypoglycemia in patients with malignant insulinoma with bone metastases.

PMID: 22525212 [PubMed - as supplied by publisher]
Enucleation of an Insulinoma of the Pancreas Using Reduced Port Surgery: Report of a Case.

Fetched: April 23rd, 2012, 11:00pm MDT

Enucleation of an Insulinoma of the Pancreas Using Reduced Port Surgery: Report of a Case.

Surg Technol Int. 2012 Dec 1;XXI:101-105

Authors: Shibao K, Higure A, Yamaguchi K, Minagawa N

Abstract
Reduced port surgery (RPS) is a new surgical modality producing increased cosmetic benefits over conventional endoscopic surgery. We herein report the first case of insulinoma of the pancreas treated by RPS. RPS enucleation was performed for a 23-year-old Japanese female who was admitted to our hospital with repeated episodes of hypoglycemia attributable to an insulinoma. The preoperative examinations confirmed the diagnosis of a solitary insulinoma of the pancreatic tail. Enucleation of the insulinoma using RPS was performed. A 2.5-cm umbilical incision was made, and three laparoscopic trocars were individually inserted into the abdominal cavity via this incision. Another 3-mm trocar was inserted from the left subcostal region. All procedures that were usually performed in conventional laparoscopic surgery were also performed by RPS: intraoperative ultrasonography, mobilization of the tail of the pancreas, enucleation of the tumor, and suturing of the stump. A mechanical manipulator, the Radius Surgical System (Radius), was used for suturing and ligation. The Radius was sufficient to overcome in-line viewing and hand/instrument collisions, and enabled us to perform precise suturing and ligation. Serial blood sugar, C-peptide immunoreactivity (CPR), and immunoreactive insulin (IRI) measurements revealed that all values were normal after resection. The patient had an uneventful postoperative course. RPS was successfully applied for enucleation of a solitary mass in the tail of the pancreas, and represents an alternative to conventional laparoscopic surgery. This method is technically feasible and results in superior cosmesis. The Radius facilitated advanced laparoscopic surgery and may also have advantages in RPS.

PMID: 22504977 [PubMed - as supplied by publisher]
[The effects and mechanisms of BTBD10 on the proliferation of islet beta cell].

Fetched: April 13th, 2012, 11:01pm MDT

[The effects and mechanisms of BTBD10 on the proliferation of islet beta cell].

Zhonghua Nei Ke Za Zhi. 2012 Feb;51(2):136-9

Authors: Liu Y, Gu ZY, Miao XY, Gong YP, Xiao YJ, Li J, Tian H, Li CL

Abstract
OBJECTIVE: To explore the role of BTBD10 overexpression in the proliferation of insulinoma cell line INS-1 and its mechanism.
METHODS: The recombined expression plasmid of pcDNA4.0-BTBD10 was constructed by gene cloning technique and was transfected into INS-1 cell by lipofectamine 2000. The stable overexpression BTBD10 of INS-1 cell was selected at 48(th) hour after transfection. INS-1 cell proliferation activity was measured by MTT method. The expression of BTBD10, protein kinase B (Akt), phospho-Akt (p-Akt), mammal target of rapamycin (mTOR) and phospho-mTOR (p-mTOR) were determined by Western blot.
RESULTS: The stable overexpression BTBD10 of INS-1 cell was successfully constructed. Overproduction of BTBD10 promoted beta cell proliferation. The phosphorylation of Akt and mTOR was increased and the ratio of p-Akt/Akt and p-mTOR/mTOR was enhanced in the INS-1 overexpressed by BTBD10. But the expression of total Akt and mTOR presented no obvious changes.
CONCLUSION: The overexpression BTBD10 of INS-1 cell could activate of Akt/mTOR signalling pathway via stimulating phospho-mTOR and Akt, and enhance overall cell protein translation, so as to promote proliferation of INS-1 cell.

PMID: 22490816 [PubMed - in process]
Solution composition impacts fibronectin immobilization on carboxymethyl-dextran surfaces and INS-1 insulin secretion.

Fetched: April 13th, 2012, 11:01pm MDT

Solution composition impacts fibronectin immobilization on carboxymethyl-dextran surfaces and INS-1 insulin secretion.

Colloids Surf B Biointerfaces. 2012 Mar 20;

Authors: Dubiel EA, Vermette P

Abstract
It is shown that solution composition during immobilization plays a critical role in the properties of fibronectin (FN) surfaces and their bioactivity towards insulinoma (INS-1) cell function. X-ray photoelectron spectroscopy revealed FN grafting onto low-fouling carboxymethyl-dextran (CMD) surfaces was successful with solutions composed of 10μM CaCl(2), 10μM MgCl(2), 10μM MnCl(2), and 10μM and 1mM NaCl, but unsuccessful with those made of 150mM NaCl or 1× PBS. Circular dichroism and photon correlation spectroscopy revealed that regardless of solution composition, no measurable differences in free FN conformation prevail. AFM imaging of FN-CMD revealed, while there are no quantitative differences in surface roughness, there are some subtle qualitative differences in topography. FN surface immobilization scheme does not influence INS-1 cell growth after 3 and 7 days regardless of the underlying substrate or solution composition. INS-1 cell insulin secretion in response to glucose is affected by the substrate and solution composition during FN immobilization.

PMID: 22483346 [PubMed - as supplied by publisher]
EUS-FNA for pancreatic neuroendocrine tumors: a tertiary cancer center experience.

Fetched: April 13th, 2012, 11:01pm MDT

EUS-FNA for pancreatic neuroendocrine tumors: a tertiary cancer center experience.

Dig Dis Sci. 2012 Mar;57(3):791-800

Authors: Atiq M, Bhutani MS, Bektas M, Lee JE, Gong Y, Tamm EP, Shah CP, Ross WA, Yao J, Raju GS, Wang X, Lee JH

Abstract
OBJECTIVES: Pancreatic neuroendocrine tumors (PNET) are fairly uncommon. Recent data highlight the importance of EUS in diagnosis of PNET. With this background, we decided to review our experience from a tertiary cancer center with regard to the presentation and clinical features of PNET and the diagnostic utility of EUS-FNA in this scenario.
METHODS: We identified patients who underwent EUS at our institution between January 1st 2001 and December 31st 2009 for a suspected PNET. Data on clinical features, cross-sectional imaging findings, EUS findings, and cytology results were collected.
RESULTS: A total of 81 patients were referred for EUS-FNA for a suspected PNET. Mean age was 58.1 years. There were 41 (50.6%) males. PNET was found incidentally in 38 (46.9%) patients. Computed tomography scanning identified a pancreatic mass in 72 out of 79 (91.1%) cases. Mean diameter of the largest lesion seen on EUS was 27.5 mm (range: 6.9-80 mm). The most common site (34; 42%) was the head of the pancreas. EUS-FNA correctly confirmed a PNET in 73 out of 81 cases with diagnostic accuracy of 90.1%. Seven (8.6%) out of 81 patients had functional lesions, including three gastrinomas and four insulinomas. Liver metastases were found in 31 out of 81 (38.3%) cases. Of the 31 patients with liver metastasis, the mean diameter of lesions on EUS was 33.9 mm compared with 23.5 mm in patients without liver metastasis (P = 0.005).
CONCLUSION: EUS-FNA is a reliable modality for further characterization of suspected lesions and for establishing a tissue diagnosis. The occurrence of complications of EUS-FNA in this setting is low. Non-functional PNET are more frequently encountered than functional PNET.

PMID: 21964743 [PubMed - indexed for MEDLINE]
The pathogenic role of cystathionine γ-lyase/hydrogen sulfide in streptozotocin-induced diabetes in mice.

Fetched: April 13th, 2012, 11:01pm MDT

The pathogenic role of cystathionine γ-lyase/hydrogen sulfide in streptozotocin-induced diabetes in mice.

Am J Pathol. 2011 Aug;179(2):869-79

Authors: Yang G, Tang G, Zhang L, Wu L, Wang R

Abstract
Reduced β-cell mass and increased activities of ATP-sensitive K(+) channels in pancreatic β cells are associated with the pathogenesis of diabetes. Cystathionine γ-lyase (CSE) is a major hydrogen sulfide (H(2)S)-producing enzyme in pancreatic β cells. Herein, we examine the effects of genetic and pharmacologic ablation of CSE on β-cell functions and their correlation with streptozotocin (STZ)-induced diabetes. Compared with wild-type mice, CSE knockout (CSE KO) mice that received STZ injections exhibited a delayed onset of diabetic status. The application of dl-propargylglycine (PPG) to inhibit CSE activity protected wild-type mice from STZ-induced hyperglycemia and hypoinsulinemia. STZ significantly increased pancreatic H(2)S production in wild-type mice but not in CSE KO mice. STZ induced more apoptotic β-cell death in wild-type mice than in CSE KO mice. STZ exposure decreased the viability of cultured INS-1E cells, which was partly reversed by PPG co-treatment. STZ also significantly stimulated H(2)S production in cultured INS-1E cells. In addition, STZ stimulated ATP-sensitive K(+) currents in pancreatic β cells from wild-type mice but not in the presence of PPG or in β cells from CSE KO mice. Sodium hydrosulfide injection instantly increased blood glucose, decreased plasma insulin, and deteriorated glucose tolerance in mice. Take together, these results provide evidence that the CSE/H(2)S system plays a critical role in regulating β-cell functions.

PMID: 21718679 [PubMed - indexed for MEDLINE]
Insulinoma in Dogs: A Review.

Fetched: April 10th, 2012, 11:00pm MDT

Insulinoma in Dogs: A Review.

J Am Anim Hosp Assoc. 2012 Apr 3;

Authors: Goutal CM, Brugmann BL, Ryan KA

Abstract
Insulinomas are rare malignant functional pancreatic tumors of the β cells that retain the ability to produce and secrete insulin. Insulinomas are the most common pancreatic neuroendocrine tumor in dogs that can induce a variety of clinical signs that result from hypoglycemia and secondary neuroglycopenic and adrenergic effects. Diagnosis and treatment is considered challenging, and the prognosis can be extremely variable depending on the therapeutic choices. This review aims to summarize and update classic knowledge with current trends in the diagnosis, treatment, and prognosis of insulinomas.

PMID: 22474047 [PubMed - as supplied by publisher]
Surgical treatment of hyperinsulinism during the course of pancreatic cancer (insulinoma) - one center experience.

Fetched: April 10th, 2012, 11:00pm MDT

Surgical treatment of hyperinsulinism during the course of pancreatic cancer (insulinoma) - one center experience.

Pol Przegl Chir. 2012 Jan 1;84(1):31-6

Authors: Grygiel K, Szmidt J, Jeleńska M, Pawlak K

Abstract
Endogenic hyperinsulinism is mainly caused by neuroendocrine tumors (insulinomas) which autonomously secrete insulin. Because the symptoms are often aspecific, a considerably delay in diagnosis occurs. The treatment consists of operative removal of the tumor from the pancreas, preceded by pre-operative localization. In this article we describe our experience with surgical removal of insulinomasMaterial and methods. We retrospectively analyzed all patients with insulinoma which were treated in our center. Definitive diagnosis was made using a 72-hours glucoses fasting test. We describe the symptoms, localization techniques and the outcomes after surgery.Results. Between January 2002 and May 2011, 45 patients (35.6% men and 64.4% female) were treated in our center. The most prevalent symptoms were altered consciousness and general malaise. The combination of CT-scan and endoscopic ultrasound had the highest (90%) sensitivity to localize tumors pre-operatively. During surgery, in 40 patients (89%) the tumor could be removed by enucleation. In the other five patients partial pancreas resection was required. In 22 patients (49%) we used intra-operative insulin level measurements to confirm complete tumor resection. Within the first month after surgery, two patients (4.4%) developed acute pancreatitis, four patients (8.8%) developed a pancreatic fistula. One patient died of multi-organ-failure. All patients were free from symptoms of hyperinsulinism after the surgery and after a median follow-up of 4.5 years.Conclusions. Based on the experience with 45 patients, surgical removal, aided by pre-operative localization with CT and endoscopic ultrasonography, is an effective and safe treatment for insulinomas.

PMID: 22472492 [PubMed - in process]
Malignant insulinoma presenting as upper gastrointestinal bleeding.

Fetched: April 10th, 2012, 11:00pm MDT

Malignant insulinoma presenting as upper gastrointestinal bleeding.

Am Surg. 2012 Apr;78(4):235-7

Authors: Medina-Franco H, Feria-Bernal G, Sánchez-Ramón A

PMID: 22472386 [PubMed - in process]
Associations of ATP-Binding Cassette Transporter A1 and G1 With Insulin Secretion in Human Insulinomas.

Fetched: April 10th, 2012, 11:00pm MDT

Associations of ATP-Binding Cassette Transporter A1 and G1 With Insulin Secretion in Human Insulinomas.

Pancreas. 2012 Mar 29;

Authors: Zhou H, Li C, Li J, Yao H, Su R, Li W, Xu M

Abstract
OBJECTIVES: Adenosine triphosphate-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) are 2 important cholesterol transporters in human pancreatic β-cells. The aim of this study was to investigate their alteration in insulinomas and their potential associations with abnormal insulin secretion in these patients. METHODS: Six patients with insulinoma and 6 healthy controls were recruited. Lipid profiles and glucose metabolism were measured. Insulin content, ABCA1, and ABCG1 in insulinomas and the adjacent islets of the 6 patients with insulinoma were detected by immunohistochemistry or immunofluorescence. RESULTS: Plasma total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride were comparable between the controls and the patients with insulinoma. Fasting glucose was less than 2.8 mmol/L, and insulin release index was greater than 0.3 in each patient. Serum insulin fell extremely, and blood glucose reached the reference range within an hour after the cutting of the tumors in 2 patients with insulinoma. Adenosine triphosphate-binding cassette transporter G1 increased in insulinomas compared with the adjacent islets. However, ABCA1 was detected neither in the adjacent islets nor in insulinomas. Adenosine triphosphate-binding cassette transporter G1 expression in insulinomas was significantly associated with fasting insulin level and insulin release index. CONCLUSIONS: Increased ABCG1 may contribute to insulin hypersecretion in insulinomas. In contrast, the undetectable ABCA1 in insulinomas may reflect a negative feedback in insulin secretion in these patients.

PMID: 22466164 [PubMed - as supplied by publisher]
β-Cell-protective effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid as a glutamate dehydrogenase activator in db/db mice.

Fetched: April 10th, 2012, 11:00pm MDT

β-Cell-protective effect of 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid as a glutamate dehydrogenase activator in db/db mice.

J Endocrinol. 2012 Mar;212(3):307-15

Authors: Han SJ, Choi SE, Yi SA, Lee SJ, Kim HJ, Kim DJ, Lee HC, Lee KW, Kang Y

Abstract
2-Aminobicyclo-(2,2,1)-heptane-2-carboxylic acid (BCH) is an activator of glutamate dehydrogenase (GDH), which is a mitochondrial enzyme with an important role in insulin secretion. We investigated the effect of BCH on the high-glucose (HG)-induced reduction in glucose-stimulated insulin secretion (GSIS), the HG/palmitate (PA)-induced reduction in insulin gene expression, and HG/PA-induced β-cell death. We also studied whether long-term treatment with BCH lowers blood glucose and improves β-cell integrity in db/db mice. We evaluated GSIS, insulin gene expression, and DNA fragmentation in INS-1 cells exposed to HG or HG/PA in the presence or absence of BCH. An in vivo study was performed in which 7-week-old diabetic db/db mice were treated with BCH (0.7 g/kg, n = 10) and placebo (n = 10) every other day for 6 weeks. After treatment, an intraperitoneal glucose tolerance test and immunohistological examinations were performed. Treatment with BCH blocked HG-induced GSIS inhibition and the HG/PA-induced reduction in insulin gene expression in INS-1 cells. In addition, BCH significantly reduced HG/PA-induced INS-1 cell death and phospho-JNK level. BCH treatment improved glucose tolerance and insulin secretion in db/db mice. BCH treatment also increased the ratio of insulin-positive β-cells to total islet area (P < 0.05) and reduced the percentage of β-cells expressing cleaved caspase 3 (P < 0.05). In conclusion, the GDH activator BCH improved glycemic control in db/db mice. This anti-diabetic effect may be associated with improved insulin secretion, preserved islet architecture, and reduced β-cell apoptosis.

PMID: 22131441 [PubMed - indexed for MEDLINE]
Epigenetic Aspects on Therapy Development for Gastroenteropancreatic Neuroendocrine Tumors.

Fetched: March 31st, 2012, 11:01pm MDT

Epigenetic Aspects on Therapy Development for Gastroenteropancreatic Neuroendocrine Tumors.

Neuroendocrinology. 2012 Mar 24;

Authors: Larsson C

Abstract
The understanding of epigenetic modifications in gastroenteropancreatic neuroendocrine tumors is a novel and still small field. Activation of the insulin-like growth factor 2 gene locus by loss of imprinting is a classical epigenetic alteration frequently observed in insulinoma. Inactivation of the MEN1 gene, commonly involved in endocrine pancreatic tumors, impairs the association with mixed lineage leukemia involved in histone H3K4me3 methylation. In addition, promising effects on tumor phenotypes such as growth, apoptosis, cell cycle arrest, and expression of neuroendocrine markers have been obtained in vitro for inhibitors of DNA methyltransferase (azacytidine) and histone deacetylation (butyrate, valproic acid, trichostatin A and MS-275). The frequent need for complementary treatments in addition to surgery in this tumor entity supports further efforts in the development and application of drugs acting at general as well as more specific epigenetic alterations.

PMID: 22456267 [PubMed - as supplied by publisher]
Zinc Transporter-8 Autoantibodies Improve Prediction of Type 1 Diabetes in Relatives Positive for the Standard Biochemical Autoantibodies.

Fetched: March 31st, 2012, 11:01pm MDT

Zinc Transporter-8 Autoantibodies Improve Prediction of Type 1 Diabetes in Relatives Positive for the Standard Biochemical Autoantibodies.

Diabetes Care. 2012 Mar 23;

Authors: Yu L, Boulware DC, Beam CA, Hutton JC, Wenzlau JM, Greenbaum CJ, Bingley PJ, Krischer JP, Sosenko JM, Skyler JS, Eisenbarth GS, Mahon JL,

Abstract
OBJECTIVEWe assessed diabetes risk associated with zinc transporter-8 antibodies (ZnT8A), islet cell antibodies (ICA), and HLA type and age in relatives of people with type 1 diabetes with the standard biochemical autoantibodies (BAA) to insulin (IAA), GAD65 (GAD65A), and/or insulinoma-associated protein 2 antigen (IA-2A).RESEARCH DESIGN AND METHODSFor this analysis, 2,256 relatives positive for at least one BAA, of whom 142 developed diabetes, were tested for ZnT8A, ICA, and HLA genotype followed by biannual oral glucose tolerance tests. ZnT8A were also tested in 911 randomly chosen antibody-negative relatives.RESULTSZnT8A were associated with the other BAA (548 of 2,256 [24.3%] BAA(+) vs. 8 of 911 [0.8%] BAA(-), P < 0.001) and BAA number (177 of 1,683 [10.5%] single-, 221 of 384 [57.6%] double-, and 150 of 189 [79.4%] triple-BAA positivity, P < 0.001). The 4-year diabetes risk was higher in single BAA(+) relatives with ZnT8A than ZnT8A(-) relatives (31 vs. 7%, P < 0.001). In multivariable analysis, age ≤20 years (hazard ratio 2.13, P = 0.03), IA-2A (2.15, P = 0.005), IAA (1.73, P = 0.01), ICA (2.37, P = 0.002), and ZnT8A (1.87, P = 0.03) independently predicted diabetes, whereas HLA type (high and moderate vs. low risk) and GAD65A did not (P = 0.81 and 0.86, respectively).CONCLUSIONSIn relatives with one standard BAA, ZnT8A identified a subset at higher diabetes risk. ZnT8A predicted diabetes independently of ICA, the standard BAA, age, and HLA type. ZnT8A should be included in type 1 diabetes prediction and prevention studies.

PMID: 22446173 [PubMed - as supplied by publisher]
[The management of postoperative pancreatic fistulas].

Fetched: March 31st, 2012, 11:01pm MDT

[The management of postoperative pancreatic fistulas].

Chirurgia (Bucur). 2011 Nov-Dec;106(6):737-41

Authors: Pătraşcu T, Doran H, Bugă C, Mihalache O, Bobircă F, Costache A, Boanţă R

Abstract
Postoperative pancreatic fistula is the most common major complication after pancreatic surgery and it can lead to prolonged hospital stay, increased costs and mortality. Its incidence is between 2 and 30%. We present a series of 100 successive patients, operated in our clinic for different pancreatic diseases. Among them, 21 had pancreaticoduodenectomies, 24- enucleation procedures for insulinomas or pancreatic adenomas, 31- distal pancreato-spleenectomies and in 24 cases a pancreatic abcess or pseudocyst was drained. A pancreatic fistula occurred in 21 patients (21%); we analyzed the treatment and outcome of these fistulas, according to our experience and to the International Study Group of Pancreatic Fistula (ISGPF) classification. 10 patients needed only medical treatment, while in 11 cases one/more new surgical procedure(s) was/were required. 15 patients had a favourable evolution and 6 other patients deceased. In persistent fistulas, as well as in those with a high output, the resection of the pancreatic remnant appears to be the best surgical option.

PMID: 22308910 [PubMed - indexed for MEDLINE]
Use of RNA interference to investigate cytokine signal transduction in pancreatic beta cells.

Fetched: March 31st, 2012, 11:01pm MDT

Use of RNA interference to investigate cytokine signal transduction in pancreatic beta cells.

Methods Mol Biol. 2012;820:179-94

Authors: Moore F, Cunha DA, Mulder H, Eizirik DL

Abstract
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by immune infiltration of the pancreatic islets resulting in an inflammatory reaction named insulitis and subsequent beta cell apoptosis. During the course of insulitis beta cell death is probably caused by direct contact with activated macrophages and T-cells, and/or exposure to soluble mediators secreted by these cells, including cytokines, nitric oxide, and free oxygen radicals. In vitro exposure of beta cells to the cytokines interleukin(IL)-1β + interferon(IFN)-γ or to tumor necrosis factor(TNF)-α + IFN-γ induces beta cell dysfunction and ultimately apoptosis. The transcription factors NF-κB and STAT1 are key regulators of cytokine-induced beta cell death. However, little is known about the gene networks regulated by these (or other) transcription factors that trigger beta cell apoptosis. The recent development of RNA interference (RNAi) technology offers a unique opportunity to decipher the cytokine-activated molecular pathways responsible for beta cell death. Use of RNAi has been hampered by technical difficulties in transfecting primary beta cells, but in recent years we have succeeded in developing reliable and reproducible protocols for RNAi in beta cells. This chapter details the methods and settings used to achieve efficient and nontoxic transfection of small interfering RNA in immortal and primary beta cells.

PMID: 22131032 [PubMed - indexed for MEDLINE]
A role for aberrant protein palmitoylation in FFA-induced ER stress and beta cell death.

Fetched: March 25th, 2012, 11:00pm MDT

A role for aberrant protein palmitoylation in FFA-induced ER stress and beta cell death.

Am J Physiol Endocrinol Metab. 2012 Mar 20;

Authors: Baldwin AC, Green CD, Olson LK, Moxley MA, Corbett JA

Abstract
Exposure of insulin producing cells to elevated levels of the free fatty acid palmitate results in the loss of β-cell function and induction of apoptosis. The induction of ER stress is one mechanism proposed to be responsible for the loss of β-cell viability in response to palmitate treatment; however, the pathways responsible for the induction of ER stress by palmitate have yet to be determined. Protein palmitoylation is a major posttranslational modification that regulates protein localization, stability and activity. Defects in, or dysregulation of protein palmitoylation could be one mechanism by which palmitate may induce ER stress in β-cells. The purpose of this study was to evaluate the hypothesis that palmitate-induced ER stress and β-cell toxicity is mediated by excess or aberrant protein palmitoylation. In a concentration-dependent fashion, palmitate treatment of RINm5F cells results in a loss of viability. Like palmitate, stearate also induces a concentration-related loss of RINm5F cell viability while the monounsaturated fatty acids such as palmoleate and oleate are not toxic to RINm5F cells. 2-bromo-palmitate (2BrP), a classical inhibitor of protein palmitoylation that has been extensively used as an inhibitor of G-protein coupled receptor signaling, attenuates palmitate-induced RINm5F cell death in a concentration-dependent manner. The protective effects of 2BrP are associated with the inhibition of [3H]-labeled palmitate incorporation into RINm5F cell protein. Further, 2BrP does not inhibit, but appears to enhance the oxidation of palmitate. The induction of ER stress in response to palmitate treatment and the activation of caspase activity are attenuated by 2BrP. Consistent with protective effects on insulinoma cells, 2BrP also attenuates the inhibitory actions of prolonged palmitate treatment on insulin secretion by isolated rat islets. These studies support a role for aberrant protein palmitoylation as a mechanism by which palmitate enhances ER stress activation and causes the loss of insulinoma cell viability.

PMID: 22436701 [PubMed - as supplied by publisher]
Modulation of Neuronal Pentraxin 1 expression in rat pancreatic β-cells submitted to chronic glucotoxic stress.

Fetched: March 25th, 2012, 11:00pm MDT

Modulation of Neuronal Pentraxin 1 expression in rat pancreatic β-cells submitted to chronic glucotoxic stress.

Mol Cell Proteomics. 2012 Mar 16;

Authors: Schvartz D, Couté Y, Brunner Y, Wollheim CB, Sanchez JC

Abstract
Insulin secretory granules are β-cell vesicles dedicated to insulin processing, storage and release. The secretion of insulin secretory granule content in response to an acute increase of glucose concentration is a highly regulated process allowing normal glycemic homeostasis. Type 2 diabetes is a metabolic disease characterized by chronic hyperglycemia. The consequent prolonged glucose exposure is known to exert deleterious effects on the function of various organs, notably impairment of insulin secretion by pancreatic β-cells, and induction of apoptosis. It has also been described that it modifies gene and protein expression in β-cells. Therefore, we hypothesized that a modulation of insulin secretory granule protein expression induced by chronic hyperglycemia may partially explain β-cell dysfunction. To identify the potential early molecular mechanisms underlying β-cell dysfunction during chronic hyperglycemia, we performed SILAC and mass spectrometry experiments to monitor changes in the insulin secretory granule proteome from INS-1E rat insulinoma β-cells cultivated either with 11 mM or 30 mM of glucose for 24h. Fourteen proteins were found as differentially expressed between these two conditions and several of these proteins were not described before to be present in β-cells. Among them, Neuronal Pentraxin 1 was only described in neurons so far. Here we investigated its expression and intracellular localization in INS-1E cells. Furthermore, its overexpression in glucotoxic conditions was confirmed at the mRNA and protein levels. According to its role in hypoxia-ischemia induced apoptosis described in neurons, this suggests that Neuronal Pentraxin 1 might be a new β-cell mediator in the AKT/GSK3 apoptotic pathway. In conclusion, the modification of specific β-cell pathways such as apoptosis and oxidative stress may partially explain the impairment of insulin secretion and β-cell failure, observed after prolonged exposure to high glucose concentrations.

PMID: 22427704 [PubMed - as supplied by publisher]
Regulation of insulin gene transcription by multiple histone acetyltransferases.

Fetched: March 25th, 2012, 11:00pm MDT

Regulation of insulin gene transcription by multiple histone acetyltransferases.

DNA Cell Biol. 2012 Jan;31(1):8-14

Authors: Sampley ML, Ozcan S

Abstract
Glucose-stimulated insulin gene transcription is mainly regulated by a 340-bp promoter region upstream of the transcription start site by beta-cell-enriched transcription factors Pdx-1, MafA, and NeuroD1. Previous studies have shown that histone H4 hyperacetylation is important for acute up-regulation of insulin gene transcription. Until now, only the histone acetyltransferase (HAT) protein p300 has been shown to be involved in this histone H4 acetylation event. In this report we investigated the role of the additional HAT proteins CREB binding protein (CBP), p300/CBP-associated factor (PCAF), and general control of amino-acid synthesis 5 (GCN5) in regulation of glucose-stimulated insulin gene transcription. Utilizing quantitative chromatin immunoprecipitation analysis, we demonstrate that glucose regulates the binding of p300, CBP, PCAF, and GCN5 to the proximal insulin promoter. siRNA-mediated knockdown of each of these HAT proteins revealed that depletion of p300 and CBP leads to a drastic decrease in histone H4 acetylation at the insulin promoter and in insulin gene expression, whereas knockdown of PCAF and GCN5 leads to a more moderate decrease in histone H4 acetylation and insulin gene expression. These data suggest that high glucose mediates the recruitment of p300, CBP, PCAF, and GCN5 to the insulin promoter and that all four HATs are important for insulin gene expression.

PMID: 21774670 [PubMed - indexed for MEDLINE]

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