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Trial - Insulinoma

Everolimus and Vatalanib in Treating Patients With Advanced Solid Tumors

Posted: April 9th, 2008, 10:00am EDT

Conditions: Gastrointestinal Carcinoid Tumor; Head and Neck Cancer; Islet Cell Tumor; Kidney Cancer; Lung Cancer; Melanoma (Skin); Neuroendocrine Carcinoma of the Skin; Pheochromocytoma; Unspecified Adult Solid Tumor, Protocol Specific
Interventions: Drug: everolimus; Drug: vatalanib; Procedure: antiangiogenesis therapy; Procedure: enzyme inhibitor therapy; Procedure: protein tyrosine kinase inhibitor therapy
Sponsors: Mayo Clinic; National Cancer Institute (NCI)
Recruiting - verified April 2008

Insulinoma and Gastrinoma Syndromes from a Single Intrapancreatic ...
Journal of Clinical Endocrinology and Metabolism, MD - Apr 4, 2008
Context: The insulinoma syndrome is marked by fasting hypoglycemia and inappropriate elevations of insulin. The gastrinoma syndrome is characterized by ...

Endocrine-Gland Derived-Vascular Endothelial Growth Factor (EG ... - Journal of Endocrinology

Posted: February 21st, 2008, 9:15am EST

Endocrine-Gland Derived-Vascular Endothelial Growth Factor (EG ...
Journal of Endocrinology - Feb 21, 2008
In the present study, we investigated the regulation of EG-VEGF gene expression by testosterone in normal rat pancreatic tissue and rat insulinoma cells ...

PubMed - Insulinoma

Adult hyperinsulinaemic hypoglycaemia caused by coexisting nesidioblastosis and insulinoma.

Fetched: May 13th, 2008, 9:00pm EDT

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Adult hyperinsulinaemic hypoglycaemia caused by coexisting nesidioblastosis and insulinoma.

Eur J Intern Med. 2008 Jun;19(4):303

Authors: Dissanayake AS, Jones V, Fernando DJ

PMID: 18471686 [PubMed - in process]
Maternal type 1 diabetes reduces the risk of islet autoantibodies: relationships with birthweight and maternal HbA(1c).

Fetched: May 9th, 2008, 9:01pm EDT

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Maternal type 1 diabetes reduces the risk of islet autoantibodies: relationships with birthweight and maternal HbA(1c).

Diabetologia. 2008 May 8;

Authors: Bonifacio E, Pflüger M, Marienfeld S, Winkler C, Hummel M, Ziegler AG

AIMS/HYPOTHESIS: The risk of type 1 diabetes is reduced in the children of mothers with type 1 diabetes compared with children of fathers with type 1 diabetes. We asked whether children of mothers with type 1 diabetes also have a decreased risk of developing islet autoantibodies, and which factors associated with maternal diabetes contribute to a reduced islet autoantibody risk in offspring. METHODS: Singleton offspring of a mother (n = 1,008) or father with type 1 diabetes (n = 578) from the BABYDIAB study were included. Children were followed from birth for the development of islet autoantibodies defined as two or more autoantibodies to insulin, glutamic acid decarboxylase or insulinoma antigen 2 in two or more blood samples. RESULTS: Islet autoantibody risk was lower in children of mothers with type 1 diabetes (5 year risk, 3.2% vs 5.7% in children of fathers with type 1 diabetes; p = 0.04). Among factors that differed between pregnancies from mothers with and without type 1 diabetes, birthweight was associated with islet autoantibody risk. Risk was reduced in children with birthweights in the lower (adjusted HR 0.33; 95% CI 0.14-0.75; p = 0.009) and upper (HR 0.45; 95% CI 0.21-0.97; p = 0.04) tertiles compared with the middle tertile. A sub-analysis of maternal HbA(1c) suggested that moderately elevated third trimester maternal HbA(1c) was also associated with a reduced islet autoantibody risk in children of mothers with type 1 diabetes (5.7-7%; HR 0.38; 95% CI 0.15-0.96; p = 0.04 vs children of mothers with HbA(1c) < 5.7%). CONCLUSIONS/INTERPRETATION: The risk of islet autoimmunity is modified by maternally influenced events such as birthweight.

PMID: 18463843 [PubMed - as supplied by publisher]
Cytological Ki-67 in pancreatic endocrine tumours: an opportunity for pre-operative grading.

Fetched: May 9th, 2008, 9:01pm EDT

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Cytological Ki-67 in pancreatic endocrine tumours: an opportunity for pre-operative grading.

Endocr Relat Cancer. 2008 Mar;15(1):175-81

Authors: Piani C, Franchi GM, Cappelletti C, Scavini M, Albarello L, Zerbi A, Giorgio Arcidiacono P, Bosi E, Manzoni MF

The cytological Ki-67 expression measured on cytological samples collected by endoscopic ultrasonography-guided fine needle aspiration cytology (EUS-FNAC) may provide pre-operative indications for pancreatic endocrine tumours (PETs) management. The aim of our study was to assess reliability of Ki-67 expression measured on cytological samples obtained by EUS-FNAC in patients with PETs. Eighteen patients with PETs underwent EUS-FNAC before surgery. Ki-67 expression was measured on FNACs and on histological sections. Using a cut-off of 2%, percent agreement of Ki-67 expression on cytological and histological samples was 89% (k-statistic: 0.78, 95% confidence intervals (95% CI): 0.5, 1.0). Using cut-off values of 2 and 10%, percent agreement was 78% (k-statistic: 0.65, 95% CI: 0.3, 0.9). Ki-67 expression measured on cytological samples obtained by EUS-FNAC before surgery showed good agreement with that measured on histological samples.

PMID: 18310285 [PubMed - indexed for MEDLINE]
Reversible translocation of EYFP-tagged STIM1 is coupled to calcium influx in insulin secreting beta-cells.

Fetched: May 3rd, 2008, 9:00pm EDT

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Reversible translocation of EYFP-tagged STIM1 is coupled to calcium influx in insulin secreting beta-cells.

Cell Calcium. 2008 Apr 29;

Authors: Tamarina NA, Kuznetsov A, Philipson LH

Calcium (Ca(2+)) signaling regulates insulin secretion in pancreatic beta-cells. STIM1 has been proposed to function as an endoplasmic reticulum (ER) Ca(2+) sensor regulating store-operated Ca(2+) entry (SOCE). Here we studied the translocation of EYFP-STIM1 in response to ER calcium depletion in mouse insulinoma MIN6 cells by fluorescent microscopy. While in resting cells EYFP-STIM1 is co-localized with an ER marker, in thapsigargin (Tg)-stimulated cells it occupied highly defined areas of the peri-PM space in punctae adjacent to, but not entirely coincident with the ER. Co-staining with fluorescent phalloidin revealed that EYFP-STIM1 punctae was located in actin-poor areas. Use of the SOCE blocker in MIN6 cells, 2-aminoethoxy diphenylborate (2-APB), prevented store depletion-dependent translocation of EYFP-STIM1 to the PM in a concentration-dependent (3.75-100muM) and reversible manner. TIRF microscopy revealed that 2-APB treatment led to the reversible disappearance of peri-PM EYFP-STIM1 punctae, while the ER structure in this compartment remained grossly unaffected. We conclude from this data that in these cells EYFP-STIM1 is delivered to a peri-PM location from the ER upon store depletion and this trafficking is reversibly blocked by 2-APB.

PMID: 18452988 [PubMed - as supplied by publisher]
Mitochondrial oxidative phosphorylation and energetic status are reflected by morphology of mitochondrial network in INS-1E and HEP-G2 cells viewed by 4Pi microscopy.

Fetched: May 3rd, 2008, 9:00pm EDT

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Mitochondrial oxidative phosphorylation and energetic status are reflected by morphology of mitochondrial network in INS-1E and HEP-G2 cells viewed by 4Pi microscopy.

Biochim Biophys Acta. 2008 Apr 10;

Authors: Plecitá-Hlavatá L, Lessard M, Santorová J, Bewersdorf J, Ježek P

Mitochondria in numerous cell types, especially in cultured cells, form a reticular network undergoing constant fusion and fission. The three dimensional (3D) morphology of these networks however has not been studied in detail to our knowledge. We have investigated insulinoma INS-1E and hepatocellular carcinoma HEP-G2 cells transfected with mitochondria-addressed GFP. Using 4Pi microscopy, 3D morphology changes responding to decreased oxidative phosphorylation and/or energetic status could be observed in these cells at an unprecedented 100 nm level of detail. In INS-1E cells cultivated at 11 mM glucose, the mitoreticulum appears predominantly as one interconnected mitochondrion with a nearly constant 262+/-26 nm tubule diameter. If cultured at 5 mM glucose, INS-1E cells show 311+/-36 nm tubules coexisting with numerous flat cisternae. Similar interconnected 284+/-38 nm and 417+/-110 nm tubules were found in HEP-G2 cells cultivated at 5 mM and hyperglycaemic 25 mM glucose, respectively. With rotenone inhibiting respiration to ~10%, disintegration into several reticula and numerous ~300 nm spheres or short tubules was observed. De-energization by uncoupling additionally led to formation of rings and bulky cisternae of 1.4+/-0.4 mum diameter. Rotenone and uncoupler acted synergically in INS-1E cells and increased fusion (ongoing with fission) forming bowl-like shapes. In HEP-G2 cells fission partially ceased with FCCP plus rotenone. Thus we have revealed previously undescribed details for shapes upon mitochondrial disintegration and clearly demonstrate that high resolution 3D microscopy is required for visualization of mitochondrial network. We recommend 4Pi microscopy as a new standard.

PMID: 18452700 [PubMed - as supplied by publisher]
Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus.

Fetched: May 3rd, 2008, 9:00pm EDT

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Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus.

J Clin Invest. 2008 May 1;

Authors: Colombo C, Porzio O, Liu M, Massa O, Vasta M, Salardi S, Beccaria L, Monciotti C, Toni S, Pedersen O, Hansen T, Federici L, Pesavento R, Cadario F, Federici G, Ghirri P, Arvan P, Iafusco D, Barbetti F,

Permanent neonatal diabetes mellitus (PNDM) is a rare disorder usually presenting within 6 months of birth. Although several genes have been linked to this disorder, in almost half the cases documented in Italy, the genetic cause remains unknown. Because the Akita mouse bearing a mutation in the Ins2 gene exhibits PNDM associated with pancreatic beta cell apoptosis, we sequenced the human insulin gene in PNDM subjects with unidentified mutations. We discovered 7 heterozygous mutations in 10 unrelated probands. In 8 of these patients, insulin secretion was detectable at diabetes onset, but rapidly declined over time. When these mutant proinsulins were expressed in HEK293 cells, we observed defects in insulin protein folding and secretion. In these experiments, expression of the mutant proinsulins was also associated with increased Grp78 protein expression and XBP1 mRNA splicing, 2 markers of endoplasmic reticulum stress, and with increased apoptosis. Similarly transfected INS-1E insulinoma cells had diminished viability compared with those expressing WT proinsulin. In conclusion, we find that mutations in the insulin gene that promote proinsulin misfolding may cause PNDM.

PMID: 18451997 [PubMed - as supplied by publisher]
Clinicopathological characteristics and non-adhesive organ culture of insulinomas.

Fetched: May 3rd, 2008, 9:00pm EDT

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Clinicopathological characteristics and non-adhesive organ culture of insulinomas.

Scand J Surg. 2008;97(1):42-9

Authors: Hoem D, Jensen D, Steine S, Thorsen TE, Viste A, Molven A

BACKGROUND AND AIMS: Insulinoma is a very rare type of islet cell tumour, but nevertheless the most common endocrine tumour of the pancreas. We aimed at reviewing our clinical experience with this tumour type and to assess whether organ culture could be obtained from surgically resected insulinoma material. MATERIAL AND METHODS: All patients with insulinomas (6 men and 10 women) referred to Haukeland University Hospital between 1986 and 2006 were included in the study. Median age of onset was 53 years (range 21-74). Biochemical diagnosis was established during a 72 h fast test. Imaging and localization of the tumours were performed with intra-operative ultrasonography, endoscopic ultrasonography, CT-scan and/or transcutaneous ultrasonography. For six patients, organ cultures were set up from tumour tissue fragments. RESULTS: The annual incidence of insulinoma was 0.8 per million. The patients generally presented with non-specific, episodic symptoms, which often were mistaken for cardiovascular, neurological or diabetic disease and in some cases delayed the diagnosis with several years. Two patients had diabetes prior to the diagnosis of insulinoma. Patient weight gain was probably due to increased food intake, compensating for the hypoglycemia. Intra-operative ultrasonography detected all tumours correctly, whereas 73% were detected by endoscopic ultrasonography and 38% by CT scan. Five insulinomas were located in the head, eight in the body and three in the tail of the pancreas. All were removed by open-access surgery, eleven cases by resection and five by enucleation. One tumour was malignant with liver metastases and two patients had tumours defined as borderline. Insulinoma tissue fragments developed into spheroids during the first week of culturing and insulin secretion into the media was demonstrated. CONCLUSIONS: Insulinomas are rare and diagnostically challenging tumours. Intra-operative ultrasonography was superior to other imaging modalities to locate the lesion. In organ culture, insulinomas readily form spheroids which may be used to yield insight into beta-cell biology.

PMID: 18450205 [PubMed - in process]
Application of the intravenous glucose tolerance test and the minimal model to patients with insulinoma - insulin sensitivity (Si) and glucose effectiveness (Sg) before and after surgical excision.

Fetched: May 1st, 2008, 9:00pm EDT

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Application of the intravenous glucose tolerance test and the minimal model to patients with insulinoma - insulin sensitivity (Si) and glucose effectiveness (Sg) before and after surgical excision.

Clin Endocrinol (Oxf). 2008 Apr 28;

Authors: Vethakkan SR, Walters JM, Gooley JL, Boston RC, Ward GM

Background: The unmodified Frequently Sampled Intravenous Glucose Tolerance Test (FSIGT) has not previously been used to assess insulin/glucose kinetics in patients with insulinoma. Objective: To measure Insulin Sensitivity (Si) and Glucose Effectiveness (Sg) by means of the FSIGT in patients with insulinoma, before and after surgical removal of the tumour. Subjects and methods: FSIGTs were performed in 5 patients, before and ~3 months post-surgery, and in 11 controls. Si and Sg were estimated using Minimal Model computer analysis of dynamic glucose and insulin data. Results: Si was lower in insulinoma patients before, compared with after surgery (3.37 + 0.62 vs. 6.24 + 1.09SE [x 10(-4)]min(-1).uU(-1).ml(-1), p<0.05). Sg was similar in patients pre- and post-surgery (3.0 + 0.67 vs 2.4 + 0.6 [x10(-2)]min(-1), NS). Conclusions: Insulin sensitivity improves after excision of an insulinoma. Glucose effectiveness is not influenced by chronic hyperinsulinaemia and hypoglycaemia.

PMID: 18445139 [PubMed - as supplied by publisher]
Rebaudioside A directly stimulates insulin secretion from pancreatic beta cells: a glucose-dependent action via inhibition of ATP-sensitive K(+)-channels.

Fetched: April 26th, 2008, 9:00pm EDT

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Rebaudioside A directly stimulates insulin secretion from pancreatic beta cells: a glucose-dependent action via inhibition of ATP-sensitive K(+)-channels.

Diabetes Obes Metab. 2008 Apr 22;

Authors: Abudula R, Matchkov VV, Jeppesen PB, Nilsson H, Aalkjær C, Hermansen K

Recently, we showed that rebaudioside A potently stimulates the insulin secretion from isolated mouse islets in a dose-, glucose- and Ca(2+)-dependent manner. Little is known about the mechanisms underlying the insulinotropic action of rebaudioside A. The aim of this study was to define the signalling system by which, rebaudioside A acts. Isolated mouse islets were used in the cAMP[(125)I] scintillation proximity assay to measure total cAMP level, and in a luminometric method to measure intracellular ATP and ADP concentrations. Conventional and permeabilized whole-cell configuration of the patch-clamp technique was used to verify the effect of rebaudioside A on ATP-sensitive K(+)-channels from dispersed single beta cells from isolated mouse islets. Insulin was measured by radioimmunoassay from insulinoma MIN6 cells. In the presence of 16.7 mM glucose, the addition of the maximally effective concentration of rebaudioside A (10(-9) M) increased the ATP/ADP ratio significantly, while it did not change the intracellular cAMP level. Rebaudioside A (10(-9) M) and stevioside (10(-6) M) reduced the ATP-sensitive potassium channel (K(ATP)) conductance in a glucose-dependent manner. Moreover, rebaudioside A stimulated the insulin secretion from MIN6 cells in a dose- and glucose-dependent manner. In conclusion, the insulinotropic effect of rebaudioside A is mediated via inhibition of ATP-sensitive K(+)-channels and requires the presence of high glucose. The inhibition of ATP-sensitive K(+)-channels is probably induced by changes in the ATP/ADP ratio. The results indicate that rebaudioside A may offer a distinct therapeutic advantage over sulphonylureas because of less risk of causing hypoglycaemia.

PMID: 18435771 [PubMed - as supplied by publisher]
Endocrine gland-derived vascular endothelial growth factor in rat pancreas: genetic expression and testosterone regulation.

Fetched: April 25th, 2008, 9:00pm EDT

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Endocrine gland-derived vascular endothelial growth factor in rat pancreas: genetic expression and testosterone regulation.

J Endocrinol. 2008 May;197(2):309-14

Authors: Morales A, Morimoto S, Díaz L, Robles G, Díaz-Sánchez V

Endocrine gland-derived vascular endothelial growth factor (EG-VEGF) is an endothelial cell mitogen, expressed essentially in steroidogenic cells. Recently, the expression of EG-VEGF in normal human pancreas and pancreatic adenocarcinoma has been demonstrated. Epidemiologically, pancreatic carcinogenesis is more frequent in males than females, and given that androgen receptors and testosterone biotransformation have been described in pancreas, we hypothesized that testosterone could participate in the regulation of EG-VEGF expression. In this study, we investigated the regulation of EG-VEGF gene expression by testosterone in normal rat pancreatic tissue and rat insulinoma cells (RINm5F). Total RNA was extracted from rat pancreas and cultured cells. Gene expression was studied by real-time PCR and protein detection by immunohistochemistry. Serum testosterone was quantified by RIA. Results showed that EG-VEGF is expressed predominantly in pancreatic islets and vascular endothelium, as well as in RINm5F cells. EG-VEGF gene expression was lower in the pancreas of rats with higher testosterone serum levels. A similar effect that was reverted by flutamide was observed in testosterone-treated RINm5F cells. In summary, testosterone down-regulated EG-VEGF gene expression in rat pancreatic tissue and RINm5F cells. This effect could be mediated by the androgen receptor. To our knowledge, this is the first time that a direct effect of testosterone on EG-VEGF gene expression in rat pancreas and RINm5F cells is demonstrated.

PMID: 18434360 [PubMed - in process]
Pancreatic beta-cells express hepcidin, an iron-uptake regulatory peptide.

Fetched: April 25th, 2008, 9:00pm EDT

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Pancreatic beta-cells express hepcidin, an iron-uptake regulatory peptide.

J Endocrinol. 2008 May;197(2):241-9

Authors: Kulaksiz H, Fein E, Redecker P, Stremmel W, Adler G, Cetin Y

Body iron is involved in various vital functions. Its uptake in the intestine is regulated by hepcidin, a bioactive peptide originally identified in plasma and urine and subsequently in the liver. In the present study, we provide evidence at the transcriptional and translational levels that hepcidin is also expressed in the pancreas of rat and man. Immunohistochemical studies localized the peptide exclusively to beta-cells of the islets of Langerhans. Immunoelectron microscopical analyses revealed that hepcidin is confined to the insulin-storing beta-cell secretory granules. As demonstrated in insulinoma-derived RINm5F cells, the expression of hepcidin in beta-cells is regulated by iron. Based on the present findings we conclude that pancreatic islets are an additional source of the peptide hepcidin. The localization of this peptide to beta-cells suggests that pancreatic beta-cells may be involved in iron metabolism in addition to their genuine function in blood glucose regulation. In view of the various linked iron/glucose disorders in the pancreas, the present findings may provide an insight into the phenomenology of intriguing mutual relationships between iron and glucose metabolisms.

PMID: 18434354 [PubMed - in process]
Insulinoma cell CaSR influences insulin secretion in a case with concurrent familial hypocalciuric hypercalcemia and malignant metastatic insulinoma.

Fetched: April 24th, 2008, 9:00pm EDT

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Insulinoma cell CaSR influences insulin secretion in a case with concurrent familial hypocalciuric hypercalcemia and malignant metastatic insulinoma.

Eur J Endocrinol. 2008 Apr 22;

Authors: Ono Y, Oda N, Ishihara S, Shimomura A, Hayakawa N, Suzuki A, Horiguchi A, Senda T, Miyakawa S, Itoh M

Context and objective Arterial stimulation and venous sampling (ASVS) is an important technique for localizing insulinoma. The principle behind ASVS is that insulin secretion is promoted from insulinoma cells by the injection of calcium into the insulinoma-feeding artery. However, the mechanism for ASVS-induced insulin secretion remains unclear. Both insulinoma and familial hypocalciuric hypercalcemia (FHH) are rare diseases. This study reports on a case in which both of these diseases occur concurrently. Design and Patient The patient with FHH also suffered from insulinoma. We reasoned that insulin secretion for ASVS is dependent on the calcium sensing receptor (CaSR). AVSV was performed on this patient. The expression of the CaSR protein and corresponding mRNA were confirmed. Results No significant changes in the plasma levels of insulin and C-peptide were observed during ASVS. The patient was clinically diagnosed as having FHH. We confirmed that a mutation in the CaSR gene was present in the genomic DNA of this patient and that there were no mutations in the MEN1 gene. In addition, expression of both CaSR mRNA and CaSR protein was confirmed in the insulinoma samples. Conclusion These results suggest that the CaSR gene is involved in ASVS-induced insulin secretion.

PMID: 18430790 [PubMed - as supplied by publisher]
N-terminal acetylation protects glucagon-like peptide GLP-1-(7-34)-amide from DPP-IV-mediated degradation retaining cAMP- and insulin-releasing capacity.

Fetched: April 22nd, 2008, 9:00pm EDT

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N-terminal acetylation protects glucagon-like peptide GLP-1-(7-34)-amide from DPP-IV-mediated degradation retaining cAMP- and insulin-releasing capacity.

Eur J Med Res. 2008 Feb 25;13(2):73-8

Authors: John H, Maronde E, Forssmann WG, Meyer M, Adermann K

Since its discovery glucagon-like peptide-1 (GLP-1) is investigated as a treatment for type II diabetes based on its major function as insulin secretagogue. A therapeutic use is, however, limited by its short biological half-life in the range of minutes, predominantly caused via degradation catalyzed by dipeptidyl peptidase IV (DPP-IV). Therefore, we aimed to design a GLP-1 analogue exhibiting resistance against DPP-IV-catalyzed inactivation while retaining its biological activity. By means of matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) we have studied the stability of the N-terminally blocked new analogue Ac-GLP-1-(7-34)-amide against DPP-IV and compared it with both unblocked GLP-1-(7-34)-amide and the major naturally occurring form GLP-1-(7-36)-amide. GLP-1-(7-36)-amide and the C-terminally two amino acid residues shorter GLP-1-(7-34)-amide rapidly generated peptide fragments truncated by the N-terminal dipeptide. In contrast, the N-terminal blocked Ac-GLP-1-(7-34)-amide was not degraded in the presence of DPP-IV over a period of at least two hours. Ac-GLP-1-(7-34)-amide induced a concentration-dependent increase of intracellular cAMP production and insulin release from rat insulinoma RIN-m5F cells to an extent comparable to that found for the N-terminally unblocked peptides GLP-1-(7-34)-amide and GLP-1-(7-36)-amide. Ac-GLP-1-(7-34)-amide may thus have the potential to act as a new long-acting GLP-1 analogue with significant resistance against DPP-IV and retained biological activity in vitro. Further research is required to investigate whether Ac-GLP-1-(7-34)-amide also exhibits its characteristics in animal models and humans.

PMID: 18424366 [PubMed - in process]
QSAR modelling of pancreatic beta-cell K(ATP) channel openers R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans using MLR-FA techniques.

Fetched: April 21st, 2008, 9:00pm EDT

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QSAR modelling of pancreatic beta-cell K(ATP) channel openers R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans using MLR-FA techniques.

Eur J Med Chem. 2008 Mar 12;

Authors: Alam SM, Samanta S, Halder AK, Basu S, Jha T

Potassium (K(+)) channel openers are a diverse group of compounds which are used for the treatment of diseases like angina pectoris, hypertension, congestive heart failure, anti-hypoglycemic (insulinoma), bronchial asthma, etc. R/S-3,4-dihydro-2,2-dimethyl-6-halo-4-(substituted phenylaminocarbonylamino)-2H-1-benzopyrans are a new series of ATP-sensitive potassium (K(ATP-pbeta)) channel openers selective towards pancreatic beta-cells. QSAR modelling was done on these series of compounds to find a more active and selective K(ATP-pbeta) channel opener selective towards beta-cells of pancreatic tissues. Wang-Ford charges, partition coefficient, molar refractivity, principle moment of inertia at X, Y and Z axes are used as predictor variables and logarithm of percentage of residual insulin secretion is treated as response variable for the modelling. Multiple linear regressions with factor analysis were performed to develop QSAR models. Four equations were obtained using different combinations of the predictor variables based on factor loadings. Regression coefficients of all descriptors used are significant at more than 95% level. Results showed that Wang-Ford charges on atom numbers 11, 17, 18, 19 and 21 are important for the inhibition of residual insulin secretion. The presence of electron withdrawing group at m- and p-position of phenyl ring B is required for the inhibition. The energy minimized geometry of the most active compound supported our modelling.

PMID: 18420311 [PubMed - as supplied by publisher]
Dual-phase computed tomographic angiography in three dogs with pancreatic insulinoma.

Fetched: April 21st, 2008, 9:00pm EDT

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Dual-phase computed tomographic angiography in three dogs with pancreatic insulinoma.

Vet Radiol Ultrasound. 2008 Mar-Apr;49(2):141-8

Authors: Mai W, Cáceres AV

This article describes the findings in three dogs with histopathologically confirmed pancreatic insulinoma using dual-phase computed tomographic angiography (CTA). In all three dogs, dual-phase CTA findings identified lesions not seen on ultrasonography, including the actual identification of the primary pancreatic neoplasm in two dogs. CTA findings were in agreement with the surgical and histopathological findings. In two dogs, the insulinomas were found to have a strong enhancement during the arterial phase of the study but not at the other phases, which stresses the importance of dual-phase computed tomography for the diagnosis of this type of pancreatic neoplasia, in agreement with current knowledge in humans.

PMID: 18418994 [PubMed - in process]
Identification of an INSM1 Binding Site in the Insulin Promoter: Negative Regulation of the Insulin Gene Transcription.

Fetched: April 18th, 2008, 9:00pm EDT

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Identification of an INSM1 Binding Site in the Insulin Promoter: Negative Regulation of the Insulin Gene Transcription.

J Endocrinol. 2008 Apr 16;

Authors: Wang HW, Muguira M, Liu WD, Zhang T, Chen C, Aucoin R, Breslin M, Lan M

In this study, an INSM1-binding site in the proximal promoter sequence of the insulin gene was identified. Co-transfection of INSM1 with rat insulin I/II promoter-driven reporter genes exhibited a 40-50% inhibitory effect on reporter activity. Mutational experiments were performed by introducing a substitution, GG to AT, into the INSM1 core binding site of the rat insulin I/II promoters. The mutated insulin promoter exhibited a 3-20 fold increase of promoter activity over the wild type promoter in several insulinoma cell lines. Moreover, INSM1 over-expression exhibited no inhibitory effect on the mutated insulin promoter. Chromatin immunoprecipitation assays using betaTC-1, mouse fetal pancreas, and Ad-INSM1 transduced human islets demonstrated that INSM1 occupies the endogenous insulin promoter sequence containing the INSM1-binding site in vivo. Binding of the INSM1 to the insulin promoter could suppress approximately 50% of insulin message in human islets. The mechanism for transcriptional repression of the insulin gene by INSM1 is mediated through the recruitment of cyclin D1 and histone deacetylase-3 to the insulin promoter. Anti-INSM1 or anti-cyclin D1 morpholino treatment of fetal mouse pancreas enhances the insulin promoter activity. These data strongly support that INSM1 is a new zinc-finger transcription factor that modulates insulin gene transcription during early pancreas development.

PMID: 18417529 [PubMed - as supplied by publisher]
[Manejo diagnóstico del insulinoma pancreático.]

Fetched: April 18th, 2008, 9:00pm EDT

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[Manejo diagnóstico del insulinoma pancreático.]

Rev Esp Enferm Dig. 2008 Mar;100(3):183-4

Authors: Varas Lorenzo MJ

PMID: 18416649 [PubMed - in process]
Peritumoral steatosis associated with insulinomas: appearance at imaging.

Fetched: April 17th, 2008, 9:00pm EDT

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Peritumoral steatosis associated with insulinomas: appearance at imaging.

Abdom Imaging. 2008 Apr 15;

Authors: Atwell TD, Lloyd RV, Nagorney DM, Fidler JL, Andrews JC, Reading CC

We report three patients with insulinoma tumors and distinct peritumoral steatosis, well demonstrated with several imaging modalities. This unique appearance can aid in pre-operative diagnosis and guide biopsy.

PMID: 18414933 [PubMed - as supplied by publisher]
The effects of cell density and device arrangement on the behavior of macroencapsulated beta-cells.

Fetched: April 15th, 2008, 9:00pm EDT

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The effects of cell density and device arrangement on the behavior of macroencapsulated beta-cells.

Cell Transplant. 2007;16(8):765-74

Authors: La Flamme KE, LaTempa TJ, Grimes CA, Desai TA

Over the last several decades, considerable research has focused on the development of cell encapsulation technology to treat a number of diseases, especially type 1 diabetes. One of the key advantages of cell encapsulation is that it permits the use of xenogenic tissue, particularly animal-derived cell lines. This is an attractive idea, because it circumvents the issue of a limited human organ supply. Furthermore, as opposed to whole islets, cell lines have a better proliferative capacity and can easily be amplified in culture to provide an endless supply of uniform cells. We have previously described a macroencapsulation device for the immunoisolation of insulin-secreting 1-cells. The aim of this work was to optimize the viability and insulin secretion of cells encapsulated within this device. Specifically, the effects of cell packing density and device membrane configuration were investigated. The results indicated that cell density plays an important role in the secretory capacity of the cells, with higher cell density leading to increased insulin secretion. Increasing the transport area of the capsule by modifying the membrane configuration also led to an improvement in the insulin output of the device.

PMID: 18087997 [PubMed - indexed for MEDLINE]
Detection Of Transketolase In Bone Marrow-Derived Insulin Producing Cells: Benfotiamine Enhances Insulin Synthesis And Glucose Metabolism.

Fetched: April 9th, 2008, 9:01pm EDT

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Detection Of Transketolase In Bone Marrow-Derived Insulin Producing Cells: Benfotiamine Enhances Insulin Synthesis And Glucose Metabolism.

Stem Cells Dev. 2008 Apr 7;

Authors: Oh SH, Witek RP, Bae SH, Darwiche HA, Jung Y, Pi L, Brown A, Petersen BE

Adult bone marrow (BM) derived insulin-producing cells (IPCs) are capable of regulating blood glucose levels in chemically induced hyperglycemic mice. Using cell transplantation therapy, fully functional BM-derived IPCs help to mediate treatment of diabetes mellitus. Here, we demonstrate the detection of the pentose phosphate pathway enzyme, transketolase, in BM-derived IPCs cultured under high glucose conditions. Benfotiamine, a known activator of transketolase, was not shown to affect the proliferation of insulinoma cell line, INS-1; however when INS-1 cells were cultured with oxythiamine, an inhibitor of transketolase, cell proliferation was suppressed. Treatment with benfotiamine activated glucose metabolism in INS-1 cells in high glucose culture conditions, and appeared to maximize the BM-derived IPCs ability to synthesize insulin. Benfotiamine was not shown to induce the glucose receptor Glut-2, however it was shown to activate glucokinase, the enzyme responsible for conversion of glucose to glucose-6-phosphate. Furthermore, benfotiamine-treated groups showed upregulation of the downstream glycolytic enzyme, glyceraldehyde phosphate dehydrogenase (GAPDH). However, in cells where the pentose phosphate pathway was blocked by oxythiamine treatment, there was a clear downregulation of Glut-2, glucokinase, insulin, and GAPDH. When benfotiamine was used to treat mice transplanted with BM-derived IPCs transplanted, their glucose level was brought to a normal range. The glucose challenge of normal mice treated with benfotiamine lead to rapidly normalized blood glucose levels. These results indicate that benfotiamine activates glucose metabolism and insulin synthesis to prevent glucose toxicity caused by high concentrations of blood glucose in diabetes mellitus.

PMID: 18393672 [PubMed - as supplied by publisher]
[Laparoscopic excision of pancreatic insulinoma. Experience with 3 cases]

Fetched: April 9th, 2008, 9:01pm EDT

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[Laparoscopic excision of pancreatic insulinoma. Experience with 3 cases]

Chir Ital. 2008 Jan-Feb;60(1):9-13

Authors: Pugliese R, Boniardi M, Sansonna F, Maggioni D, Scandroglio I, Costanzi A, Rapetti R, Oppizzi G, Loli P

Laparoscopic treatment of lesions of the distal pancreas has gained favour worldwide in the last decade. The objective of this study was to analyze 3 cases of insulinoma successfully treated with the laparoscopic approach. From 2000 to 2007 in our institution 3 patients with insulinoma of the left pancreas were treated with a laparoscopic approach. The insulinoma was diagnosed by helical CT scan, Two cases were treated by left pancreatectomy and one by enucleation. The resections were achieved by laparoscopy with no conversion to laparotomy. There were no intraoperative complications. Average blood loss was 180 mi (range: 150-350). Mean operative time was 232 minutes (range: 225-240). Morbidity consisted in one mild pancreatic fistula after left pancreatectomy that was healed by conservative treatment after 24 days. The mean hospital stay was 13 days (range: 10-20). During the follow-up insulinoma symptoms have disappeared in all patients. This study confirms the feasibility of laparoscopic resection for insulinoma. Operative times were quite acceptable and the conversion rate was nil. Times to oral intake and walking were shorter than after open surgery, as was the mean postoperative hospital stay.

PMID: 18389742 [PubMed - in process]
The CM cell line derived from liver metastasis of malignant human insulinoma is not a valid beta cell model for in vitro studies.

Fetched: April 4th, 2008, 9:00pm EDT

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The CM cell line derived from liver metastasis of malignant human insulinoma is not a valid beta cell model for in vitro studies.

J Cell Physiol. 2008 Apr 2;

Authors: Gragnoli C

The CM cell line is derived from the ascitic fluid of a patient with liver metastasis of a malignant insulinoma. Insulin levels potentially derived from the insulinoma were detected only once in vivo in the subject with the malignant pancreatic tumor and hypoglycemia. After multiple unsuccessful attempts to detect insulin in the culture medium, insulin levels were again detected only once in vitro. In our repeated experiments, we extensively exposed early-passages of the CM cell line to 0.91 mM glucose and acutely to increasingly higher glucose concentrations (2.75, 5.5, 11, and 22 mM) and did not detect any insulin secretion as well as any significant insulin cell content. The electronic microscopic examinations of several vials containing early-passages of the CM cell lines showed a polyclonal nature of the cells mostly resembling fibroblasts. The karyotype detected severe and consistent chromosomal aberrations of the CM cell line, including the chromosome 11 tetraploidy and the genetic material translocation in three out of four chromosomes 11 at the insulin gene locus 11p15.1. These data, unfortunately, exclude the possibility of considering the CM cell line as a valid beta cell model in vitro. J. Cell. Physiol. (c) 2008 Wiley-Liss, Inc.

PMID: 18384119 [PubMed - as supplied by publisher]
Overexpression of vascular endothelial growth factor in vitro using deferoxamine: a new drug to increase islet vascularization during transplantation.

Fetched: April 1st, 2008, 9:03pm EDT

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Overexpression of vascular endothelial growth factor in vitro using deferoxamine: a new drug to increase islet vascularization during transplantation.

Transplant Proc. 2008 Mar;40(2):473-6

Authors: Langlois A, Bietiger W, Mandes K, Maillard E, Belcourt A, Pinget M, Kessler L, Sigrist S

During pancreatic islet transplantation, delayed and insufficient revascularization can deprive islets of oxygen and nutrients, resulting in cell death and early graft failure. Deferoxamine (DFO), an iron chelator, increases vascular endothelial growth factor (VEGF) expression in cells. The aim of this work was to study the effect of DFO on beta-cell and pancreatic islet viability as well as VEGF expression. beta-cell lines from rat insulinoma (Rin m5f) and primary cultures of pancreatic islets from Wistar rats were incubated with DFO (10, 100, and 1000 mumol/L). The viability was evaluated using fluorescein diacetate/propidium iodide for dying pancreatic islets and using cell titers for Rin m5f. Expression of VEGF messenger RNA (mRNA) was quantified using reverse transcriptase polymerase chain reaction (RT-PCR). Finally, VEGF secretion was determined using enzyme-linked immunosorbent assays at 1 to 3 days after treatment. The addition of 10 mumol/L of DFO preserved Rin m5F viability at 24 hours after treatment (10 mumol/L; 101.33% +/- 5.66%; n = 7). However, 100 and 1000 mumol/L of DFO induced cell death (68.92% +/- 5.83% and 65.89% +/- 5.83%, respectively; n = 4). In the same way, viability of pancreatic islets in the presence of DFO was preserved. RT-PCR analysis showed stimulation of VEGF mRNA in the presence of 10 mumol/L of DFO in islets at 3 days after culture. Finally, 10 mumol/L of DFO stimulated secretion of VEGF 7.95 +/- 0.84 versus 1.80 +/- 1.10 pg/mug total protein with 10 mumol/L of DFO in rat islets at 3 days after culture, n = 3; P < .001). The use of DFO to stimulate VEGF expression and increase islet vascularization may be a realistic approach to improve islet viability during transplantation.

PMID: 18374106 [PubMed - in process]
Biodritin microencapsulated human islets of langerhans and their potential for type 1 diabetes mellitus therapy.

Fetched: April 1st, 2008, 9:03pm EDT

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Biodritin microencapsulated human islets of langerhans and their potential for type 1 diabetes mellitus therapy.

Transplant Proc. 2008 Mar;40(2):433-5

Authors: Campos-Lisbôa AC, Mares-Guia TR, Grazioli G, Goldberg AC, Sogayar MC

BACKGROUND: Microencapsulation of pancreatic islets with polymeric compounds constitutes an attractive alternative therapy for type 1 diabetes mellitus. The major limiting factor is the availability of a biocompatible and mechanically stable polymer. We investigated the potential of Biodritin, a novel polymer constituted of alginate and chondroitin sulfate, for islet microencapsulation. METHODS: Biodritin microcapsules were obtained using an air jet droplet generator and gelated with barium or calcium chloride. Microencapsulated rat insulinoma RINm5F cells were tested for viability using the [3-(4,5-dimetyl-thiazol-2-yl)-2,5-diphenyl-tetrazoliumbromide] [MTT] colorimetric assay. Microencapsulated rat pancreatic islets were coincubated with macrophages derived from mouse peritoneal liquid to assess the immunomodulatory potential of the microcapsules, using quantitative real time-PCR (qPCR). Biodritin biocompatibility was demonstrated by subcutaneous injection of empty microcapsules into immunocompetent Wistar rats. Insulin secretion by microencapsulated human pancreatic islets was evaluated using an electrochemoluminescent assay. Microencapsulated human islets transplanted into chemically induced diabetic mice were monitored for reversal of hyperglycemia. RESULTS: The metabolic activity of microencapsulated RINm5F cells persisted for at least 15 days. Interleukin-1beta expression by macrophages was observed during coculture with islets microencapsulated with Biodritin-CaCl(2), but not with Biodritin-BaCl(2). No statistical difference in glucose-stimulated insulin secretion was observed between nonencapsulated and microencapsulated islets. Upon microencapsulated islet transplantation, the blood glucose level of diabetic mice normalized; they remained euglycemic for at least 60 days, displaying normal oral glucose tolerance tests. CONCLUSION: This study demonstrated that Biodritin can be used for islet microencapsulation and reversal of diabetes; however, further investigations are required to assess its potential for long-term transplantation.

PMID: 18374092 [PubMed - in process]
The ATP/DNA Ratio Is a Better Indicator of Islet Cell Viability Than the ADP/ATP Ratio.

Fetched: April 1st, 2008, 9:03pm EDT

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The ATP/DNA Ratio Is a Better Indicator of Islet Cell Viability Than the ADP/ATP Ratio.

Transplant Proc. 2008 Mar;40(2):346-50

Authors: Suszynski TM, Wildey GM, Falde EJ, Cline GW, Maynard KS, Ko N, Sotiris J, Naji A, Hering BJ, Papas KK

Real-time, accurate assessment of islet viability is critical for avoiding transplantation of nontherapeutic preparations. Measurements of the intracellular ADP/ATP ratio have been recently proposed as useful prospective estimates of islet cell viability and potency. However, dead cells may be rapidly depleted of both ATP and ADP, which would render the ratio incapable of accounting for dead cells. Since the DNA of dead cells is expected to remain stable over prolonged periods of time (days), we hypothesized that use of the ATP/DNA ratio would take into account dead cells and may be a better indicator of islet cell viability than the ADP/ATP ratio. We tested this hypothesis using mixtures of healthy and lethally heat-treated (HT) rat insulinoma cells and human islets. Measurements of ATP/DNA and ADP/ATP from the known mixtures of healthy and HT cells and islets were used to evaluate how well these parameters correlated with viability. The results indicated that ATP and ADP were rapidly (within 1 hour) depleted in HT cells. The fraction of HT cells in a mixture correlated linearly with the ATP/DNA ratio, whereas the ADP/ADP ratio was highly scattered, remaining effectively unchanged. Despite similar limitations in both ADP/ADP and ATP/DNA ratios, in that ATP levels may fluctuate significantly and reversibly with metabolic stress, the results indicated that ATP/DNA was a better measure of islet viability than the ADP/ATP ratio.

PMID: 18374063 [PubMed - in process]
[Insulinoma]

Fetched: March 29th, 2008, 9:00pm EDT

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[Insulinoma]

Klin Med (Mosk). 2008;86(2):70-6

Authors:

The authors review statistical, pathogenic, and clinical aspects of insulinima, a rare pancreatic tumor growing from beta-cells of islets of Langerhans. Its functioning is associated with periodical impulsive ejection of insulin, its precursors, and relative peptides in large quantities, which results in hypoglycemic state. Acute neuropsychic disturbances, which may include depression of consciousness of varios degrees or psychic and motor disturbances, are a clinical of hypoglycemic attacks. When consciousness remains, the leading clinical syndrome is vegetative dysfunction. However, hypoglycemia does not have specific signs. This state should be differentiated from neurological, psychic, cardiovascular problems etc. The article describes diagnostic methods in insulinoma; their informative value is evaluated. Special attention is paid to cases of wrong diagnosis. The authors describe their own observation of insulinoma, which illustrates difficulties in its revealing. At the same time, the authors affirm that sufficient information make it possible for doctors to establish timely diagnosis of this disease.

PMID: 18368799 [PubMed - in process]
Malignant insulinoma presenting as metastatic liver tumor. Case report and review of the literature.

Fetched: March 28th, 2008, 9:00pm EDT

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Malignant insulinoma presenting as metastatic liver tumor. Case report and review of the literature.

J Exp Clin Cancer Res. 2007 Dec;26(4):603-7

Authors: Baldelli R, Ettorre G, Vennarecci G, Pasimeni G, Carboni F, Lorusso R, Barnabei A, Appetecchia M

Insulin-secreting tumors are the commonest hormone-producing neoplasm of the gastrointestinal tract. They occur with an incidence of 4 cases per million per year. About 10% of them are metastatic and malignant insulinomas very rarely observed in children and in elderly. We report a rare case of very large malignant insulinoma in a 71-year-old woman admitted in our Oncological Institute on October 2005. She presented with fasting hypoglicemia (blood glucose 35 mg/dl) and high serum insulin levels (insulin 115.9 microU/ml). A computerized tomographic scan showed a pancreatic tail lesion of about 6 cm in max diameter and multiple liver metastases. A whole body scintiscan using 111In-DTPA-D-Phe1-octreotide was made and an increased uptake in the tail of the pancreas has been found. The patient was submitted to liver biopsy and the diagnosis of a metastatic insulin-secreting tumor was immunoistochemically confirmed. Due to the presence of some hypoglicemic episodes uncontrolled by medical treatment, on December 2005 the patient was admitted to surgical intervention with a body and tail pancreatic resection. Post-operatively the patient experienced again syncope with hypoglycemia and hyperinsulinemia. It was then decided to start a schedule of treatment with somatostatin analog (octreotide subcutaneously 500 microg three times a day) with a good control of blood glucose levels (101 mg/dl). A trans-arterial chemioembolization was planned but the patient died for pancreatic and cardiovascular complications before this treatment started.

PMID: 18365560 [PubMed - in process]
Involvement of the cGMP pathway in mediating the insulin-inhibitory effect of melatonin in pancreatic beta-cells.

Fetched: March 28th, 2008, 9:00pm EDT

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Involvement of the cGMP pathway in mediating the insulin-inhibitory effect of melatonin in pancreatic beta-cells.

J Pineal Res. 2008 Mar 24;

Authors: Stumpf I, Mühlbauer E, Peschke E

Recent investigations have demonstrated an influence of melatonin on insulin secretion in pancreatic beta-cells. The effects are receptor-mediated via two parallel signaling pathways. The aim of this study was to examine the relevance of a second melatonin receptor (MT2) as well as the involvement of a third signaling cascade in mediating melatonin effects, i.e. the cyclic guanosine monophosphate (cGMP) pathway. Our results demonstrate that the insulin-inhibiting effect of melatonin could be partly reversed by preincubation with the unspecific melatonin receptor antagonist luzindole as well as by the MT2-receptor-specific antagonist 4P-PDOT (4-phenyl-2-propionamidotetraline). As melatonin is known to modulate cGMP concentration via the MT2 receptor, these data indicate transmission of the melatonin effects via the cGMP transduction cascade. Molecular investigations established the presence of different types of guanylate cyclases, cGMP-specific phosphodiesterases and cyclic nucleotide-gated channels in rat insulinoma beta-cells (INS1). Moreover, variations in mRNA expression were found when comparing day and night values as well as different states of glucose metabolism. Incubation experiments provided evidence that 3-isobutyl-1-methylxanthine (IBMX)-stimulated cGMP concentrations were significantly decreased in INS1 cells exposed to melatonin for 1 hr in a dose- and time-dependent manner. This effect could also be reversed by application of luzindole and 4P-PDOT. Stimulation with 8-Br-cGMP resulted in significantly increased insulin production. In conclusion, it could be demonstrated that the melatonin receptor subtype MT2 as well as the cGMP signaling pathway are involved in mediating the insulin-inhibiting effect of melatonin.

PMID: 18363673 [PubMed - as supplied by publisher]
Diminished phosphodiesterase-8B potentiates biphasic insulin response to glucose.

Fetched: March 28th, 2008, 9:00pm EDT

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Diminished phosphodiesterase-8B potentiates biphasic insulin response to glucose.

Endocrinology. 2008 Feb;149(2):741-8

Authors: Dov A, Abramovitch E, Warwar N, Nesher R

cAMP activates multiple signal pathways, crucial for the pancreatic beta-cells function and survival and is a major potentiator of insulin release. A family of phosphodiesterases (PDEs) terminate the cAMP signals. We examined the expression of PDEs in rat beta-cells and their role in the regulation of insulin response. Using RT-PCR and Western blot analyses, we identified PDE3A, PDE3B, PDE4B, PDE4D, and PDE8B in rat islets and in INS-1E cells and several possible splice variants of these PDEs. Specific depletion of PDE3A with small interfering (si) RNA (siPDE3A) led to a small (67%) increase in the insulin response to glucose in INS-1E cells but not rat islets. siPDE3A had no effect on the glucagon-like peptide-1 (10 nmol/liter) potentiated insulin response in rat islets. Depletion in PDE8B levels in rat islets using similar technology (siPDE8B) increased insulin response to glucose by 70%, the potentiation being of similar magnitude during the first and second phase insulin release. The siPDE8B-potentiated insulin response was further increased by 23% when glucagon-like peptide-1 was included during the glucose stimulus. In conclusion, PDE8B is expressed in a small number of tissues unrelated to glucose or fat metabolism. We propose that PDE8B, an 3-isobutyl-1-methylxanthine-insensitive cAMP-specific phosphodiesterase, could prove a novel target for enhanced insulin response, affecting a specific pool of cAMP involved in the control of insulin granule trafficking and exocytosis. Finally, we discuss evidence for functional compartmentation of cAMP in pancreatic beta-cells.

PMID: 17991719 [PubMed - indexed for MEDLINE]
Differential expression of the five somatostatin receptor subtypes in human benign and malignant insulinomas - predominance of receptor subtype 4.

Fetched: March 26th, 2008, 9:00pm EDT

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Differential expression of the five somatostatin receptor subtypes in human benign and malignant insulinomas - predominance of receptor subtype 4.

Endocr Pathol. 2007;18(2):79-85

Authors: Portela-Gomes GM, Stridsberg M, Grimelius L, Rorstad O, Janson ET

Insulinomas constitute a subgroup of pancreatic endocrine tumors showing B cell differentiation and clinical symptoms related to inappropriate insulin secretion (WHO). Many endocrine tumors express somatostatin receptors (sstrs), which can be visualized by octreotide scintigraphy; however, about half of all insulinomas are reported to be negative. Previous immunohistochemical investigations with antibodies to sstr subtypes 1, 2, 3, and 5 have revealed differences in expression between various neuroendocrine tumors. In the present study, the immunoreactivity to all five human sstr was studied in ten benign and six malignant human insulinomas. Sstr4 was the receptor subtype most frequently expressed in both benign and malignant tumors. A difference in the immunohistochemical sstr5 expression pattern was seen between benign and malignant tumors: Three of the six malignant tumors, but none of the benign tumors, expressed sstr5. The other receptor subtypes were expressed in low numbers with no difference between benign and malignant tumors. The finding of a strong expression of sstr4 in both benign and malignant insulinomas suggests that this receptor subtype could be of importance for diagnostic and therapeutic use.

PMID: 17916997 [PubMed - indexed for M

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Pancreas (48 unread)

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