Rare Cancer News & Clinical Trials

Pancreas (69 unread)

Capecitabine, Temozolomide and Bevacizumab for Metastatic or Unresectable Pancreatic Neuroendocrine Tumors

Posted: January 10th, 2012, 8:00am MST

Conditions: Gastrinoma; Glucagonoma; Insulinoma; Pancreatic Polypeptide Tumor; Recurrent Islet Cell Carcinoma; Recurrent Pancreatic Cancer; Somatostatinoma; Stage III Pancreatic Cancer; Stage IV Pancreatic Cancer
Interventions: Drug: capecitabine; Drug: temozolomide; Biological: bevacizumab
Sponsors: Stanford University; National Cancer Institute (NCI)
Not yet recruiting - verified January 2012

Conga challenge to fund research into rare cancer - Evening Standard

Posted: December 21st, 2011, 12:35am MST

Evening Standard

Conga challenge to fund research into rare cancer
Evening Standard
Natalie Lobel, 32, from Tooting, was diagnosed with malignant insulinoma, a form of neuroendocrine cancer, this year after she suffered a huge seizure and her blood sugar levels dropped dangerously low. Miss Lobel was told the condition was so ...

The Nuclear Orphan Receptor Nur77 Is a Lipotoxicity Sensor Regulating Glucose-Induced Insulin Secretion in Pancreatic β-Cells.

Fetched: February 5th, 2012, 10:00pm MST

The Nuclear Orphan Receptor Nur77 Is a Lipotoxicity Sensor Regulating Glucose-Induced Insulin Secretion in Pancreatic β-Cells.

Mol Endocrinol. 2012 Feb 2;

Authors: Briand O, Helleboid-Chapman A, Ploton M, Hennuyer N, Carpentier R, Pattou F, Vandewalle B, Moerman E, Gmyr V, Kerr-Conte J, Eeckhoute J, Staels B, Lefebvre P

Abstract
The NR4A orphan nuclear receptors Nur77, Nurr1, and Nor1 exert multiple cellular and metabolic functions. These transcriptional regulators are activated in response to extracellular stresses, including lipotoxic fatty acids (FA) and proinflammatory cytokines. The contribution of NR4As to β-cell pathophysiology is, however, unknown. We have therefore examined the role of NR4As as downstream contributors to FA-induced β-cell dysfunctions. Human pancreatic islets and insulinoma β-cells were used to determine transcriptional programs elicited by NR4A, which were compared to those triggered by palmitate treatment. Functional studies evaluated the consequence of an increased NR4A expression on insulin biosynthesis and secretion and cell viability in insulinoma β-cells. FA and cytokine treatment increased NR4A expression in pancreatic β-cells, with Nur77 being most highly inducible in murine β-cells. Nur77, Nurr1, or Nor1 modulated common and distinct clusters of genes involved notably in cation homeostasis and insulin gene transcription. By altering zinc homeostasis, insulin gene transcription, and secretion, Nur77 was found to be a major transcriptional mediator of part of FA-induced β-cell dysfunctions. The repressive role of Nur77 in insulin gene regulation was tracked down to protein-protein interaction with FoxO1, a pivotal integrator of the insulin gene regulatory network. The present study identifies a member of the NR4A nuclear receptor subclass, Nur77/NR4A1, as a modulator of pancreatic β-cell biology. Together with its previously documented role in liver and muscle, its role in β-cells establishes Nur77 as an important integrator of glucose metabolism.

PMID: 22301783 [PubMed - as supplied by publisher]

Permalink for 'Time dynamics of autoantibodies are coupled to phenotypes and add to the heterogeneity of autoimmune diabetes in adults: the HUNT study, Norway.'

Time dynamics of autoantibodies are coupled to phenotypes and add to the heterogeneity of autoimmune diabetes in adults: the HUNT study, Norway.

Fetched: February 4th, 2012, 10:01pm MST

Time dynamics of autoantibodies are coupled to phenotypes and add to the heterogeneity of autoimmune diabetes in adults: the HUNT study, Norway.

Diabetologia. 2012 Feb 2;

Authors: Sørgjerd EP, Skorpen F, Kvaløy K, Midthjell K, Grill V

Abstract
AIMS: The aetiology of latent autoimmune diabetes in adults (LADA), assessed by autoimmune markers, is insufficiently clarified. We cross-sectionally investigated the prevalence and prospectively the prediabetic and postdiabetic presence of antibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 and zinc transporter 8 in LADA and in type 1 diabetes. METHODS: We included 208 'classic' type 1, 161 LADA and 302 type 2 diabetic cases from the second (HUNT2: 1995-1997) and third (HUNT3: 2006-2008) Nord-Trøndelag health surveys. Prospective data were available for 59 type 1, 44 LADA and 302 type 2 diabetic cases followed from HUNT2 to HUNT3. From HUNT3, 24 type 1 diabetic and 31 LADA incident cases were available. RESULTS: Cross-sectionally, 90% of LADA cases were positive for only one antibody (10% multiple-antibody-positive). Prospectively, 59% of GADA-positive LADA patients in HUNT2 were no longer positive in HUNT3. LADA patients who became negative possessed less frequently risk HLA haplotypes and were phenotypically more akin to those with type 2 diabetes than to those who stayed positive. Still, those losing positivity differed from those with type 2 diabetes by lower C-peptide levels (p = 0.009). Of incident LADA cases in HUNT3, 64% were already antibody-positive in HUNT2, i.e. before diabetes diagnosis. These incident LADA cases were phenotypically more akin to type 1 diabetes than were those who did not display positivity in HUNT2. CONCLUSION/INTERPRETATION: The pattern of antibodies, the postdiabetic loss or persistence as well as the prediabetic absence or presence of antibodies influence LADA phenotypes. Time-dependent presence or absence of antibodies adds new modalities to the heterogeneity of LADA.

PMID: 22297581 [PubMed - as supplied by publisher]

Insulinoma diagnosed in the postpartum: clinical and immunohistochemical features.

Fetched: February 4th, 2012, 10:01pm MST

Insulinoma diagnosed in the postpartum: clinical and immunohistochemical features.

Gynecol Endocrinol. 2012 Feb 2;

Authors: Rodrigues Queiróz AJ, Nazareno LS, Miranda JE, Borges de Azevedo AE, Teixeira da Cruz CA, Carneiro FP, Florêncio da Costa AC, Lofrano-Porto A

Abstract
Insulinomas are rare pancreatic β-cell tumors with an estimated incidence of 1:250.000 persons/year. We present a novel case of insulinoma manifesting immediately after childbirth. Eight days after delivery, a 21-year-old, previously healthy woman presented paresthesia in hands, upper and lower limbs muscle weakness with difficult walking, which worsened during breastfeeding sessions. Laboratory tests showed blood glucose levels between 37 and 55 mg/dL with inappropriately normal insulin levels (7.78 μUI/mL; normal range: 5-29). An abdominal computed tomography showed a nodular lesion measuring 2 cm at the head of the pancreas. Tumor enucleation resulted in complete resolution of hypoglycemia. Histopathological and immunohistochemical analysis were consistent with an insulinoma. About 27 cases of insulinoma associated with pregnancy have been reported to date, mostly diagnosed before the 16th week. The beginning of symptoms soon after delivery is less common. Understanding the interactions between pancreatic β-cell function and all the physiological metabolic and hormonal adaptations associated with gestation is essential for the adequate management of hypoglycemic disorders in pregnant women.

PMID: 22296647 [PubMed - as supplied by publisher]

Age-related islet autoantibody incidence in offspring of patients with type 1 diabetes.

Fetched: February 2nd, 2012, 10:01pm MST

Age-related islet autoantibody incidence in offspring of patients with type 1 diabetes.

Diabetologia. 2012 Jan 31;

Authors: Ziegler AG, Bonifacio E,

Abstract
AIMS/HYPOTHESIS: Seroconversion to islet autoantibodies precedes type 1 diabetes. This study aimed to identify periods of high seroconversion incidence, which could be targeted for mechanistic and therapeutic studies. METHODS: Incidence of islet autoantibodies was calculated in 1,650 genetically at-risk children followed with measurements of islet autoantibodies and thyroid autoantibodies at age 9 months and 2, 5, 8, 11, 14 and 17 years. Peak incidence periods were confirmed in a second cohort of 150 children followed until age 6 years with three-monthly samples up to age 3 years. RESULTS: Islet autoantibody incidence (per 1,000 person-years) was 18.5 until age 9 months, 21 from 9 months to 2 years and <10 for intervals after age 2 years. The second cohort confirmed peak incidence around age 9 months and demonstrated an absence of seroconversion before this age. Seroconversion to insulin autoantibodies occurred earlier than other autoantibodies (p < 0.01 against glutamic acid decarboxylase [GAD]-, insulinoma-associated protein 2 [IA-2]- and zinc transporter 8 [ZnT8]-autoantibodies). Early peak seroconversion incidence was most evident in children with high-risk HLA DR3/4-DQ8 or DR4/4-DQ8 genotypes. CONCLUSION: The age period 9 months to 2 years is associated with a high incidence of activation of type 1 diabetes-associated autoimmunity in genetically at-risk children and should be targeted for effective primary prevention strategies.

PMID: 22289814 [PubMed - as supplied by publisher]

Melatonin influences insulin secretion primarily via MT(1) receptors in rat insulinoma cells (INS-1) and mouse pancreatic islets.

Fetched: February 2nd, 2012, 10:01pm MST

Melatonin influences insulin secretion primarily via MT(1) receptors in rat insulinoma cells (INS-1) and mouse pancreatic islets.

J Pineal Res. 2012 Jan 30;

Authors: Mühlbauer E, Albrecht E, Bazwinsky-Wutschke I, Peschke E

Abstract
Several studies have revealed that melatonin affects the insulin secretion via MT(1) and MT(2) receptor isoforms. Owing to the lack of selective MT(1) receptor antagonists, we used RNA interference technology to generate an MT(1) knockdown in a clonal β-cell line to evaluate whether melatonin modulates insulin secretion specifically via the MT(1) receptor. Incubation experiments were carried out, and the insulin concentration in supernatants was measured using a radioimmunoassay. Furthermore, the intracellular cAMP was determined using an enzyme-linked immunosorbent assay. Real-time RT-PCR indicated that MT(1) knockdown resulted in a significant increase in the rIns1 mRNA and a significantly elevated basal insulin secretion of INS-1 cells. Incubation with melatonin decreased the amount of glucagon-like peptide 1 or inhibited the glucagon-stimulated insulin release of INS-1 cells, while, in MT(1) -knockdown cells, no melatonin-induced reduction in insulin secretion could be found. No decrease in 3-isobutyl-1-methylxanthine-stimulated intracellular cAMP in rMT(1) -knockdown cells was detectable after treatment with melatonin either, and immunocytochemistry proved that MT(1) knockdown abolished phosphorylation of cAMP-response-element-binding protein. In contrast to the INS-1 cells, preincubation with melatonin did not sensitize the insulin secretion of rMT(1) -knockdown cells. We also monitored insulin secretion from isolated islets of wild-type and melatonin-receptor knockout mice ex vivo. In islets of wild-type mice, melatonin treatment resulted in a decrease in insulin release, whereas melatonin treatment of islets from MT(1) knockout and MT(1/2) double-knockout mice did not show a significant effect. The data indicate that melatonin inhibits insulin secretion, primarily via the MT(1) receptor in rat INS-1 cells and isolated mouse islets.

PMID: 22288848 [PubMed - as supplied by publisher]

ATP13A2 (PARK9) polymorphisms influence the neurotoxic effects of manganese.

Fetched: February 2nd, 2012, 10:01pm MST

ATP13A2 (PARK9) polymorphisms influence the neurotoxic effects of manganese.

Neurotoxicology. 2012 Jan 20;

Authors: Rentschler G, Covolo L, Haddad AA, Lucchini RG, Zoni S, Broberg K

Abstract
INTRODUCTION: A higher prevalence of individuals affected by Parkinsonism was found in Valcamonica, Italy. This may be related to ferro-alloy smelters in the area, releasing manganese (Mn) in the air, soil and water for about a century. There exists individual susceptibility for Mn neurotoxicity. AIM: To analyse how polymorphism in genes regulating Mn metabolism and toxicity can modify neurophysiological effects of Mn exposure. MATERIALS AND METHODS: Elderly (N=255) and adolescents (N=311) from Northern Italy were examined for neuromotor and olfactory functions. Exposure to Mn was assessed in blood and urine by atomic absorption spectroscopy and in soil by a portable instrument based on X-Ray fluorescence technology. Polymorphisms in the Parkinson-related gene ATPase type 13A2 (ATP13A2, also called PARK9: rs3738815, rs2076602, rs4920608, rs2871776 and rs2076600), and in the secretory pathway Ca(2+)/Mn(2+) ATPase isoform 1 gene (SPCA1: rs218498, rs3773814 and rs2669858) were analysed by TaqMan probes. RESULTS: For both adolescents and elderly, negative correlations between Mn in soil and motor coordination (R(s)=-0.20, p<0.001; R(s)=-0.13, p=0.05, respectively) were demonstrated. Also among adolescents, negative correlations were seen between Mn in soil with odor identification (R(s)=-0.17, p<0.01). No associations were seen for Mn in blood or urine. ATP13A2 polymorphisms rs4920608 and rs2871776 significantly modified the effects of Mn exposure on impaired motor coordination in elderly (p for interaction=0.029, p=0.041, respectively), also after adjustments for age and gender. The rs2871776 altered a binding site for transcription factor insulinoma-associated 1. CONCLUSIONS: ATP13A2 variation may be a risk marker for neurotoxic effects of Mn in humans.

PMID: 22285144 [PubMed - as supplied by publisher]

[Surgery for neuroendocrine tumors of the gastroenteropancreatic system (GEP-NET).]

Fetched: February 2nd, 2012, 10:01pm MST

[Surgery for neuroendocrine tumors of the gastroenteropancreatic system (GEP-NET).]

Internist (Berl). 2012 Feb 1;

Authors: Goretzki PE, Starke A, Akca A, Lammers BJ

Abstract
Surgical treatment is still the only curative treatment proven for patients with neuroendocrine tumors (NET) of the gastroenteropancreatic system. In addition to the therapy of incidental findings, the treatment of NET with variable aggressiveness and often good long-term prognosis requires a thorough preoperative assessment and a surgical procedure that is based on each individual case. Treatment can be surgery alone (if the disease is locally confined) or can be combined with other therapies.Early NET of the stomach and rectum can be cured endoscopically without further diagnostics, while early findings of the appendix can be treated by an appendectomy. Functionally active pancreatic NET and NET of the small intestine are often preoperatively diagnosed based on symptoms. Thus, it is possible to refer the patient to a NET center, if necessary. Stratification of the necessary treatment combination can be made early.An alternative to radical surgical treatment is the operative reduction of the tumor size and hormone production in metastasized NET, which can lead to improved life expectancy and quality of life. Combination with other treatment forms is absolutely necessary in these patients.It has been proven useful to divide the large group of NET based on the different tumor locations, hormone activity, and the degree of differentiation of the tumor. Early forms, locoregionally limited tumor stages, and tumor stages with distant metastases are considered separately.

PMID: 22290318 [PubMed - as supplied by publisher]

Permalink for 'Accurate Combined Preoperative Localization of Insulinomas Aid the Choice for Enucleation: A Single Institution Experience over 25 Years.'

Accurate Combined Preoperative Localization of Insulinomas Aid the Choice for Enucleation: A Single Institution Experience over 25 Years.

Fetched: January 31st, 2012, 10:01pm MST

Accurate Combined Preoperative Localization of Insulinomas Aid the Choice for Enucleation: A Single Institution Experience over 25 Years.

Hepatogastroenterology. 2012 Jan 26;59(116)

Authors: Zhang T, Mu Y, Qu L, Wang X, Lv Z, Du J, Guo Q, Ba J, Dou J, Lu J

Abstract
Background/Aims: To assess the accuracy of combined preoperative localizations and analyze the change in management strategy of operation of insulinoma. Methodology: One hundred and seventy-two patients with a diagnosis of insulinoma at a tertiary hospital between 1985 and 2010 were reviewed, where accurate combined preoperative localization before surgical exploration was the primary management policy of insulinoma. Operation details for 147 patients were checked. Results: An average of 2.89 preoperative localization studies including 1.61 non-invasive studies and 1.28 invasive studies were utilized per patient. Contrast-enhanced ultrasonography (CEUS) was the most sensitive invasive modality (88.1%) whereas magnetic resonance imaging (MRI) was the most sensitive non-invasive modality (64.0%). All 147 patients underwent complete surgical resection which included 126 enucleations and 18 distal pancreatectomies with a cure rate of 95.2% (140/147) at a median follow-up of 45 months (range 1-248). The postoperative morbidity and long-term outcome of enucleation was similar to distal pancreatectomy despite a higher rate of microscopic margin involvement. Conclusions: Accurate combined preoperative localization of insulinomas is useful of the choice of enucleation, eliminates the need for blind distal pancreatectomy and avoids re-operation. Whenever possible, a pancreas-sparing approach such as enucleation should be adopted.

PMID: 22281978 [PubMed - as supplied by publisher]

Rapamycin protects against dominant negative-HNF1A-induced apoptosis in INS-1 cells.

Fetched: January 28th, 2012, 10:01pm MST

Rapamycin protects against dominant negative-HNF1A-induced apoptosis in INS-1 cells.

Apoptosis. 2011 Nov;16(11):1128-37

Authors: Farrelly AM, Kilbride SM, Bonner C, Prehn JH, Byrne MM

Abstract
HNF1A-maturity onset diabetes of the young (HNF1A-MODY) is caused by mutations in Hnf1a gene encoding the transcription factor hepatocyte nuclear factor 1alpha (HNF1A). An increased rate of apoptosis has been associated with the decrease in beta-cell mass that is a hallmark of HNF1A-MODY and other forms of diabetes. In a cellular model of HNF1A-MODY, we have recently shown that signalling through mammalian target of rapamycin (mTOR) is decreased by the overexpression of a dominant-negative mutant of HNF1A (DN-HNF1A). mTOR is a protein kinase which has important roles in cell metabolism and growth, but also in cell survival, where it has been shown to be both protective and detrimental. Here, we show that pharmacological inhibition of mTOR activity with rapamycin protected INS-1 cells against DN-HNF1A-induced apoptosis. Rapamycin also prevented DN-HNF1A-induced activation of AMP-activated protein kinase (AMPK), an intracellular energy sensor which we have previously shown to mediate DN-HNF1A-induced apoptosis. Conversely, activation of mTOR with leucine potentiated DN-HNF1A-induced apoptosis. Gene silencing of raptor (regulatory associated protein of mTOR), a subunit of mTOR complex 1 (mTORC1), also conferred protection on INS-1 cells against DN-HNF1A-induced apoptosis, confirming that mTORC1 mediates the protective effect. The potential relevance of this effect with regards to the clinical use of rapamycin as an immunosuppressant in diabetics post-transplantation is discussed.

PMID: 21874357 [PubMed - indexed for MEDLINE]

Permalink for 'Impaired transforming growth factor-beta (TGF-β) transcriptional activity and cell proliferation control of a menin in-frame deletion mutant associated with multiple endocrine neoplasia type 1 (MEN1).'

Impaired transforming growth factor-beta (TGF-β) transcriptional activity and cell proliferation control of a menin in-frame deletion mutant associated with multiple endocrine neoplasia type 1 (MEN1).

Fetched: January 27th, 2012, 10:01pm MST

Impaired transforming growth factor-beta (TGF-β) transcriptional activity and cell proliferation control of a menin in-frame deletion mutant associated with multiple endocrine neoplasia type 1 (MEN1).

J Biol Chem. 2012 Jan 24;

Authors: Canaff L, Vanbellinghen JF, Kaji H, Goltzman D, Hendy GN

Abstract
Multiple Endocrine Neoplasia type 1 (MEN1) is characterized by tumors of the parathyroid, enteropancreas and anterior pituitary. The MEN1 gene encodes the tumor suppressor menin of 610 amino acids that has multiple protein partners and activities. The particular pathways, that when lost, lead to tumorigenesis. are not known. We demonstrated that members of a three-generation MEN1 kindred are heterozygous for a donor splice-site mutation at the beginning of intron 3 (IVS3+1G>A). Lymphoblastoid cells of a mutant gene carrier had, in addition to the wild-type menin transcript, an aberrant transcript resulting from use of a cryptic splice-site within exon III that splices to the start of exon IV. The predicted menin Δ(184-218) mutant has an in-frame deletion of 35 amino acids, but is otherwise of wild-type sequence. The transfected menin Δ(184-218) mutant was well expressed and fully able to mediate the normal inhibition of the activity of the transcriptional regulators JunD and NF-κB. However, it was defective in mediating TGF-β-stimulated Smad3 action in promoter-reporter assays in insulinoma cells. Importantly, lymphoblastoid cells from an individual heterozygous for the mutation had reduced TGF-β-induced (Smad3) transcriptional activity, but normal JunD and NF-κB function. In addition, the mutant gene carrier lymphoblastoid cells proliferated faster and were less responsive to the cytostatic effects of TGF-β than cells from an unaffected family member. In conclusion, the menin mutant exhibits selective loss of the TGF-β signaling pathway and loss of cell proliferation control contributing to the development of MEN1.

PMID: 22275377 [PubMed - as supplied by publisher]

Insulin-secreting INS-1E cells express functional TRPV1 channels.

Fetched: January 27th, 2012, 10:01pm MST

Insulin-secreting INS-1E cells express functional TRPV1 channels.

Islets. 2012 Jan 1;4(1)

Authors: Jabin Fågelskiöld A, Kannisto K, Boström A, Hadrovic B, Farre C, Eweida M, Wester K, Islam MS

Abstract
We have studied whether functional TRPV1 channels exist in the INS-1E cells, a cell type used as a model for β-cells, and in primary β-cells from rat and human. The effects of the TRPV1 agonists capsaicin and AM404 on the intracellular free Ca2+ concentration ([Ca2+]i) in the INS-1E cells were studied by fura-2 based microfluorometry. Capsaicin increased [Ca2+]i in a concentration-dependent manner, and the [Ca2+]i increase was dependent on extracellular Ca2+. AM404 also increased [Ca2+]i in the INS-1E cells. Capsazepine, a specific antagonist of TRPV1, completely blocked the capsaicin- and AM404-induced [Ca2+]i increases. Capsaicin did not increase [Ca2+]i in primary β-cells from rat and human. Whole cell patch clamp configuration was used to record currents across the plasma membrane in the INS-1E cells. Capsaicin elicited inward currents that were inhibited by capsazepine. Western blot analysis detected TRPV1 proteins in the INS-1E cells and the human islets. Immunohistochemistry was used to study the expression of TRPV1, but no TRPV1 protein immunoreactivity was detected in the human islet cells and the human insulinoma cells. We conclude that the INS-1E cells, but not the primary β-cells, express functional TRPV1 channels.

PMID: 22274646 [PubMed - as supplied by publisher]

New therapeutic options for metastatic malignant insulinomas.

Fetched: January 27th, 2012, 10:01pm MST

New therapeutic options for metastatic malignant insulinomas.

Clin Endocrinol (Oxf). 2011 Sep;75(3):277-84

Authors: de Herder WW, van Schaik E, Kwekkeboom D, Feelders RA

Abstract
Insulinomas are the most common, functioning, pancreatic neuroendocrine tumours. The great majority (>90%) of insulinomas are nonmetastatic at presentation and can be surgically cured. The <10% patients with distant (liver-bone) metastases have a median survival of < 2 years. Everolimus and sunitinib have been recently introduced as targeted therapies for metastatic pancreatic neuroendocrine tumours. An additional advantage of everolimus in the treatment of patients with metastatic insulinomas is its capability to increase blood glucose levels. Peptide receptor radiotherapy using radiolabelled somatostatin analogues has also been shown to be successful in controlling tumour growth of metastatic pancreatic neuroendocrine tumours. In patients with metastatic insulinomas, this therapeutic modality was also effective in controlling hypoglycaemia, even in the presence of tumour regrowth. With the introduction of these new therapeutic modalities, the therapeutic arsenal for the 'tailor-made' approach of patients with metastatic insulinomas is further expanded.

PMID: 21649688 [PubMed - indexed for MEDLINE]

Heat shock protein 90 is a promising target for effective growth inhibition of gastrointestinal neuroendocrine tumors.

Fetched: January 20th, 2012, 10:01pm MST

Heat shock protein 90 is a promising target for effective growth inhibition of gastrointestinal neuroendocrine tumors.

Int J Oncol. 2012 Jan 10;

Authors: Gloesenkamp C, Nitzsche B, Lim AR, Normant E, Vosburgh E, Schrader M, Ocker M, Scherübl H, Höpfner M

Abstract
Treatment of gastroenteropancreatic neuroendocrine tumors (GEP-NET) is still unsatisfactory and innovative therapeutic approaches are urgently needed. Heat shock protein 90 (Hsp90) is overexpressed in a wide range of tumor types and is an emerging target for the treatment of cancer. However, the potential activity of Hsp90 inhibitors in GEP-NET has not yet been investigated. We studied the antineoplastic activity of the Hsp90 inhibitor IPI-504 on GEP‑NET cells, and characterized its mechanism of action. In human insulinoma (CM) and pancreatic carcinoid (BON) cells IPI-504 induced a dose-dependent growth inhibition by almost 70%. The antiproliferative effect of IPI-504 correlated with a reduction in protein levels of the IGF-1 receptor. Additionally, several proteins of the PI3K/AKT/mTOR pathway, downstream of IGF-1 receptor activation in GEP-NETs, were downregulated as a consequence of Hsp90 inhibition. Combination treatment of IPI-504 with mTOR- or AKT-inhibitors led to additive antiproliferative effects. In addition, effects of IGF-1 receptor tyrosine kinase inhibition were strongly enhanced by IPI-504. Cancer gene expression profiling and FACS analysis revealed that IPI-504 antiproliferative effects were due to both induction of cell cycle arrest and apoptosis. A modified chick chorioallantoic membrane (CAM) assay confirmed the antineoplastic activity of IPI-504 in GEP-NETs in vivo. In conclusion, this study showed that Hsp90 inhibition may be an attractive target for innovative GEP-NET treatment alone or in combination with either IGF-1R or mTOR inhibitors.

PMID: 22246317 [PubMed - as supplied by publisher]

Hypoglycemia, a rare presentation of a solid pseudopapillary neoplasm of the pancreas: A case report.

Fetched: January 13th, 2012, 10:00pm MST

Hypoglycemia, a rare presentation of a solid pseudopapillary neoplasm of the pancreas: A case report.

Turk J Gastroenterol. 2011 Oct;22(5):544-7

Authors: Arafah M, Kfoury H, Naseem S

Abstract
A solid pseudopapillary neoplasm of the pancreas is an uncommon and 'enigmatic' pancreatic neoplasm of low malignant potential generally occurring in young women. The pathologic features of this tumor are characteristic, and adequate surgical intervention is associated with an excellent prognosis. We report the first case of combined solid pseudopapillary neoplasm and islet cell hyperplasia of the pancreas in the pediatric age group. A 16-year-old Saudi female presented to the Emergency Room with a history of frequent attacks of hypoglycemia. Radiologically, a mass in the tail of the pancreas was identified. The pre-operative diagnosis of insulinoma was suggested, and en bloc distal pancreatectomy with splenectomy was performed. A solid pseudopapillary neoplasm and islet cell hyperplasia of the tail of the pancreas was diagnosed by routine histology and by immunohistochemistry. The patient was treated successfully and is now in good health with regular follow-up for the last 13 months. In the pediatric age group, these tumors are very rare and can present as repeated episodes of hypoglycemia. This association sheds light on the histogenesis of solid pseudopapillary neoplasm of the pancreas and also allows appropriate and prompt management to be undertaken by the clinicians.

PMID: 22234766 [PubMed - in process]

Permalink for 'Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat.'

Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat.

Fetched: January 13th, 2012, 10:00pm MST

Chronic treatment with a glucokinase activator delays the onset of hyperglycaemia and preserves beta cell mass in the Zucker diabetic fatty rat.

Diabetologia. 2012 Jan 11;

Authors: Futamura M, Yao J, Li X, Bergeron R, Tran JL, Zycband E, Woods J, Zhu Y, Shao Q, Maruki-Uchida H, Goto-Shimazaki H, Langdon RB, Erion MD, Eiki J, Zhou YP

Abstract
AIMS/HYPOTHESIS: Glucokinase activators (GKAs) are currently being developed as new therapies for type 2 diabetes and have been shown to enhance beta cell survival and proliferation in vitro. Here, we report the effects of chronic GKA treatment on the development of hyperglycaemia and beta cell loss in the male Zucker diabetic fatty (ZDF) rat, a model of type 2 diabetes with severe obesity. METHODS: Cell protection by GKA was studied in MIN6 and INS-1 cells exposed to hydrogen peroxide. Glucose homeostasis and beta cell mass were evaluated in ZDF rats dosed for 41 days with Cpd-C (a GKA) or glipizide (a sulfonylurea) as food admixtures at doses of approximately 3 and 10 mg kg(-1) day(-1). RESULTS: Incubation of MIN6 and INS-1 832/3 insulinoma cell cultures with GKA significantly reduced cell death and impairment of intracellular NADH production caused by exposure to hydrogen peroxide. Progression from prediabetes (normoglycaemia and hyperinsulinaemia) to overt diabetes (hyperglycaemia and hypoinsulinaemia) was significantly delayed in male ZDF rats by in-feed treatment with Cpd-C, but not glipizide. Glucose tolerance, tested in the fifth week of treatment, was also significantly improved by Cpd-C, as was pancreatic insulin content and beta cell area. In a limited immunohistochemical analysis, Cpd-C modestly and significantly enhanced the rate of beta cell proliferation, but not rates of beta cell apoptosis relative to untreated ZDF rats. CONCLUSIONS/INTERPRETATION: These findings suggest that chronic activation of glucokinase preserves beta cell mass and delays disease in the ZDF rat, a model of insulin resistance and progressive beta cell failure.

PMID: 22234649 [PubMed - as supplied by publisher]

Posterior approach pancreaticoduodenectomy: best option for hepatic artery anatomical variants.

Fetched: January 13th, 2012, 10:00pm MST

Posterior approach pancreaticoduodenectomy: best option for hepatic artery anatomical variants.

Hepatogastroenterology. 2011 Nov-Dec;58(112):2112-4

Authors: Lupaşcu C, Moldovanu R, Andronic D, Ursulescu C, Vasiluţă C, Răileanu G, Fotea V, Târcoveanu E

Abstract
Pancreaticoduodenectomy is the best treatment for the patients with malignant tumors of the pancreatic head. However, the procedure is also recommended in some benign pancreatic tumors. The posterior approach allows early dissection of the superior mesenteric artery, portal vein and retroportal pancreatic lamina, before any pancreatic or digestive transection. We present a 42 year old woman diagnosed with a pancreatic tumor. The clinical and biological data suggested the diagnosis of insulinoma. The computed tomography showed a nodule located in the pancreatic head with a typical vascular pattern for endocrine tumor. The exam also revealed a rare vascular variant, a common hepatic artery which arises from the superior mesenteric artery. A pancreaticoduodenectomy has been performed. We used the posterior approach which allowed the correct dissection and exposure of the abnormal common hepatic artery. The postoperative course was uneventful. Posterior approach during the pancreaticoduodenectomies avoids arterial injuries that might compromise the liver arterial supply. It is especially indicated when preoperative imaging studies diagnose anatomic variants of the hepatic arteries.

PMID: 22234079 [PubMed - in process]

Surgical Management of Insulinomas in Multiple Endocrine Neoplasia Type 1.

Fetched: January 11th, 2012, 10:01pm MST

Surgical Management of Insulinomas in Multiple Endocrine Neoplasia Type 1.

Pancreas. 2012 Jan 5;

Authors: Giudici F, Nesi G, Brandi ML, Tonelli F

Abstract
OBJECTIVE: This study aimed to evaluate the accuracy of preoperative and intraoperative diagnostic tools and the surgical strategy to obtain cure in multiple endocrine neoplasia type 1 (MEN-1) patients affected with insulinoma. METHODS: Eight MEN-1 patients (1992-2009) were operated on for hypoglycemic crisis. Preoperative tumor localization was carried out. Ultrasound and modification of the insulin/glucose (I/G) ratio were applied intraoperatively. Pancreatic lesions larger than 0.5 cm were removed by resection of the most affected pancreatic region and by enucleation of nodules in least affected regions. RESULTS: Two pancreatoduodenectomies and 6 distal pancreatectomies were performed; enucleation of nodules was necessary in 6 patients. There was no postoperative mortality. At the histopathologic analysis, a mean of 6 macrotumors and of 15.5 microlesions were found. Intraoperative ultrasound proved a sensitivity of 87.5% for detecting pancreatic insulinoma. Decrease in the I/G ratio after resection predicted postoperative outcome in all patients. At a mean follow-up of 81.5 months, all patients were normoglycemic with no evidence of disease recurrence. CONCLUSIONS: Multiple endocrine neoplasia type 1 insulinomas should be considered surgically curable. Pancreatic resection seems preferable to a less radical surgical approach in ensuring higher cure rates. Intraoperative ultrasound and I/G ratio are of value in the assessment of surgical decision and in the evaluation of the surgical cure.

PMID: 22228047 [PubMed - as supplied by publisher]

Activation of the unfolded protein response pathway causes ceramide accumulation in yeast and INS-1E insulinoma cells.

Fetched: January 5th, 2012, 10:00pm MST

Activation of the unfolded protein response pathway causes ceramide accumulation in yeast and INS-1E insulinoma cells.

J Lipid Res. 2011 Dec 30;

Authors: Epstein S, Kirkpatrick CL, Castillon GA, Muniz M, Riezman I, David FP, Wollheim CB, Riezman H

Abstract
Sphingolipids are not only important components of membranes but also have functions in protein trafficking and intracellular signalling. The LCB1 gene encodes a subunit of the serine palmitoyltransferase, which is responsible for the first step of sphingolipid synthesis. Here we show that activation of the unfolded protein response (UPR) can restore normal ceramide levels and viability in yeast cells with a conditional defect in LCB1. Dependence on UPR was demonstrated by showing the HAC1-dependence of the suppression. A similar induction of ceramides by UPR seems to take place in mammalian cells. In rat pancreatic INS-1E cells, UPR activation induces the transcription of the CerS6 gene which encodes a ceramide synthase. This correlates with the specific accumulation of ceramide with a C16 fatty acyl chain upon UPR activation. Therefore our study reveals a novel connection between UPR induction and ceramide synthesis that seems to be conserved between yeast and mammalian cells.

PMID: 22210926 [PubMed - as supplied by publisher]

Image-Guided Robotic Radiosurgery (CyberKnife) for Pancreatic Insulinoma: Is Laparoscopy Becoming Old?

Fetched: January 5th, 2012, 10:00pm MST

Image-Guided Robotic Radiosurgery (CyberKnife) for Pancreatic Insulinoma: Is Laparoscopy Becoming Old?

Surg Innov. 2011 Dec 30;

Authors: Sigismondo Huscher CG, Mingoli A, Sgarzini G, Mereu A, Gasperi M

Abstract
Insulinomas constitute about 25% of endocrine pancreatic tumors. Laparoscopic surgery is the treatment of choice. However, pancreas-related complications rate is very high, even in experienced hands, ranging up to 37%. Alternative procedures such as embolization with trisacryl have not been accepted by the surgical community. Image-guided robotic radiosurgery or stereotactic radiosurgery (CyberKnife) is a minimally invasive procedure delivering large doses of ionizing radiation to a well-defined target. CyberKnife radiosurgery is successfully used in brain cancer, lung cancer, prostate cancer, liver metastases, kidney cancer, and pancreatic cancer. The authors present the first case to their knowledge of a benign functioning insulinoma successfully treated by a CyberKnife technique with a 3-year follow-up.

PMID: 22209958 [PubMed - as supplied by publisher]

Carcinoma of Two Parathyroid Glands Caused by a Novel MEN1 Gene Mutation - a Rare Feature of the MEN1 Syndrome.

Fetched: January 2nd, 2012, 10:00pm MST

Carcinoma of Two Parathyroid Glands Caused by a Novel MEN1 Gene Mutation - a Rare Feature of the MEN1 Syndrome.

Medicina (Kaunas). 2011 Dec 30;47(11)

Authors: Juodelė L, Serapinas D, Sabaliauskas G, Krasauskienė A, Krasauskas V, Verkauskienė R, Barkauskienė D, Juozaitytė E

Abstract
Multiple endocrine neoplasia type 1 (MEN 1) is a rare syndrome inherited in an autosomal dominant pattern, characterized by combinations of tumors of the parathyroid glands, pituitary gland, and pancreatic islet cells and more rare tumors of endocrine organs and nonendocrine tissues. Germline mutations in the MEN1 gene are responsible for the MEN 1 syndrome, leading to an inactive form of menin protein. Benign lesions of the parathyroid glands are characteristic in patients with the MEN 1 syndrome; however, patients can develop parathyroid carcinomas very rarely. This report presents a clinical case of the MEN 1 syndrome: a 39-year-old woman underwent surgery for carcinoma of two parathyroid glands as well as was treated for pituitary prolactinoma, which caused infertility, and malignant insulinoma; the patient had multiple subcutaneous lipomas as well. Genetic analysis revealed a novel germline mutation in the MEN 1 gene - a nucleotide insertion at codon 43 in exon 2 (c.129insA), which caused the occurrence of the MEN 1 syndrome. The clinical case of the MEN 1 syndrome presented here is relevant in gathering the data on etiopathogenesis of not only MEN 1 syndrome, but an extremely rare pathology - parathyroid carcinoma - as well.

PMID: 22207168 [PubMed - as supplied by publisher]

Sensitivity of Amyloid Formation by Human Islet Amyloid Polypeptide to Mutations at Residue 20.

Fetched: January 2nd, 2012, 10:00pm MST

Sensitivity of Amyloid Formation by Human Islet Amyloid Polypeptide to Mutations at Residue 20.

J Mol Biol. 2011 Dec 21;

Authors: Cao P, Tu LH, Abedini A, Levsh O, Akter R, Patsalo V, Schmidt AM, Raleigh DP

Abstract
Islet amyloid polypeptide (IAPP, amylin) is responsible for amyloid formation in type 2 diabetes and in islet cell transplants. The only known natural mutation found in mature human IAPP is a Ser20-to-Gly missense mutation, found with small frequency in Chinese and Japanese populations. The mutation appears to be associated with increased risk of early-onset type 2 diabetes. Early measurements in the presence of organic co-solvents showed that S20G-IAPP formed amyloid more quickly than the wild type. We confirm that the mutant accelerates amyloid formation under a range of conditions including in the absence of co-solvents. Ser20 adopts a normal backbone geometry, and the side chain makes no steric clashes in models of IAPP amyloid fibers, suggesting that the increased rate of amyloid formation by the mutant does not result from the relief of steric incompatibility in the fiber state. Transmission electronic microscopy, circular dichroism, and seeding studies were used to probe the structure of the resulting fibers. The S20G-IAPP peptide is toxic to cultured rat INS-1 (transformed rat insulinoma-1) β-cells. The sensitivity of amyloid formation to the identity of residue 20 was exploited to design a variant that is much slower to aggregate and that inhibits amyloid formation by wild-type IAPP. An S20K mutant forms amyloid with an 18-fold longer lag phase. Thioflavin T binding assays, together with experiments using a p-cyanophenylalanine (p-cyanoPhe) variant of human IAPP, show that the designed S20K mutant inhibits amyloid formation by human IAPP. The experiments illustrate how p-cyanoPhe can be exploited to monitor amyloid formation even in the presence of other amyloidogenic proteins.

PMID: 22206987 [PubMed - as supplied by publisher]

Permalink for '[Intraoperative localization of recurrent pancreatic insulinoma-a resected case of the metastatic lesions in the residual pancreas and the lymph node].'

[Intraoperative localization of recurrent pancreatic insulinoma-a resected case of the metastatic lesions in the residual pancreas and the lymph node].

Fetched: January 2nd, 2012, 10:00pm MST

[Intraoperative localization of recurrent pancreatic insulinoma-a resected case of the metastatic lesions in the residual pancreas and the lymph node].

Gan To Kagaku Ryoho. 2011 Nov;38(12):2023-6

Authors: Fujisaki S, Tomita R, Park E, Hirano T, Sakurai K, Takayama T, Nemoto N

Abstract
We describe herein a 39-year-old woman with tumor recurrence in the residual pancreas and metastasis to the lymph node about 5 years after an eneclation for insulinoma in the body of the pancreas. A certain day in the morning in June 2002, she was immediately admitted to our hospital due to impairment of consciousness based hypoglycemia. On diagnostic imaging including an arterial stimulation venous sampling, localization of the recurrent lesions was not identified. In October 2002, we underwent laparotomy for the purpose of localization of the recurrent lesions and treatment. During the operation, peripheral blood glucose level, portal blood glucose level and portal insulin level were measured periodically. The mobilization started from the tail of the pancreas. Blood glucose levels were gradually elevated during the mobilization. The pancreas was mobilized to the right edge of the portal vein and was resected. Histopathological diagnosis was recurrent insulinoma in a peripancreatic lymph node and intra-pancreatic subcapsular tumor embolization. Postoperative course was uneventful. More than 8 years after surgery, she is doing well without signs of recurrence.

PMID: 22202272 [PubMed - in process]

Permalink for 'Rat glucagon receptor mRNA is directly regulated by glucose through transactivation of the carbohydrate response element binding protein.'

Rat glucagon receptor mRNA is directly regulated by glucose through transactivation of the carbohydrate response element binding protein.

Fetched: December 28th, 2011, 10:01pm MST

Rat glucagon receptor mRNA is directly regulated by glucose through transactivation of the carbohydrate response element binding protein.

Biochem Biophys Res Commun. 2011 Dec 16;

Authors: Iizuka K, Tomita R, Takeda J, Horikawa Y

Abstract
The glucagon receptor (Gcgr) is essential for maintaining glucose homeostasis in the liver and for stimulating insulin secretion in pancreatic β-cells. Glucose induces rat Gcgr mRNA expression; however, the precise mechanism remains unknown. We previously have studied the role of the carbohydrate response element binding protein (ChREBP), a glucose-activated transcription factor, in the regulation of glucose-stimulated gene expression. The G-box has previously been reported to be responsible for glucose regulation of Gcgr mRNA expression. The G-box comprises two E-boxes separated by 3bp, which distinguishes it from the carbohydrate response element (ChoRE), which has 5-bp spacing between the two E-boxes. In the rat Gcgr promoter, a putative ChoRE (-554bp/-538bp) is localized near the G-box (-543bp/-529bp). In rat INS-1E insulinoma cells, deletion studies of the rat Gcgr promoter show that ChoRE is a minimal glucose response element. Moreover, reporter assays using a pGL3 promoter vector, which harbors ChoRE and chromatin immunoprecipitation assays reveal that ChoRE is a functional glucose response element in the rat Gcgr promoter. Furthermore, In contrast, glucagon partly suppresses glucose-induced expression of Gcgr mRNA. Thus, ChREBP directly regulates rat Gcgr expression in INS-1E cells. In addition, negative feedback looping between ChREBP and GCGR may further contribute to the regulation of glucose-induced gene expression.

PMID: 22198437 [PubMed - as supplied by publisher]

Group VIA PLA2 (iPLA2β) is Activated Upstream of p38 MAP Kinase in Pancreatic Islet Beta Cell Signaling.

Fetched: December 26th, 2011, 10:00pm MST

Group VIA PLA2 (iPLA2β) is Activated Upstream of p38 MAP Kinase in Pancreatic Islet Beta Cell Signaling.

J Biol Chem. 2011 Dec 22;

Authors: Song H, Wohltmann M, Tan M, Bao S, Ladenson JH, Turk J

Abstract
Group VIA Phospholipase A(2) (iPLA(2)β) in pancreatic islet β-cells participates in glucose-stimulated insulin secretion and Sarco(endo)plasmic Reticulum ATPase (SERCA) inhibitor-induced apoptosis, and both are attenuated by pharmacologic or genetic reductions in iPLA(2)β activity and amplified by iPLA(2)β overexpression. While exploring signaling events that occur downstream of iPLA(2)β activation, we found that p38 MAP Kinase (MAPK) is activated by phosphorylation in INS-1 insulinoma cells and mouse pancreatic islets, that this increases with iPLA(2)β expression level, and that it is stimulated by the iPLA(2)β reaction product arachidonic acid. The insulin secretagogue D-glucose also stimulates β-cell p38 MAPK phosphorylation, and this is prevented by the iPLA(2)β inhibitor BEL. Insulin secretion induced by D-glucose and forskolin is amplified by overexpressing iPLA(2)β in INS-1 cells and in mouse islets, and the p38 MAPK inhibitor PD169316 prevents both responses. The SERCA inhibitor thapsigargin also stimulates phosphorylation of both β-cell MAP Kinase Kinase (MKK) isoforms and p38 MAPK, and BEL prevents both events. Others have reported that iPLA(2)β products activate Rho family G-proteins that promote MKK activation via a mechanism inhibited by C. difficile Toxin B, which we find to inhibit thapsigargin-induced β-cell p38 MAPK phosphorylation. Thapsigargin-induced β-cell apoptosis and ceramide generation are also prevented by the p38 MAPK inhibitor PD169316. These observations indicate that p38 MAPK is activated downstream of iPLA(2)β in β-cells incubated with insulin secretagogues or thapsigargin, that this requires prior iPLA(2)β activation, and that p38 MAPK participates in the β-cell functional responses of insulin secretion and apoptosis in which iPLA(2)β participates.

PMID: 22194610 [PubMed - as supplied by publisher]

Expression and therapeutic relevance of heat shock protein 90 in pancreatic endocrine tumors.

Fetched: December 26th, 2011, 10:00pm MST

Expression and therapeutic relevance of heat shock protein 90 in pancreatic endocrine tumors.

Endocr Relat Cancer. 2011 Dec 22;

Authors: Mayer P, Harjung A, Breinig M, Fischer L, Ehemann V, Malz M, Scherübl H, Britsch S, Werner J, Kern MA, Bläker H, Schirmacher P, Bergmann F

Abstract
Pancreatic endocrine tumors (PET) represent a heterogenous group of neoplasms. Although surgical resection is considered a safe and effective treatment for many PET, therapeutic options for inoperable and progressive PET are limited. The expression of heat shock protein (Hsp) 90 was investigated in 120 clinically and pathomorphologically well-characterized PET from 84 patients, using immunohistochemistry. In addition, in 19 snap-frozen PET and 3 healthy pancreatic tissues, we performed immunoblot analyses, and in 15 snap-frozen PET and 3 healthy pancreatic tissues, we investigated the expression of Hsp90-isoforms by means of semiquantitative RT-PCR. Functional tests were conducted using the human pancreas carcinoid cell line BON and the mouse insulinoma cell line β-TC-3. Hsp90 was expressed in 95 % of the PET patients. The transcript levels of the Hsp90-isoforms Hsp90α, Hsp90β, Glucose-related-protein 94, and TNF Receptor-Associated Protein 1 were significantly increased in PET compared with non-neoplastic pancreatic tissues. The treatment of the cell lines BON and β-TC-3 with the Hsp90-inhibitors 17-allylamino-17-demethoxygeldanamycin and 17-dimethylaminoethylamino-17-demethoxy-geldanamycin resulted in significant, dose-dependent reduction of cell viability, cell cycle arrest, and increased apoptosis. Furthermore, Hsp90-inhibition induced the degradation and inactivation of several oncogenetic Hsp90-client-proteins in a time- and dose-dependent manner. Hsp90-inhibitors increased the therapeutic effects of doxorubicin and 5-fluorucacil in BON and β-TC-3 cells. Hsp90 is expressed in the vast majority of PET and its inhibition reveals significant treatment effects in vitro. Thus, Hsp90 qualifies as a promising new target.

PMID: 22194440 [PubMed - as supplied by publisher]

[The role and mechanism of high expression of cyclin B2 in MEN1 insulinoma].

Fetched: December 26th, 2011, 10:00pm MST

[The role and mechanism of high expression of cyclin B2 in MEN1 insulinoma].

Sheng Li Xue Bao. 2011 Dec 25;63(6):555-64

Authors: Wu T, Huang XH

Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a dominantly inherited tumor syndrome characterized by development of various combinations of tumors in multiple endocrine glands, including the pituitary, parathyroid or pancreas. MEN1 results from mutations in tumor suppressor gene Men1, which encodes nuclear protein menin. Menin has been shown to preferentially repress cell proliferation in endocrine tissues including pancreatic beta cells. Herein, the present study was to explore the potential mechanisms underlying menin in repressing cell proliferation in mice MEN1 insulinoma. In the Gene Set Enrichment Analysis (GSEA), Ccnb2 (encoding cyclin B2) was up-regulated in pancreatic islets of Men1-excised mice after 14-day tamoxifen-feeding. Immunofluorescence with antibody against cyclin B2 revealed that the expression of cyclin B2 was greatly increased in MEN1 insulinoma. In Men1(-/-) cells, Men1 ablation leaded to an increase in cyclin B2 expression. Immunofluorescent staining by phospho-H3S10 antibody revealed the increasing number of Men1(-/-) cells in mitosis. Cells were seeded at a density of 5 × 10(4), then counted on day 2, 4 and 6, and the cell growth curve revealed Men1 ablation increased the cell proliferation. In contrast, knockdown of cyclin B2 by shRNA diminished the number of cells in mitosis and reduced cell proliferation. Further, chromatin immunoprecipitation (ChIP) assay indicated that menin affected the histone modification of the promoter of Ccnb2 by reducing the level of histone H3 lysine 4 tri-methylation (H3K4me3) and histone H3 acetylation but not affecting the level of histone H3 lysine 9 tri-methylation (H3K9me3) or histone H3 lysine 27 tri-methylation (H3K27me3). Our results suggest that menin may inhibit MEN1 insulinoma by suppressing cyclin B2 expression via histone modification.

PMID: 22193451 [PubMed - in process]

Improved control of severe hypoglycemia in patients with malignant insulinomas by peptide receptor radionuclide therapy.

Fetched: December 26th, 2011, 10:00pm MST

Improved control of severe hypoglycemia in patients with malignant insulinomas by peptide receptor radionuclide therapy.

J Clin Endocrinol Metab. 2011 Nov;96(11):3381-9

Authors: van Schaik E, van Vliet EI, Feelders RA, Krenning EP, Khan S, Kamp K, Valkema R, van Nederveen FH, Teunissen JJ, Kwekkeboom DJ, de Herder WW

Abstract
CONTEXT: Insulinomas are relatively rare neuroendocrine tumors of the pancreas. Only 10% are considered malignant. Control of insulin hypersecretion and hypoglycemia in patients with malignant insulinomas may be extremely difficult. Different medications and chemotherapy schedules have been used.
PATIENTS: Five patients with metastatic insulinomas and severe, poorly controllable, hypoglycemia are described. These patients required continuous glucose infusion to control severe hypoglycemia, which were induced by the high levels of insulin secretion. Conventional medications, such as diazoxide, or streptozotocin-based chemotherapies had been used to control hypoglycemia but were ineffective and/or produced adverse effects. All patients were treated with sc octreotide.
INTERVENTION: Peptide receptor radionuclide therapy with radiolabeled-somatostatin analogs was used.
RESULTS: After the start of radiolabeled somatostatin analog therapy, the five patients with metastatic insulinomas had stable disease for a mean period of 27 months. During these months, the patients were without any hypoglycemic episodes. Finally, three of five patients died because of progressive disease.
CONCLUSIONS: Radiolabeled somatostatin analog therapy can stabilize tumor growth and can be very successful in further controlling severe hypoglycemia in malignant insulinomas. In our series, this eventually resulted in improved survival outside the hospital setting.

PMID: 21917872 [PubMed - indexed for MEDLINE]

H2O2-induced Ca2+ influx and its inhibition by N-(p-amylcinnamoyl) anthranilic acid in the beta-cells: involvement of TRPM2 channels.

Fetched: December 26th, 2011, 10:00pm MST

H2O2-induced Ca2+ influx and its inhibition by N-(p-amylcinnamoyl) anthranilic acid in the beta-cells: involvement of TRPM2 channels.

J Cell Mol Med. 2009 Sep;13(9B):3260-7

Authors: Bari MR, Akbar S, Eweida M, Kühn FJ, Gustafsson AJ, Lückhoff A, Islam MS

Abstract
Type 2 melastatin-related transient receptor potential channel (TRPM2), a member of the melastatin-related TRP (transient receptor potential) subfamily is a Ca(2+)-permeable channel activated by hydrogen peroxide (H(2)O(2)). We have investigated the role of TRPM2 channels in mediating the H(2)O(2)-induced increase in the cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)) in insulin-secreting cells. In fura-2 loaded INS-1E cells, a widely used model of beta-cells, and in human beta-cells, H(2)O(2) increased [Ca(2+)](i), in the presence of 3 mM glucose, by inducing Ca(2+) influx across the plasma membrane. H(2)O(2)-induced Ca(2+) influx was not blocked by nimodipine, a blocker of the L-type voltage-gated Ca(2+) channels nor by 2-aminoethoxydiphenyl borate, a blocker of several TRP channels and store-operated channels, but it was completely blocked by N-(p-amylcinnamoyl)anthranilic acid (ACA), a potent inhibitor of TRPM2. Adenosine diphosphate phosphate ribose, a specific activator of TRPM2 channel and H(2)O(2), induced inward cation currents that were blocked by ACA. Western blot using antibodies directed to the epitopes on the N-terminal and on the C-terminal parts of TRPM2 identified the full length TRPM2 (TRPM2-L), and the C-terminally truncated TRPM2 (TRPM2-S) in human islets. We conclude that functional TRPM2 channels mediate H(2)O(2)-induced Ca(2+) entry in beta-cells, a process potently inhibited by ACA.

PMID: 19382906 [PubMed - indexed for MEDLINE]

PANCREATIC β-CELLS DEPEND ON BASAL EXPRESSION OF ACTIVE ATF6α-p50 FOR CELL SURVIVAL EVEN UNDER NON-STRESS CONDITIONS.

Fetched: December 24th, 2011, 10:01pm MST

PANCREATIC β-CELLS DEPEND ON BASAL EXPRESSION OF ACTIVE ATF6α-p50 FOR CELL SURVIVAL EVEN UNDER NON-STRESS CONDITIONS.

Am J Physiol Cell Physiol. 2011 Dec 21;

Authors: Teodoro T, Odisho T, Sidorova E, Volchuk A

Abstract
ATF6 is one of three principle ER stress response proteins and becomes activated when ER homeostasis is perturbed. ATF6 functions to increase ER capacity by stimulating transcription of ER-resident chaperone genes such as GRP78. Using an antibody that recognizes active ATF6α-p50 we found that active ATF6α was detected in insulinoma cells and rodent islets even under basal conditions and the levels were further increased by ER stress. To examine the function of ATF6α-p50 we depleted endogenous ATF6α-p50 levels using siRNA in insulinoma cells. Knock-down of endogenous ATF6α-p50 levels by ~60% resulted in a reduction in the steady-state levels of GRP78 mRNA and protein levels in non-stressed cells. Furthermore, ATF6α knock-down resulted in an apoptotic phenotype. We hypothesized that removal of the ATF6α branch of the UPR would result in ER stress. However, neither the PERK, nor the IRE1 pathways of the UPR were significantly activated in ATF6α knock-down cells, although these cells were more sensitive to ER stress inducing compounds. Interestingly, phosphorylation of JNK, p38 and c-jun were elevated in ATF6αknock-down cells and inhibition of JNK or p38 kinases prevented apoptosis. These results suggest that ATF6α may have a role in maintaining β-cell survival even in the absence of ER stress.

PMID: 22189555 [PubMed - as supplied by publisher]

Effective Therapy of Insulinoma by Using Long-Acting Somatostatin Analogue. A Case Report and Literature Review.

Fetched: December 23rd, 2011, 10:00pm MST

Effective Therapy of Insulinoma by Using Long-Acting Somatostatin Analogue. A Case Report and Literature Review.

Exp Clin Endocrinol Diabetes. 2011 Dec 20;

Authors: Jawiarczyk A, Bolanowski M, Syrycka J, Bednarek-Tupikowska G, Kałużny M, Kołodziejczyk A, Domosławski P

Abstract
We are reporting a case of 68-year-old woman with insulinoma, after a non-successful tumor surgery and a long-term diazoxide treatment. She had a lot of hypoglycemia cases, and a weight gain of 50 kg. An abdominal CT scan demonstrated a tumor 28 mm in the diameter, in the head of the pancreas. The patient did not agree for the repeated insulinoma surgery. Furthermore, we found a lesion in the left adrenal gland (14 mm in the diameter) and in the right lung (8 mm in the diameter). Pheochromocytoma was diagnosed on the basis of hypertension, elevated levels of normetanephrine in the 24-h urine collection, and an elevated level of norepinephrine in a plasma sample. After the left adrenal gland removal we observed lower blood pressure. Since we had revealed the presence of somatostatin receptors by the somatostatin receptors scintigraphy, we decided to control hypoglycemia by a monthly subcutaneous administration of the long-acting lanreotide. Because of higher glucose levels (300-400 mg/dl) we started an intense insulin therapy. Nowadays, the patient feels better, she has lost 20 kg of her body weight, and we have observed normal blood glucose levels during the long-term lanreotide treatment. We have noticed neither side effects nor hypoglycemic episodes and we have reduced the dose of insulin. The presented case can be an evidence of the effective treatment of the pancreatic neuroendocrine tumor of insulinoma type, with somatostatin analogue.

PMID: 22187292 [PubMed - as supplied by publisher]

Radiopeptide imaging and therapy in europe.

Fetched: December 23rd, 2011, 10:00pm MST

Radiopeptide imaging and therapy in europe.

J Nucl Med. 2011 Dec;52 Suppl 2:42S-55S

Authors: Ambrosini V, Fani M, Fanti S, Forrer F, Maecke HR

Abstract
Receptor targeting with radiolabeled peptides has become an important topic, particularly in nuclear oncology. Strong research efforts are under way in radiopharmaceutical science laboratories and in nuclear medicine departments in Europe. The target receptors belong to the large family of G-protein-coupled receptors. The prototypes of these radiopeptides are based on analogs of somatostatin targeting somatostatin receptor-positive tumors, particularly well-differentiated neuroendocrine tumors. These radiopeptides have an important impact not only on diagnosis but also on targeted radionuclide therapy of these tumors. Besides the registered radiopeptide (111)In-pentetreotide, efficient SPECT tracers labeled with (99m)Tc and PET agents based on generator-produced (68)Ga have been developed and used in the clinic. In parallel to the development of diagnostic agents, radiopeptides labeled with the β(-) emitters (90)Y and (177)Lu are also widely used. Because the same chelators and therefore the same conjugates can be used in diagnosis and therapy, they constitute ideal theranostic pairs. This progress is driven not only by scientists and clinicians but also by patient interest groups. New radiopeptides targeting other G-protein-coupled receptors are entering the clinic, among them glucagon-like peptide 1 receptor-targeting molecules. This receptor is overexpressed on literally all benign insulinomas. (111)In-labeled derivatives of the insulinotropic 39-mer peptide exendin-4 were beneficial in the pre- and perioperative localization of these benign lesions. In contrast, lack of localization may indicate malignant insulinoma. The bombesin- and gastrin-releasing peptide receptor family is potentially important because these receptors are overexpressed on major human tumors such as prostate tumors, breast tumors, gastrointestinal stromal tumors, and vessels of ovarian cancer. (99m)Tc-labeled peptides for SPECT and (68)Ga-, as well as (64)Cu-labeled agonists or antagonists, have been studied in breast tumors, prostate tumors, gastrointestinal stromal tumors, and gliomas with considerable success. A phase I therapeutic study with a (177)Lu-labeled agonist has been completed. There are not enough clinical data available to reveal the significance of these new modalities in patient care, but several phase I studies are under way in larger patient cohorts using PET agents. Another G-protein-coupled receptor with high overexpression on human tumors is the gastrin/cholecystokinin-2 receptor. It is overexpressed in more than 90% of cases of medullary thyroid cancer, in small cell lung cancer, and in a subgroup of neuroendocrine tumors. Correlating with in vitro receptor localization using autoradiography of 27 patients with metastasized medullary thyroid cancer, SPECT or planar imaging of these patients resulted in a 95% sensitivity of tumor localization. Finally, another G-protein-coupled receptor is found in brain tumors and peritumoral vessels. Literally all cases of glioblastoma multiforme overexpress the neurokinin type 1 receptor; the natural ligand is substance P, which was metabolically stabilized, labeled with (90)Y and (213)Bi, and injected into resection cavities or directly into tumors, which were critically located via a catheter system. The major advantage of this approach appeared to be the facilitated resectability of tumors, particularly in those patients who had been treated up front with the locoregional approach. It appears that neoadjuvant treatment before resection is a valid concept. Finally, another peptide family, the arginine-glycine-aspartate-based radiotracers, has made it to the clinic labeled with a variety of radioisotopes for monitoring the integrins α(v)β(3) overexpressed during tumor angiogenesis.

PMID: 22144555 [PubMed - in process]

Metabolic complications of endocrine surgery in companion animals.

Fetched: December 21st, 2011, 10:01pm MST

Metabolic complications of endocrine surgery in companion animals.

Vet Clin North Am Small Anim Pract. 2011 Sep;41(5):847-68, v

Authors: de Brito Galvao JF, Chew DJ

Abstract
Metabolic complications of endocrine surgery occur commonly and precautions should be taken to avoid potentially life-threatening situations and to lessen expense associated with a more extended hospital stay. Common complications of endocrine surgery as well as prevention strategies will be reviewed for pancreatic, parathyroid, and adrenal surgery.

PMID: 21889689 [PubMed - indexed for MEDLINE]

(18)F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma.

Fetched: December 20th, 2011, 10:01pm MST

(18)F-radiolabeled analogs of exendin-4 for PET imaging of GLP-1 in insulinoma.

Eur J Nucl Med Mol Imaging. 2011 Dec 15;

Authors: Kiesewetter DO, Gao H, Ma Y, Niu G, Quan Q, Guo N, Chen X

Abstract
PURPOSE: Glucagon-like peptide type 1 (GLP-1) is an incretin peptide that augments glucose-stimulated insulin release following oral consumption of nutrients. Its message is transmitted via a G protein-coupled receptor called GLP-1R, which is colocalized with pancreatic β-cells. The GLP-1 system is responsible for enhancing insulin release, inhibiting glucagon production, inhibiting hepatic gluconeogenesis, inhibiting gastric mobility, and suppression of appetite. The abundance of GLP-1R in pancreatic β-cells in insulinoma, a cancer of the pancreas, and the activity of GLP-1 in the cardiovascular system have made GLP-1R a target for molecular imaging. METHODS: We prepared (18)F radioligands for GLP-1R by the reaction of [(18)F]FBEM, a maleimide prosthetic group, with [Cys(0)] and [Cys(40)] analogs of exendin-4. The binding affinity, cellular uptake and internalization, in vitro stability, and uptake and specificity of uptake of the resulting compounds were determined in an INS-1 xenograft model in nude mice. RESULTS: The [(18)F]FBEM-[Cys(x)]-exendin-4 analogs were obtained in good yield (34.3 ± 3.4%, n = 11), based on the starting compound [(18)F]FBEM), and had a specific activity of 45.51 ± 16.28 GBq/μmol (1.23 ± 0.44 Ci/μmol, n = 7) at the end of synthesis. The C-terminal isomer, [(18)F]FBEM-[Cys(40)]-exendin-4, had higher affinity for INS-1 tumor cells (IC(50) 1.11 ± 0.057 nM) and higher tumor uptake (25.25 ± 3.39 %ID/g at 1 h) than the N-terminal isomer, [(18)F]FBEM-[Cys(0)]-exendin-4 (IC(50) 2.99 ± 0.06 nM, uptake 7.20 ± 1.26 %ID/g at 1 h). Uptake of both isomers into INS-1 tumor, pancreas, stomach, and lung could be blocked by preinjection of nonradiolabeled [Cys(x)]-exendin-4 (p < 0.05). CONCLUSION: [(18)F]FBEM-[Cys(40)]-exendin-4 and [(18)F]FBEM-[Cys(0)]-exendin-4 have high affinity for GLP-1R and display similar in vitro cell internalization. The higher uptake into INS-1 xenograft tumors exhibited by [(18)F]FBEM-[Cys(40)]-exendin-4 suggests that this compound would be the better tracer for imaging GLP-1R.

PMID: 22170321 [PubMed - as supplied by publisher]

Susceptibility of Human Pancreatic β Cells for Cytomegalovirus Infection and the Effects on Cellular Immunogenicity.

Fetched: December 20th, 2011, 10:01pm MST

Susceptibility of Human Pancreatic β Cells for Cytomegalovirus Infection and the Effects on Cellular Immunogenicity.

Pancreas. 2012 Jan;41(1):39-49

Authors: Smelt MJ, Faas MM, de Haan BJ, Draijer C, Hugenholtz GC, de Haan A, Engelse MA, de Koning EJ, de Vos P

Abstract
OBJECTIVES: Human cytomegalovirus (HCMV) infection has been suggested to be a causal factor in the development of type 1 diabetes, posttransplantation diabetes, and the failure of islet allografts. This effect of CMV has been interpreted as an indirect effect on the immune system rather than direct infection-induced cell death. In the present study, we investigated (i) the susceptibility of β cells to HCMV infection, (ii) regulation of immune cell-activating ligands, (iii) release of proinflammatory cytokines, and (iv) the effects on peripheral blood mononuclear cell (PBMC) activation.
METHODS: CM insulinoma cells and primary β cells were HCMV-infected in vitro using a laboratory and a clinical HCMV strain. The susceptibility to infection was measured by the expression of viral genes and proteins. Furthermore, expression levels of Major Histocompatibility Complex I, Intracellular Adhesion Molecule-1, and Lymphocyte Function Associated Antigen-3 and the release of proinflammatory cytokines were determined. In addition, PBMC activation to HCMV-infected β cells was determined.
RESULTS: β Cells were susceptible to HCMV infection. Moreover, the infection increased the cellular immunogenicity, as demonstrated by an increased MHC I and ICAM-1 expression and an increased proinflammatory cytokine release. Human cytomegalovirus-infected CM cells potently activated PBMCs. The infection-induced effects were dependent on both viral "sensing" and viral replication.
CONCLUSIONS: In vivo β-cell HCMV infection and infection-enhanced cellular immunogenicity may have important consequences for native or transplanted β-cell survival.

PMID: 22158077 [PubMed - in process]

Sphingosine kinase 1 knockdown reduces insulin synthesis and secretion in a rat insulinoma cell line.

Fetched: December 20th, 2011, 10:01pm MST

Sphingosine kinase 1 knockdown reduces insulin synthesis and secretion in a rat insulinoma cell line.

Arch Biochem Biophys. 2011 Dec 4;

Authors: Hasan NM, Longacre MJ, Stoker S, Kendrick MA, Druckenbrod NR, Laychock SG, Mastrandrea LD, Macdonald MJ

Abstract
To evaluate the role of sphingosine kinase 1 (SphK1) in insulin secretion, we used stable transfection to knock down the expression of the Sphk1 gene in the rat insulinoma INS-1 832/13 cell line. Cell lines with lowered Sphk1 mRNA expression and SphK1 enzyme activity (SK11 and SK14) exhibited lowered glucose- and 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH) plus glutamine-stimulated insulin release and low insulin content associated with decreases in the mRNA of the insulin 1 gene. Overexpression of the rat or human Sphk1 cDNA restored insulin secretion and total insulin content in the SK11 cell line, but not in the SK14 cell line. The Sphk1 cDNA-transfected SK14 cell line expressed significantly less SphK1 activity than the Sphk1 cDNA-transfected SK11 cells suggesting that the shRNA targeting SK14 was more effective in silencing the exogenous rat Sphk1 mRNA. The results indicate that SphK1 activity is important for insulin synthesis and secretion.

PMID: 22155656 [PubMed - as supplied by publisher]

Dual energy spectral CT imaging of insulinoma-Value in preoperative diagnosis compared with conventional multi-detector CT.

Fetched: December 20th, 2011, 10:01pm MST

Dual energy spectral CT imaging of insulinoma-Value in preoperative diagnosis compared with conventional multi-detector CT.

Eur J Radiol. 2011 Dec 5;

Authors: Lin XZ, Wu ZY, Tao R, Guo Y, Li JY, Zhang J, Chen KM

Abstract
OBJECTIVE: The aim of this study was to investigate the value of dual energy spectral CT (DEsCT) imaging in preoperative diagnosis of insulinomas in comparison with conventional multi-detector CT (MDCT). MATERIALS AND METHODS: Thirty-five patients were included in this study with 14 underwent the conventional dual-phase CT imaging (from March 2009 to January 2010) and 21 underwent the dual-phase DEsCT imaging (from February 2010 to May 2011). CT images were interpreted prospectively by two radiologists in consensus before operation. All the patients had diagnosis confirmed pathologically. The accuracy of preoperative diagnosis of insulinomas between DEsCT imaging and conventional MDCT, and between different kinds of images of DEsCT was compared. RESULTS: There were 39 confirmed lesions among the 35 patients (23 and 16 tumors in the spectral CT group and MDCT group, respectively). MDCT detected 11 of 16 tumors. DEsCT imaging detected 20 of 23 tumors separately with the monochromatic image or the iodine density image, and 22 of 23 tumors with the combination of the two kinds of images. The sensitivity for the preoperative diagnosis of insulinoma was 95.7% with the combination of monochromatic and iodine density images in DEsCT imaging, statistically higher than that with the conventional MDCT (68.8%) (p=0.033). CONCLUSION: Dual energy spectral CT imaging has higher sensitivity in preoperative diagnosis of insulinomas compared with conventional MDCT. The combination of monochromatic image and iodine density image can improve the diagnostic sensitivity of insulinomas.

PMID: 22153746 [PubMed - as supplied by publisher]

Permalink for 'Applying intraoperative insulin level monitoring for tumor removal in a patient with recurrent pancreatic multiple insulinomas.'

Applying intraoperative insulin level monitoring for tumor removal in a patient with recurrent pancreatic multiple insulinomas.

Fetched: December 20th, 2011, 10:01pm MST

Applying intraoperative insulin level monitoring for tumor removal in a patient with recurrent pancreatic multiple insulinomas.

J Formos Med Assoc. 2011 Jun;110(6):410-4

Authors: Chen PY, Wu TJ, Ou HY, Li MC, Hu SC, Huang SM

PMID: 21741010 [PubMed - indexed for MEDLINE]

Permalink for '[Small interfering RNA-mediated islet neogenesis associated protein gene silencing inhibits the proliferation of INS-1 islet cells].'

[Small interfering RNA-mediated islet neogenesis associated protein gene silencing inhibits the proliferation of INS-1 islet cells].

Fetched: December 20th, 2011, 10:01pm MST

[Small interfering RNA-mediated islet neogenesis associated protein gene silencing inhibits the proliferation of INS-1 islet cells].

Nan Fang Yi Ke Da Xue Xue Bao. 2009 Oct;29(10):2040-3

Authors: Sha JP, Xue YM, Chen X, Long K, Liang HC, Sang D, Mao RR, Lin Z

Abstract
OBJECTIVE: To investigate the effect of small interfering RNA (siRNA)-mediated islet neogenesis associated protein (INGAP) gene silencing on the proliferation of islet cells.
METHODS: Different siRNAs targeting INGAP gene were designed and transfected into INS-1 islet cells, and the expression levels of INGAP mRNA and protein following the transfection were detected using RT-PCR, flow cytometry and Western blotting. The proliferation of the transfected INS-1 cells was evaluated using MTT assay.
RESULTS: Compared with those in the irrelevant siRNA, empty vector control, and un-transfected groups, the expression levels of INGAP mRNA and protein in the cells transfected with siRNA6 were reduced significantly. The cell proliferation rate significantly increased after transfection with siRNA6 (P<0.05).
CONCLUSION: siRNA targeting INGAP can effectively down-regulate INGAP expression and inhibit the proliferation of INS-1 cells.

PMID: 19861261 [PubMed - indexed for MEDLINE]

Improved quality of life in patients treated with Peptide radionuclides.

Fetched: December 8th, 2011, 10:00pm MST

Improved quality of life in patients treated with Peptide radionuclides.

World J Nucl Med. 2011 Jul;10(2):115-21

Authors: Traub-Weidinger T, Raderer M, Uffmann M, Angelberger P, Kurtaran A, Leimer M, Preitfellner J, Dudczak R, Virgolini I

Abstract
Peptide receptor radionuclide therapy (PRRT) has recently been established as an important treatment modality for somatostatin receptor (SSTR)-positive tumors. The purpose of this study was to evaluate the clinical response, side-effects as well as the quality of life following (90)Y-DOTA-lanreotide (DOTALAN) and/or (90)Y-DOTA-Tyr (3)-DPhe(1)-octreotide (DOTATOC) therapy in patients with progressive metastatic disease during a 6-year follow-up period. Following dosimetric evaluation with (111)In-DOTALAN and (111)In-DOTATOC, 13 patients with estimated absorbed tumor doses of >5 Gy/GBq (carcinoid, n = 5; radioiodine-negative thyroid cancer, n = 4; gastrinoma, n = 1; insulinoma, n = 1; glucagonoma, n = 1; glomus jugularis tumor, n = 1) were assigned for PRRT. A dose of 925 MBq of (90)Y-DOTALAN (four patients) or 1.85-3.7 GBq of (90)Y-DOTATOC (10 patients) was administered intravenously and repeated every 4-8 weeks. Tumor dosimetry was performed prior to and under therapy, re-staging every 2-3 months. Pain intensity, Karnofsky score and general symptoms were evaluated in order to determine quality of life. Patients were followed until death. Altogether, 53 infusions of PRRT (1.85-14.1 GBq) were administered. After the first follow-up of 3 months of (90)Y-DOTALAN therapy, stable disease (SD) was observed in one patient and progressive disease (PD) in three patients. With (90)Y-DOTATOC therapy, SD was found in all 10 patients. During the re-evaluation period (4-27 months), one patient had to be shifted from (90)Y-DOTALAN to (90)Y-DOTATOC therapy due to reduced (111)In-DOTALAN uptake after 5.5 GBq. In the first 6 months after PRRT with DOTATOC, SD was found in nine of 10 patients and PD in one patient. Thereafter, SD was observed in two patients and PD in eight patients. Nine of 13 patients after PRRT with either DOTALAN or DOTATOC died. None of the patients had experienced severe acute hematological side-effects. Transient thrombocytopenia or lymphocytopenia was seen in 10 patients after 3.7 GBq, and a skin reaction in one patient. Total accumulated kidney dose ranged between 4 and 64 Gy, with reduced creatinine clearance in two patients. Pain relief was achieved in three of three patients after ~3.7 GBq ERT within 4-6 months. Appetite, weight, Karnofsky score and general well-being had improved in patients with SD during and after therapy. Based on the results of this study conducted on a small group of patients, we conclude that PRRT may offer an alternative treatment option for SSTR-positive tumors, with only mild transient side-effects and a marked improvement in the quality of life.

PMID: 22144870 [PubMed - in process]

Permalink for 'β-Cell subcellular localization of glucose-stimulated Mn uptake by X-ray fluorescence microscopy: implications for pancreatic MRI.'

β-Cell subcellular localization of glucose-stimulated Mn uptake by X-ray fluorescence microscopy: implications for pancreatic MRI.

Fetched: December 8th, 2011, 10:00pm MST

β-Cell subcellular localization of glucose-stimulated Mn uptake by X-ray fluorescence microscopy: implications for pancreatic MRI.

Contrast Media Mol Imaging. 2011 Nov;6(6):474-81

Authors: Leoni L, Dhyani A, La Riviere P, Vogt S, Lai B, Roman BB

Abstract
Manganese (Mn) is a calcium (Ca) analog that has long been used as a magnetic resonance imaging (MRI) contrast agent for investigating cardiac tissue functionality, for brain mapping and for neuronal tract tracing studies. Recently, we have extended its use to investigate pancreatic β-cells and showed that, in the presence of MnCl(2) , glucose-activated pancreatic islets yield significant signal enhancement in T(1) -weigheted MR images. In this study, we exploited for the first time the unique capabilities of X-ray fluorescence microscopy (XFM) to both visualize and quantify the metal in pancreatic β-cells at cellular and subcellular levels. MIN-6 insulinoma cells grown in standard tissue culture conditions had only a trace amount of Mn, 1.14 ± 0.03 × 10(-11) µg/µm(2) , homogenously distributed across the cell. Exposure to 2 m m glucose and 50 µ m MnCl(2) for 20 min resulted in nonglucose-dependent Mn uptake and the overall cell concentration increased to 8.99 ± 2.69 × 10(-11) µg/µm(2) . When cells were activated by incubation in 16 m m glucose in the presence of 50 µ m MnCl(2) , a significant increase in cytoplasmic Mn was measured, reaching 2.57 ± 1.34 × 10(-10) µg/µm(2) . A further rise in intracellular concentration was measured following KCl-induced depolarization, with concentrations totaling 1.25 ± 0.33 × 10(-9) and 4.02 ± 0.71 × 10(-10) µg/µm(2) in the cytoplasm and nuclei, respectively. In both activated conditions Mn was prevalent in the cytoplasm and localized primarily in a perinuclear region, possibly corresponding to the Golgi apparatus and involving the secretory pathway. These data are consistent with our previous MRI findings, confirming that Mn can be used as a functional imaging reporter of pancreatic β-cell activation and also provide a basis for understanding how subcellular localization of Mn will impact MRI contrast. Copyright © 2011 John Wiley & Sons, Ltd.

PMID: 22144025 [PubMed - in process]

Permalink for 'Cytoprotective effect of Coreopsis tinctoria extracts and flavonoids on tBHP and cytokine-induced cell injury in pancreatic MIN6 cells.'

Cytoprotective effect of Coreopsis tinctoria extracts and flavonoids on tBHP and cytokine-induced cell injury in pancreatic MIN6 cells.

Fetched: December 8th, 2011, 10:00pm MST

Cytoprotective effect of Coreopsis tinctoria extracts and flavonoids on tBHP and cytokine-induced cell injury in pancreatic MIN6 cells.

J Ethnopharmacol. 2011 Nov 28;

Authors: Dias T, Liu B, Jones P, Houghton PJ, Mota-Filipe H, Paulo A

Abstract
ETHOPHARMACOLOGICAL RELEVANCE: Coreopsis tinctoria flowering tops infusion is traditionally used in Portugal for treating the symptoms of diabetes. Recent studies have revealed its antihyperglycemic activity when administered for 3 weeks to a STZ-induced glucose intolerance model in the rat and glucose tolerance regain was even clearer and pancreatic function recovery was achieved when administering Coreopsis tinctoria flavonoid-rich AcOEt fraction. AIM OF THE STUDY: In this study we aimed to evaluate the protective effect of Coreopsis tinctoria flowering tops aqueous extract, AcOEt fraction and the pure compounds marein and flavanomarein, against beta-cell injury, in a mouse insulinoma cell line (MIN6) challenged with pro-oxidant tert-Butyl-Hydroperoxide (tBHP) or cytokines. MATERIALS AND METHODS: The protective effects of Coreopsis tinctoria fowering tops extracts and pure compounds were evaluated through pre-incubating MIN6 cells with samples followed by treatment with tBHP (400μM for 2h) after which viability was determined through ATP measurements. In order to assess whether plant extracts were involved in decreasing reactive oxygen species, superoxide anion production was determined through a lucigenin-enhanced chemiluminescent method. Lastly, the direct influence of Coreopsis tinctoria extracts and main compounds on cell survival/apoptosis was determined measuring caspase 3 and 7 cleavage induced by cytokines. RESULTS: Coreopsis tinctoria flowering tops extracts (25-100μg/mL) and pure compounds (200-400μM), when pre-incubated with MIN6 cells did not present any cytotoxicity, instead they increased cell viability in a dose dependent manner when challenged with tBHP. Treatment with this pro-oxidant also showed a rise in superoxide radical anion formation in MIN6 cells. This increase was significantly reduced by treatment with superoxide dismutase enzyme (SOD) but not by pre-treatment with Coreopsis tinctoria flowering tops extracts. Caspase 3/7 activation measurements show that Coreopsis tinctoria flowering tops extracts, as well as marein and flavanomarein, significantly inhibit apoptosis. CONCLUSIONS: Coreopsis tinctoria extracts and pure compounds show cytoprotection that seems to be due to inhibition of the apoptotic pathway, and not through a decrease on superoxide radical production.

PMID: 22143153 [PubMed - as supplied by publisher]

$Permalink for 'Multiple endocrine neoplasia type 1 presenting as refractory epilepsy and polyneuropathy - A case report.'$

Multiple endocrine neoplasia type 1 presenting as refractory epilepsy and polyneuropathy - A case report.

Fetched: December 8th, 2011, 10:00pm MST

Multiple endocrine neoplasia type 1 presenting as refractory epilepsy and polyneuropathy - A case report.

J Neurol Sci. 2011 Dec 1;

Authors: de Paiva AR, Castro LH, Rodrigues W, Passarelli V, Jorge CL, Brotto MW, Hirata MT, Marchiori PE

Abstract
Hypoglycemia is a well recognized cause of acute symptomatic seizures. The fact that hypoglycemia can cause peripheral neuropathy is less appreciated. We describe a case of insulinoma associated peripheral neuropathy. A 17 year-old previously healthy man was referred for investigation of refractory epilepsy. A history of recurrent seizures, slowly progressive weakness of his feet and hands, and weight gain was obtained. Physical examination showed signs of a chronic sensory-motor polyneuropathy. He was diagnosed with insulinoma and primary hyperparathyroidism, characterizing multiple endocrine neoplasia, type 1 syndrome. Cases of insulinoma associated peripheral neuropathy are very rare. The more characteristic clinical picture appears to be distal weakness, worse in the intrinsic hand and feet muscles, and no or mild sensory signs. Peripheral nervous system symptoms may not completely resolve, despite removal of the cause of hyperinsulinism/hypoglycemia and full reversion of central nervous system symptoms. Mechanisms underlying hypoglycemic neuropathy are still poorly understood.

PMID: 22138026 [PubMed - as supplied by publisher]

Modeling pharmacological inhibition of mast cell degranulation as a therapy for insulinoma.

Fetched: December 8th, 2011, 10:00pm MST

Modeling pharmacological inhibition of mast cell degranulation as a therapy for insulinoma.

Neoplasia. 2011 Nov;13(11):1093-100

Authors: Soucek L, Buggy JJ, Kortlever R, Adimoolam S, Monclús HA, Allende MT, Swigart LB, Evan GI

Abstract
Myc, a pleiotropic transcription factor that is deregulated and/or overexpressed in most human cancers, instructs multiple extracellular programs that are required to sustain the complex microenvironment needed for tumor maintenance, including remodeling of tumor stroma, angiogenesis, and inflammation. We previously showed in a model of pancreatic β-cell tumorigenesis that acute Myc activation in vivo triggers rapid recruitment of mast cells to the tumor site and that this is absolutely required for angiogenesis and macroscopic tumor expansion. Moreover, systemic inhibition of mast cell degranulation with sodium cromoglycate induced death of tumor and endothelial cells in established tumors. Hence, mast cells are required both to establish and to maintain the tumors. Whereas this intimates that selective inhibition of mast cell function could be therapeutically efficacious, cromoglycate is not a practical drug for systemic delivery in humans, and no other systemic inhibitor of mast cell degranulation has hitherto been available. PCI-32765 is a novel inhibitor of Bruton tyrosine kinase (Btk) that blocks mast cell degranulation and is currently in clinical trial as a therapy for B-cell non-Hodgkin lymphoma. Here, we show that systemic treatment of insulinoma-bearing mice with PCI-32765 efficiently inhibits Btk, blocks mast cell degranulation, and triggers collapse of tumor vasculature and tumor regression. These data reinforce the notion that mast cell function is required for maintenance of certain tumor types and indicate that the Btk inhibitor PCI-32765 may be useful in treating such diseases.

PMID: 22131884 [PubMed - in process]

[Recurrent hypoglycemia and a large intraabdominal tumor in a 61-year-old woman].

Fetched: December 8th, 2011, 10:00pm MST

[Recurrent hypoglycemia and a large intraabdominal tumor in a 61-year-old woman].

Dtsch Med Wochenschr. 2011 Dec;136(49):2542-6

Authors: Kahl C, Jost K, Knauerhase A, Leithäuser M, Freund M, Bunke D, Rothacker D, Hampel R

Abstract
History and admission findings: A 61-year-old woman was found unconscious by her husband. The emergency doctor detected hypoglycemia (blood glucose 1.7 mmol/l). This was the first such event, the patient had not been known to have diabetes mellitus. At admission the physical examination and the laboratory findings revealed no abnormalities.Investigations: A fasting test was aborted shortly after the start because of the onset of neurological symptoms. An insulinoma was excluded by detecting suppressed levels of insulin and C-peptide. Computed tomography of the abdomen revealed a mesenteric tumour of 9 cm in diameter, which was identified immunhistologically as a grade 1 follicular lymphoma (FL). After exclusion of endocrinological causes the recurrent hypoglycaemia was diagnozed as part of a paraneoplastic syndrome associated with a non-islet cell tumour hypoglycaemia (NICTH) with a newly diagnosed FL.Treatment and course: Specific medication with the CD20 antibody rituximab (375 mg/m2, once per week for a total of four cycles) was initiated. There were no further episodes of hypoglycaemia. After one year the patient remains free of any symptoms.Conclusions: After exclusion of any endocrinological reasons for hypoglycemia, differential diagnosis should include NICTH as paraneoplastic syndrome. In rare cases a hematological malignancy may be the underlying disease. The specific treatment of this disease likewise represents the causal treatment of NICTH.

PMID: 22131074 [PubMed - in process]

Anti-Diabetic Effects of Rice Hull Smoke Extract in Alloxan-Induced Diabetic Mice.

Fetched: December 8th, 2011, 10:00pm MST

Anti-Diabetic Effects of Rice Hull Smoke Extract in Alloxan-Induced Diabetic Mice.

J Agric Food Chem. 2011 Nov 30;

Authors: Yang JY, Kang MY, Nam SH, Friedman M

Abstract
We investigated the protective effect of a liquid rice hull smoke extract (RHSE) against diabetes in alloxan-induced diabetic mice. Anti-diabetic effects of RHSE were evaluated in both the rat insulinoma-1 cell line (INS-1) and diabetic ICR mice induced by intraperitoneal (ip) injection of alloxan. Alloxan treatment (10 mM) increased cellular reactive oxygen species (ROS) levels in the INS-1 cells, which were inversely related to cell viabilities. RHSE also inhibited alloxan-induced nitric oxide (NO) generation through inhibition of inducible nitric oxide synthase (iNOS) gene expression and suppressed the inflammatory reaction in INS-1 cells through inhibition of expression of pro-inflammatory genes, including tumor necrosis factor-α (TNF-α), interleukins-1β (IL-1β), and interleukin-6 (IL-6). Dietary administration of 0.5% or 1% RHSE to alloxan-induced diabetic mice caused a decrease in blood glucose and increases in both serum insulin and hepatic glycogen levels. RHSE induced decreases in glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) levels and an increase in the glucokinase (GCK) level. These changes resulted in restoring glucose-regulating enzyme levels to control values. Histopathology showed that alloxan also induced damage of Langerhans islet cells of the pancreas and liver necrosis associated with diabetes. Oral administration of RHSE restored the islet and liver cells to normal levels. RHSE-supplemented functional food could protect insulin-producing islet cells against damage triggered by oxidative stress and local inflammation associated with diabetes.

PMID: 22129064 [PubMed - as supplied by publisher]

Reexpression of oncoprotein MafB in proliferative β-cells and Men1 insulinomas in mouse.

Fetched: November 30th, 2011, 10:00pm MST

Reexpression of oncoprotein MafB in proliferative β-cells and Men1 insulinomas in mouse.

Oncogene. 2011 Nov 28;

Authors: Lu J, Hamze Z, Bonnavion R, Herath N, Pouponnot C, Assade F, Fontanière S, Bertolino P, Cordier-Bussat M, Zhang CX

Abstract
MafB, a member of the large Maf transcription factor family, is essential for the embryonic and terminal differentiation of pancreatic α- and β-cells. However, the role of MafB in the control of adult islet-cell proliferation remains unknown. Considering its oncogenic potential in several other tissues, we investigated the possible alteration of its expression in adult mouse β-cells under different conditions of proliferation. We found that MafB, in general silenced in these cells, was reexpressed in ∼30% of adaptive β-cells both in gestational female mice and in mice fed with a high-fat diet. Importantly, reactivated MafB expression was also observed in the early β-cell lesions and insulinomas that developed in β-cell specific Men1 mutant mice, appearing in >80% of β-cells in hyperplasic or dysplastic islets from the mutant mice >4 months of age. Moreover, MafB expression could be induced by glucose stimulation in INS-1 rat insulinoma cells. The induction was further reinforced following Men1 knockdown by siRNA. Furthermore, MafB overexpression in cultured βTC3 cells enhanced cell foci formation both in culture medium and on soft agar, accompanied with the increased expression of Cyclin B1 and D2. Conversely, MafB downregulation by siRNA transfection reduced BrdU incorporation in INS-1E cells. Taken together, our data reveal that Men1 inactivation leads to MafB reexpression in mouse β-cells in vivo, and provides evidence that deregulated ectopic MafB expression may have a hitherto unknown role in adult β-cell proliferation and Men1-related tumorigenesis.Oncogene advance online publication, 28 November 2011; doi:10.1038/onc.2011.538.

PMID: 22120711 [PubMed - as supplied by publisher]

Permalink for 'The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: Role of NADH and consequences for insulin secretion.'

The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: Role of NADH and consequences for insulin secretion.

Fetched: November 28th, 2011, 10:01pm MST

The level of menadione redox-cycling in pancreatic β-cells is proportional to the glucose concentration: Role of NADH and consequences for insulin secretion.

Toxicol Appl Pharmacol. 2011 Nov 15;

Authors: Heart E, Palo M, Womack T, Smith PJ, Gray JP

Abstract
Pancreatic β-cells release insulin in response to elevation of glucose from basal (4-7mM) to stimulatory (8-16mM) levels. Metabolism of glucose by the β-cell results in the production of low levels of reactive oxygen intermediates (ROI), such as hydrogen peroxide (H(2)O(2)), a newly recognized coupling factor linking glucose metabolism to insulin secretion. However, high and toxic levels of H(2)O(2) inhibit insulin secretion. Menadione, which produces H(2)O(2) via redox cycling mechanism in a dose-dependent manner, was investigated for its effect on β-cell metabolism and insulin secretion in INS-1 832/13, a rat β-cell insulinoma cell line, and primary rodent islets. Menadione-dependent redox cycling and resulting H(2)O(2) production under stimulatory glucose exceeded several-fold those reached at basal glucose. This was paralleled by a differential effect of menadione (0.1-10μM) on insulin secretion, which was enhanced at basal, but inhibited at stimulatory glucose. Redox cycling of menadione and H(2)O(2) formation was dependent on glycolytically-derived NADH, as inhibition of glycolysis and application of non-glycogenic insulin secretagogues did not support redox cycling. In addition, activity of plasma membrane electron transport, a system dependent in part on glycolytically-derived NADH, was also inhibited by menadione. Menadione-dependent redox cycling was sensitive to the NQO1 inhibitor dicoumarol and the flavoprotein inhibitor diphenylene iodonium, suggesting a role for NQO1 and other oxidoreductases in this process. These data may explain the apparent dichotomy between the stimulatory and inhibitory effects of H(2)O(2) and menadione on insulin secretion.

PMID: 22115979 [PubMed - as supplied by publisher]

Endocrine oncology in pregnancy.

Fetched: November 28th, 2011, 10:01pm MST

Endocrine oncology in pregnancy.

Best Pract Res Clin Endocrinol Metab. 2011 Dec;25(6):911-26

Authors: Lansdown A, Rees DA

Abstract
Endocrine tumours occur rarely in pregnant women but present clinicians with unique challenges. A high index of suspicion is often required to make a diagnosis since the symptoms and signs associated with many of these tumours, including insulinoma, adrenocortical carcinoma and phaeochromocytoma, mimic those of normal pregnancy or its complications, such as pre-eclampsia. The evidence base which informs management is very limited hence decisions on investigation and therapy must be individualised and undertaken jointly by the multidisciplinary medical team and the patient. The optimal strategy will depend on the nature and stage of the endocrine tumour, gestational stage, treatments available and patient wishes. Thus, surgical intervention, appropriately timed, may be considered in pregnancy for resectable adrenocortical carcinoma or phaeochromocytoma, but delayed until the postpartum period for well-differentiated thyroid cancer. Medical therapy may be required to reduce the drive to tumour growth, control symptoms of hormone excess and to minimise the risks of surgery, anaesthesia or labour.

PMID: 22115166 [PubMed - in process]

Essential Role of the Small GTPase Ran in Postnatal Pancreatic Islet Development.

Fetched: November 28th, 2011, 10:01pm MST

Essential Role of the Small GTPase Ran in Postnatal Pancreatic Islet Development.

PLoS One. 2011;6(11):e27879

Authors: Xia F, Dohi T, Martin NM, Raskett CM, Liu Q, Altieri DC

Abstract
The small GTPase Ran orchestrates pleiotropic cellular responses of nucleo-cytoplasmic shuttling, mitosis and subcellular trafficking, but whether deregulation of these pathways contributes to disease pathogenesis has remained elusive. Here, we generated transgenic mice expressing wild type (WT) Ran, loss-of-function Ran T24N mutant or constitutively active Ran G19V mutant in pancreatic islet β cells under the control of the rat insulin promoter. Embryonic pancreas and islet development, including emergence of insulin(+) β cells, was indistinguishable in control or transgenic mice. However, by one month after birth, transgenic mice expressing any of the three Ran variants exhibited overt diabetes, with hyperglycemia, reduced insulin production, and nearly complete loss of islet number and islet mass, in vivo. Deregulated Ran signaling in transgenic mice, adenoviral over-expression of WT or mutant Ran in isolated islets, or short hairpin RNA (shRNA) silencing of endogenous Ran in model insulinoma INS-1 cells, all resulted in decreased expression of the pancreatic and duodenal homeobox transcription factor, PDX-1, and reduced β cell proliferation, in vivo. These data demonstrate that a finely-tuned balance of Ran GTPase signaling is essential for postnatal pancreatic islet development and glucose homeostasis, in vivo.

PMID: 22114719 [PubMed - in process]

[Munchausen syndrome in an extreme form of factitious disorder].

Fetched: November 28th, 2011, 10:01pm MST

[Munchausen syndrome in an extreme form of factitious disorder].

Harefuah. 2011 Oct;150(10):778-9, 815, 814

Authors: Gil E, Mintsman I, Wolfowitz E

Abstract
Patients suffering from this disorder mimic symptoms of diseases and seek medical procedures and operations. We present a case of a patient who underwent a thorough investigation for unexplained persistent hypoglycemia. According to the algorithm approach to the non-diabetic patient, we measured insulin and c-peptide plasma levels while glucose levels were low and looked for sulphonylurea, blood and urine traces. Following the above, an endoscopic ultrasound demonstrated a small pancreatic lesion and an explorative laparotomy was performed to detect an insulinoma. This procedure was complicated by partial colectomy due to colonic gangrene. Following the patient's recovery, hypoglycemia recurred and the laboratory tests were repeated, revealing trace amounts of glipizide in her serum and urine. Studies which examined the prevalence of the phenomenon among cases of unexplained hypoglycemia, including patients who were operated for presumed insulinoma, were reviewed. No specific therapy for factitious disorder has been established. Management is based upon psychotherapy which is often not very effective. We recommend that one has to keep in mind that negative tests for sulphonylurea traces in serum and urine, do not contradict the diagnosis of factitious disorder, and it is recommended to repeat these tests several times.

PMID: 22111121 [PubMed - in process]

Global histone modification pattern predicts poor prognosis in organic hyperinsulinism.

Fetched: November 24th, 2011, 10:00pm MST

Global histone modification pattern predicts poor prognosis in organic hyperinsulinism.

Horm Metab Res. 2011 Nov;43(12):858-64

Authors: Raffel A, Krausch M, Roushan K, Anlauf M, Henopp T, Hafner D, Lehwald N, Kröpil F, Schott M, Eisenberger CF, Knoefel WT, Stoecklein NH

Abstract
Here we tested whether global histone modifications predict survival in organic hyperinsulinism and whether global histone modification pattern can be used to distinguish benign from malignant primary insulinoma. A tissue microarray (TMA) was built, using samples from 63 patients with organic hyperinsulinism. The TMA was classified according to the WHO classification of 2004 [WHO 1A: benign insulinoma (wdPET); WHO 1B: unknown behavior (wdPETub); WHO 2/3: malignant insulinoma (wdPEC/pdPEC)]. The TMA consisted of tissue cores from islands of Langerhans, primary insulinomas, lymph node metastases, and hepatic metastases. Immunohistochemistry was performed on consecutive TMA slides with antibodies against H3K9Ac, H3K18Ac, H4K12Ac, H3K4diMe, and H4R3diMe. The Remmele immunoreactive scoring system was used to classify the staining. The IHC staining results were correlated to the WHO-classification of 2004 as well as to clinical follow-up data (mean: 107 months; range: 1-312 months). A nuclear staining pattern was observed for all antibodies directed against histone H3 and H4 acetylation/methylation sites. We observed significant differences in the distribution of the medians across all investigated tissue types (H3K9Ac, p=0.004; H3K18Ac, p=0.001; H4K12Ac, p=0.006; H4R3diMe, p=0.002) except for H3K4diMe (p=0.183). Correlation of the histone modification with the WHO-classification and clinical follow-up data, showed in the dichotomized groups ["low" (score 0-3), "moderate" (4-7) vs. "high" (≥8)] that patients with lower H3K18Ac levels ("low + moderate") had a significantly decreased relapse-free survival vs. patients with high H3K18Ac levels (p=0.038). The WHO classification and age were also of significant prognostic impact upon univariate analysis. A backwards Cox proportional hazards model revealed the independent prognostic effekt of H3K18Ac levels. Our data revealed low K18 acetylation levels of histone H3 as independent prognostic factor in organic hyperinsulinism. This result warrants validation with independent data sets of organic hyperinsulinism, but is in line with several previous studies in different cancer entities. The broad applicability of this potential biomarker might lead to standardized diagnostic tests in near future and may help to manage insulinoma patients more effectively.

PMID: 22105476 [PubMed - in process]

Permalink for 'HLA-DQB1 genotypes and islet cell autoantibodies against GAD65 and IA-2 in relation to development of diabetes post partum in women with gestational diabetes mellitus.'

HLA-DQB1 genotypes and islet cell autoantibodies against GAD65 and IA-2 in relation to development of diabetes post partum in women with gestational diabetes mellitus.

Fetched: November 24th, 2011, 10:00pm MST

HLA-DQB1 genotypes and islet cell autoantibodies against GAD65 and IA-2 in relation to development of diabetes post partum in women with gestational diabetes mellitus.

Diabetes Res Clin Pract. 2011 Nov 19;

Authors: Papadopoulou A, Lynch KF, Anderberg E, Landin-Olsson M, Hansson I, Agardh CD, Lernmark A, Berntorp K

Abstract
AIMS: To study HLA-DQB1 genes and islet cell autoantibodies against glutamic acid decarboxylase 65 (GADA) and insulinoma antigen-2 (IA-2A) in relation to diabetes post partum in mothers with diagnosed gestational diabetes mellitus (GDM). METHODS: During 2003-2004, women undergoing a 75g oral glucose tolerance test (OGTT) during pregnancy were invited to participate in the Mamma Study. Cut-off level defining GDM was a 2-h capillary blood glucose of 7.8mmol/L. 1-2 years after delivery a 75g OGTT was performed, GADA and IA-2A were measured and HLA-DQB1 genes analysed. Data were available for 452 mothers with previous GDM and 168 randomly selected control subjects. RESULTS: HLA-DQB1*0602 was negatively associated with GDM (p=0.033) and with development of diabetes post partum (p=0.017), whereas high risk HLA were not associated with GDM or with diabetes. The presence of GADA post partum was positively associated with diabetes post partum (p=0.0009), but not with impaired glucose tolerance. CONCLUSIONS: Mothers with GDM and HLA-DQB1*0602 were less likely to develop diabetes after pregnancy, and type 1 diabetes associated high risk HLA genes did not predict type 1 diabetes post partum. Additionally, GADA were positively associated with diabetes development.

PMID: 22104260 [PubMed - as supplied by publisher]

Glucagon-like peptide 1 receptor plays a critical role in geniposide-regulated insulin secretion in INS-1 cells.

Fetched: November 24th, 2011, 10:00pm MST

Glucagon-like peptide 1 receptor plays a critical role in geniposide-regulated insulin secretion in INS-1 cells.

Acta Pharmacol Sin. 2011 Nov 21;

Authors: Guo LX, Xia ZN, Gao X, Yin F, Liu JH

Abstract
Aim:To explore the role of the glucagon-like peptide 1 receptor (GLP-1R) in geniposide regulated insulin secretion in rat INS-1 insulinoma cells.Methods:Rat INS-1 insulinoma cells were cultured. The content of insulin in the culture medium was measured with ELISA assay. GLP-1R gene in INS-1 cells was knocked down with shRNA interference. The level of GLP-1R protein in INS-1 cells was measured with Western blotting.Results:Geniposide (0.01-100 μmol/L) increased insulin secretion from INS-1 cells in a concentration-dependent manner. Geniposide (10 μmol/L) enhanced acute insulin secretion in response to both the low (5.5 mmol/L) and moderately high levels (11 mmol/L) of glucose. Blockade of GLP-1R with the GLP-1R antagonist exendin (9-39) (200 nmol/L) or knock-down of GLP-1R with shRNA interference in INS-1 cells decreased the effect of geniposide (10 μmol/L) on insulin secretion stimulated by glucose (5.5 mmol/L).Conclusion:Geniposide increases insulin secretion through glucagon-like peptide 1 receptors in rat INS-1 insulinoma cells.

PMID: 22101168 [PubMed - as supplied by publisher]

Basolateral rather than apical primary cilia on neuroepithelial cells committed to delamination.

Fetched: November 20th, 2011, 10:01pm MST

Basolateral rather than apical primary cilia on neuroepithelial cells committed to delamination.

Development. 2011 Nov 17;

Authors: Wilsch-Bräuninger M, Peters J, Paridaen JT, Huttner WB

Abstract
Delamination of neural progenitors from the apical adherens junction belt of the neuroepithelium is a hallmark of cerebral cortex development and evolution. Specific cell biological processes preceding this delamination are largely unknown. Here, we identify a novel, pre-delamination state of neuroepithelial cells in mouse embryonic neocortex. Specifically, in a subpopulation of neuroepithelial cells that, like all others, exhibit apical-basal polarity and apical adherens junctions, the re-establishing of the primary cilium after mitosis occurs at the basolateral rather than the apical plasma membrane. Neuroepithelial cells carrying basolateral primary cilia appear at the onset of cortical neurogenesis, increase in abundance with its progression, selectively express the basal (intermediate) progenitor marker Tbr2, and eventually delaminate from the apical adherens junction belt to become basal progenitors, translocating their nucleus from the ventricular to the subventricular zone. Overexpression of insulinoma-associated 1, a transcription factor known to promote the generation of basal progenitors, increases the proportion of basolateral cilia. Basolateral cilia in cells delaminating from the apical adherens junction belt are preferentially found near spot-like adherens junctions, suggesting that the latter provide positional cues to basolateral ciliogenesis. We conclude that re-establishing a basolateral primary cilium constitutes the first known cell biological feature preceding neural progenitor delamination.

PMID: 22096071 [PubMed - as supplied by publisher]

Permalink for 'An important minority of prediabetic first-degree relatives of type 1 diabetic patients derives from seroconversion to persistent autoantibody positivity after 10 years of age.'

An important minority of prediabetic first-degree relatives of type 1 diabetic patients derives from seroconversion to persistent autoantibody positivity after 10 years of age.

Fetched: November 20th, 2011, 10:01pm MST

An important minority of prediabetic first-degree relatives of type 1 diabetic patients derives from seroconversion to persistent autoantibody positivity after 10 years of age.

Diabetologia. 2011 Nov 18;

Authors: Vermeulen I, Weets I, Costa O, Asanghanwa M, Verhaeghen K, Decochez K, Ruige J, Casteels K, Wenzlau J, Hutton JC, Pipeleers DG, Gorus FK,

Abstract
AIMS/HYPOTHESIS: The appearance of autoantibodies (Abs) before diabetes onset has mainly been studied in young children. However, most patients develop type 1 diabetes after the age of 15 years. In first-degree relatives aged under 40 years, we investigated the frequency of seroconversion to (persistent) Ab positivity, progression to diabetes and baseline characteristics of seroconverters according to age. METHODS: Abs against insulin (IAA), glutamate decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A) and zinc transporter 8 (ZnT8A) were measured during follow-up of 7,170 first-degree relatives. RESULTS: We identified 379 (5.3%) relatives with positivity for IAA, GADA, IA-2A and/or ZnT8A (Ab(+)) at first sampling and 224 (3.1%) at a later time point. Most seroconversions occurred after the age of 10 years (63%). During follow-up, Abs persisted more often in relatives initially Ab(+) (76%) than in seroconverters (53%; p < 0.001). In both groups diabetes developed at a similar pace and almost exclusively with Ab persistence (136 of 139 prediabetic individuals). For both groups, progression was more rapid if Abs appeared before the age of 10 years. Baseline characteristics at seroconversion did not vary significantly according to age. CONCLUSIONS/INTERPRETATION: Seroconversion to (persistent) Ab(+) occurs regardless of age. Although the progression rate to diabetes is higher under age 10 years, later seroconverters (up to age 40 years) have similar characteristics when compared with age-matched initially Ab(+) relatives and generate an important minority of prediabetic relatives, warranting their identification and, eventually, enrolment in prevention trials.

PMID: 22095238 [PubMed - as supplied by publisher]

Permalink for 'Menin Missense Mutants Encoded by the MEN1 Gene that Are Targeted to the Proteasome: Restoration of Expression and Activity by CHIP siRNA.'

Menin Missense Mutants Encoded by the MEN1 Gene that Are Targeted to the Proteasome: Restoration of Expression and Activity by CHIP siRNA.

Fetched: November 20th, 2011, 10:01pm MST

Menin Missense Mutants Encoded by the MEN1 Gene that Are Targeted to the Proteasome: Restoration of Expression and Activity by CHIP siRNA.

J Clin Endocrinol Metab. 2011 Nov 16;

Authors: Canaff L, Vanbellinghen JF, Kanazawa I, Kwak H, Garfield N, Vautour L, Hendy GN

Abstract
Context:In multiple endocrine neoplasia type 1 (MEN1) characterized by tumors of parathyroid, enteropancreas, and anterior pituitary, missense mutations in the MEN1 gene product, menin, occur in a subset of cases. The mutant proteins are degraded by the proteasome. However, whether their expression and activity can be restored is not known.Objective:Our objective was to functionally characterize a panel of 16 menin missense mutants, including W423R and S443Y identified in new MEN1 families, with respect to protein stability, targeting to the proteasome and restoration of expression by proteasome inhibitors and expression and function by small interfering RNA technology.Methods:Flag-tagged wild-type (WT) and missense menin mutant expression vectors were transiently transfected in human embryonic kidney (HEK293) and/or rat insulinoma (Rin-5F) cells.Results:The majority of mutants were short-lived, whereas WT menin was stable. Proteasome inhibitors MG132 and PS-341 and inhibition of the chaperone, heat-shock protein 70 (Hsp70), or the ubiquitin ligase, COOH terminus of Hsp70-interacting protein (CHIP), by specific small interfering RNA, restored the levels of the mutants, whereas that of WT menin was largely unaffected. Inhibition of CHIP restored the ability of mutants to mediate normal functions of menin: TGF-β up-regulation of the promoters of its target genes, the cyclin-dependent kinase inhibitors p15 and p21 as well as TGF-β inhibition of cell numbers.Conclusion:When the levels of missense menin mutants that are targeted to the proteasome are normalized they may function similarly to WT menin. Potentially, targeting specific components of the proteasome chaperone pathway could be beneficial in treating a subset of MEN1 cases.

PMID: 22090276 [PubMed - as supplied by publisher]

Culturing INS-1 cells on CDPGYIGSR-, RGD- and fibronectin surfaces improves insulin secretion and cell proliferation.

Fetched: November 20th, 2011, 10:01pm MST

Culturing INS-1 cells on CDPGYIGSR-, RGD- and fibronectin surfaces improves insulin secretion and cell proliferation.

Acta Biomater. 2011 Nov 4;

Authors: Kuehn C, Dubiel EA, Sabra G, Vermette P

Abstract
Rat insulinoma cells (INS-1), an immortalized pancreatic beta cell line, were cultured on low-fouling carboxymethyl-dextran (CMD) layers bearing fibronectin, the tripeptide Arg-Gly-Asp (RGD) or CDPGYIGSR, a laminin nonapeptide. INS-1 cells were non-adherent on CMD and RGE but adhered to fibronectin- and peptide-coated CMD surfaces and to tissue culture polystyrene (TCPS). On CMD-bearing fibronectin and the peptides, INS-1 cells showed higher glucose-stimulated insulin secretion compared to those on TCPS, bare CMD and RGE. INS-1 cells experienced a net cell growth, with the lowest found after 7days on CMD and the highest on fibronectin. Similarly, cells on RGD and CDPGYIGSR showed lower net growth rates than those on fibronectin. Expression of E-cadherin and integrins α(v)β(3) and α(5) were similar between the conditions, except for α(5) expression on fibronectin, RGD and CDPGYIGSR. Larger numbers of Ki-67-positive cells were found on CDPGYIGSR, TCPS, fibronectin and RGD. Cells in all conditions expressed Pdx1.

PMID: 22085924 [PubMed - as supplied by publisher]

5-Hydroxy-eicosapentaenoic acid is an endogenous GPR119 agonist and enhances glucose-dependent insulin secretion.

Fetched: November 16th, 2011, 10:01pm MST

5-Hydroxy-eicosapentaenoic acid is an endogenous GPR119 agonist and enhances glucose-dependent insulin secretion.

Biochem Biophys Res Commun. 2011 Nov 6;

Authors: Kogure R, Toyama K, Hiyamuta S, Kojima I, Takeda S

Abstract
GPR119 is one of the G-protein-coupled receptors expressed in pancreatic β-cells and intestinal endocrine cells. Since agonists to GPR119 stimulate glucose-dependent insulin secretion, GPR119 agonists are anticipated to promote anti-diabetic effects and control of glucose homeostasis. Here, we reported that an omega-3 unsaturated fatty acid metabolite, 5-hydroxy-eicosapentaenoic acid (5-HEPE), was a potent agonist for GPR119 and enhanced glucose-dependent insulin secretion. 5-HEPE stimulated cAMP accumulation in mouse MIN6 insulinoma cells and human HuTu80 intestinal adenocarcinoma cells. These effects were blunted by GPR119-specific siRNA. Recombinant GPR119 also responded to 5-HEPE as well as authentic agonists. Several previous reports have indicated the beneficial biological effects of omega-3 unsaturated fatty acids, and epidemiological studies have suggested that these fatty acids plays a protective role against diabetes. However, the molecular pharmacology and receptor identifications of omega-3 unsaturated fatty acids and their metabolites have not yet been well investigated. It is hoped that our findings will encourage novel investigations into the molecular relationships between omega-3 fatty acids and diabetes.

PMID: 22079287 [PubMed - as supplied by publisher]

Permalink for 'The plant hormone abscisic acid increases in human plasma after hyperglycemia and stimulates glucose consumption by adipocytes and myoblasts.'

The plant hormone abscisic acid increases in human plasma after hyperglycemia and stimulates glucose consumption by adipocytes and myoblasts.

Fetched: November 16th, 2011, 10:01pm MST

The plant hormone abscisic acid increases in human plasma after hyperglycemia and stimulates glucose consumption by adipocytes and myoblasts.

FASEB J. 2011 Nov 10;

Authors: Bruzzone S, Ameri P, Briatore L, Mannino E, Basile G, Andraghetti G, Grozio A, Magnone M, Guida L, Scarfì S, Salis A, Damonte G, Sturla L, Nencioni A, Fenoglio D, Fiory F, Miele C, Beguinot F, Ruvolo V, Bormioli M, Colombo G, Maggi D, Murialdo G, Cordera R, De Flora A, Zocchi E

Abstract
The plant hormone abscisic acid (ABA) is released from glucose-challenged human pancreatic β cells and stimulates insulin secretion. We investigated whether plasma ABA increased during oral and intravenous glucose tolerance tests (OGTTs and IVGTTs) in healthy human subjects. In all subjects undergoing OGTTs (n=8), plasma ABA increased over basal values (in a range from 2- to 9-fold). A positive correlation was found between the ABA area under the curve (AUC) and the glucose AUC. In 4 out of 6 IVGTTs, little or no increase of ABA levels was observed. In the remaining subjects, the ABA increase was similar to that recorded during OGTTs. GLP-1 stimulated ABA release from an insulinoma cell line and from human islets, by ∼10- and 2-fold in low and high glucose, respectively. Human adipose tissue also released ABA in response to high glucose. Nanomolar ABA stimulated glucose uptake, similarly to insulin, in rat L6 myoblasts and in murine 3T3-L1 cells differentiated to adipocytes, by increasing GLUT-4 translocation to the plasma membrane. Demonstration that a glucose load in humans is followed by a physiological rise of plasma ABA, which can enhance glucose uptake by adipose tissues and muscle cells, identifies ABA as a new mammalian hormone involved in glucose metabolism.-Bruzzone, S., Ameri, P., Briatore, L., Mannino, E., Basile, G., Andraghetti, G., Grozio, A., Magnone, M., Guida, L., Scarfì, S., Salis, A., Damonte, G., Sturla, L., Nencioni, A., Fenoglio, D., Fiory, F., Miele, C., Beguinot, F., Ruvolo, V., Bormioli, M., Colombo, G., Maggi, D., Murialdo, G., Cordera, R., De Flora, A., Zocchi, E. The plant hormone abscisic acid increases in human plasma after hyperglycemia and stimulates glucose consumption by adipocytes and myoblasts.

PMID: 22075645 [PubMed - as supplied by publisher]

Permalink for 'AKT inhibition by triciribine alone or as combination therapy for growth control of gastroenteropancreatic neuroendocrine tumors.'

AKT inhibition by triciribine alone or as combination therapy for growth control of gastroenteropancreatic neuroendocrine tumors.

Fetched: November 16th, 2011, 10:01pm MST

AKT inhibition by triciribine alone or as combination therapy for growth control of gastroenteropancreatic neuroendocrine tumors.

Int J Oncol. 2011 Nov 7;

Authors: Gloesenkamp CR, Nitzsche B, Ocker M, Di Fazio P, Quint K, Hoffmann B, Scherübl H, Höpfner M

Abstract
Up-regulation of phosphatidylinositol-3-kinase (PI3K)-AKT signaling facilitates tumor cell growth and inhibits cell demise. The AKT-pathway also plays an important role in cytostatic therapy resistance and response to hypoxia and angiogenesis. Using real-time cell proliferation assay we examined the potency of triciribine in three distinct neuroendocrine gastrointestinal tumor cell lines. Also we investigated triciribine's induction of apoptosis and effects on a broad range of cancer-associated gene products. Furthermore, we characterized the role of PTEN as a possible predictor of sensitivity to triciribine in GEP-NETs. We also looked for additive anti-neoplastic effects of triciribine when combined with conventional cytostatic drugs or other targeted drugs, affecting different molecules of the PI3K-AKT-pathway and we assessed the potency of triciribine to inhibit tumor growth in vivo, by using the chick chorioallantoic membrane assay. Treatment of insulinoma (CM) or gut neuroendocrine tumor cells (STC-1) with triciribine significantly reduced tumor cell growth by 59% and 65%, respectively. By contrast, the highly expressing PTEN carcinoid cell line BON did not respond, even at higher doses. Combinations of triciribine with classic cytostatic drugs as well as drugs targeting other molecules of the PI3K-AKT-pathway led to synergistic anti-proliferative effects. Additional in vivo-evaluations confirmed the anti-neoplastic potency of triciribine. Thus, our data show that inhibition the AKT-pathway potently reduces the growth of GEP-NET cells alone or in combination therapies. AKT inhibition may provide a rationale for future evaluations.

PMID: 22075556 [PubMed - as supplied by publisher]

Permalink for 'The predictive value of mean platelet volume in differential diagnosis of non-functional pancreatic neuroendocrine tumors from pancreatic adenocarcinomas.'

The predictive value of mean platelet volume in differential diagnosis of non-functional pancreatic neuroendocrine tumors from pancreatic adenocarcinomas.

Fetched: November 16th, 2011, 10:01pm MST

The predictive value of mean platelet volume in differential diagnosis of non-functional pancreatic neuroendocrine tumors from pancreatic adenocarcinomas.

Eur J Intern Med. 2011 Dec;22(6):e95-8

Authors: Karaman K, Bostanci EB, Aksoy E, Kurt M, Celep B, Ulas M, Dalgic T, Surmelioglu A, Hayran M, Akoglu M

Abstract
OBJECTIVE: The aim of the present study is to evaluate in a retrospective manner the diagnostic value of mean platelet volume (MPV) in pancreatic adenocarcinomas and pancreatic neuroendocrine tumors (PNETs).
PATIENTS AND METHODS: A total of 92 patients, who were admitted for pancreatic adenocarcinoma (n=76) and PNET (n=16) between March 2007 and December 2009, were analyzed retrospectively for demographics and clinical information.
RESULTS: Thirty-nine patients (51.3%) had a resectable, whereas 37 patients (48.7%) had an unresectable pancreatic adenocarcinoma. Nine patients (56.3%) had a non-functional PNET, 6 patients (37.5%) had an insulinoma, and the remaining one patient had a gastrinoma. The mean age was 59.3±10.5 for pancreatic adenocarcinomas and 45.1±10.6 for PNETs. The mean age at diagnosis was significantly higher in patients with pancreatic adenocarcinomas than the patients with PNET (p<0.001). Preoperative mean hemoglobin levels were significantly lower in patients with pancreatic adenocarcinoma than those with PNET (12.4±1.8g/dl vs 13.7±2.2g/dl), (p<0.013). The preoperative median MPV levels were significantly lower in patients with PNET 7.8fL (7.2-9.4) than in patients with pancreatic adenocarcinomas 8.6fL (6.6-13.5), (p<0.014). In subgroup analysis, a significant difference in MPV levels was mainly caused by the difference between pancreatic adenocarcinomas and non-functional PNETs (p=0.017). The cut-off value of MPV level for detection of PNETs was calculated as≤7.8fL using ROC analysis [Sensitivity: 66.7%, specificity: 75.9%, AUC: 0.734 (0.587-0.880) p=0.022]. In logistic regression analysis, independent predictive factors for determining PNETs in the differential diagnosis of pancreatic adenocarcinomas were calculated as age (OR=0.068, 95% CI: 0.012-0.398), Ca 19-9 (OR=0.039, 95% CI: 0.006-0.263), MPV (OR=0.595, 95% CI: 0.243-1.458), and hemoglobin (OR=1.317, 95% CI: 0.831-2.086).
CONCLUSION: Age, Ca 19-9, MPV, and hemoglobin levels have diagnostic value for distinguishing PNETs from pancreatic adenocarcinomas.

PMID: 22075321 [PubMed - in process]

Permalink for 'Targeting tumor-associated endothelial cells: anti-VEGFR2-immunoliposomes mediate tumor-vessel disruption and inhibit tumor growth.'

Targeting tumor-associated endothelial cells: anti-VEGFR2-immunoliposomes mediate tumor-vessel disruption and inhibit tumor growth.

Fetched: November 10th, 2011, 10:01pm MST

Targeting tumor-associated endothelial cells: anti-VEGFR2-immunoliposomes mediate tumor-vessel disruption and inhibit tumor growth.

Clin Cancer Res. 2011 Nov 7;

Authors: Wicki A, Rochlitz C, Ritschard R, Orleth A, Albrecht I, Herrmann R, Christofori G, Mamot C

Abstract
PURPOSE: Angiogenesis is a key process in tumor progression. By binding vascular endothelial growth factor (VEGF), VEGF receptor-2 (VEGFR2) is a main signaling transducer in tumor-associated angiogenesis. Accordingly, therapeutic approaches against the VEGF/VEGFR2 signaling axis have been designed. However, an efficient and specific chemotherapeutic targeting of tumor-associated endothelial cells has not yet been achieved. EXPERIMENTAL DESIGN: We have employed anti-VEGFR2 antibodies covalently linked to pegylated liposomal doxorubicin (PLD) to specifically ablate tumor-associated endothelial cells in the Rip1Tag2 mouse model of insulinoma, in the MMTV-PyMT mouse model of breast cancer, and in the HT29 human colon cancer xenograft transplantation model. RESULTS: In each model, anti-VEGFR2-targeted immunoliposomes loaded with doxorubicin (anti-VEGFR2-ILs-dox) were superior in therapeutic efficacy to empty liposomes, empty anti-VEGFR2, antibodies alone, and PLD. Efficacy was similar to that of the oral VEGFR1, -2 and -3 inhbitor PTK787. Detailed histopathological and molecular analysis revealed a strong anti-angiogenic effect of anti-VEGFR2-ILs-dox, and the observed anti-angiogenic therapy was significantly more efficient in reducing tumor burden in well-vascularized transgenic mouse models as compared to the less-vascularized xenograft model.CONCLUSIONS: Anti-VEGFR2 immunoliposomes provide a highly efficient approach to selectively deplete VEGFR2-expressing tumor vasculature. They offer a novel and promising anti-cancer strategy.

PMID: 22065082 [PubMed - as supplied by publisher]

Loss of Bmal1 leads to uncoupling and impaired glucose-stimulated insulin secretion in β-cells.

Fetched: November 4th, 2011, 11:01pm MDT

Loss of Bmal1 leads to uncoupling and impaired glucose-stimulated insulin secretion in β-cells.

Islets. 2011 Nov 1;3(6):381-8

Authors: Lee J, Kim MS, Li R, Liu VY, Fu L, Moore DD, Ma K, Yechoor VK

Abstract
The circadian clock has been shown to regulate metabolic homeostasis. Mice with a deletion of Bmal1, a key component of the core molecular clock, develop hyperglycemia and hypoinsulinemia, suggesting β-cell dysfunction. However, the underlying mechanisms are not fully known. In this study, we investigated the mechanisms underlying the regulation of β-cell function by Bmal1. We studied β-cell function in global Bmal1-/- mice, in vivo and in isolated islets ex vivo, as well as in rat insulinoma cell lines with shRNA-mediated Bmal1 knockdown. Global Bmal1-/- mice develop diabetes secondary to a significant impairment in glucose-stimulated insulin secretion (GSIS). There is a blunting of GSIS in both isolated Bmal1-/- islets and in Bmal1 knockdown cells, as compared to controls, suggesting that this is secondary to a loss of cell-autonomous effect of Bmal1. In contrast to previous studies, in these Bmal1-/- mice on a C57Bl/6 background, the loss of stimulated insulin secretion, interestingly, is with glucose but not to other depolarizing secretagogues, suggesting that events downstream of membrane depolarization are largely normal in Bmal1-/- islets. This defect in GSIS occurs as a result increased mitochondrial uncoupling with consequent impairment of glucose-induced mitochondrial potential generation and ATP synthesis, due to an upregulation of Ucp2. Inhibition of Ucp2, in isolated islets, leads to a rescue of the glucose-induced ATP production and insulin secretion in Bmal1-/- islets. Thus, Bmal1 regulates mitochondrial energy metabolism to maintain normal GSIS and its disruption leads to diabetes due to a loss of GSIS.

PMID: 22045262 [PubMed - in process]

Preoperative Tumor Studies Using MRI or CT in Patients with Clinically Suspected Insulinoma.

Fetched: November 4th, 2011, 11:01pm MDT

Preoperative Tumor Studies Using MRI or CT in Patients with Clinically Suspected Insulinoma.

Pancreatology. 2011 Oct 26;11(5):487-494

Authors: Daneshvar K, Grenacher L, Mehrabi A, Kauczor HU, Hallscheidt P

Abstract
Purpose: Insulinomas are rare tumors that originate from the islet cells of the pancreas. The aims of this study were to localize insulinomas preoperatively using CT and/or MRI in correlation with postoperative pathological results. Patients and Methods: Between December 2001 and June 2010, 27 consecutive patients with clinically suspected insulinoma were surgically treated in our university hospital. Preoperative CT (14 of 27 patients) and MRI studies (14 of 27 patients, one patient had both MRI and CT), operation reports, intraoperative ultrasonography reports, and pathological diagnoses were analyzed retrospectively. For each lesion, images were analyzed based on the presence of enhancement or the characteristics of signal intensities. Pathologic correlation was available for all the lesions. Results: The female: male ratio was 2.9, with a mean age of 47.5 years (range 12-82) . Preoperative tumor localization was achieved by means of MRI and CT. A focal pancreatic lesion, which was hypointense on T(1)-weighted sequences, was detected on all the MR images (14 of 27 patients; 100%). These lesions were isointense (4 cases) to slightly hyperintense (10 of 14 cases) on T(2)-weighted sequences. In T(1)-weighted fat-suppressed contrast-enhanced sequences, there were two types of enhancement: homogeneously hyperintense lesions (in 10 of 14 cases) or peripherally hyper-, centrally isointense (in 4 of 14 cases). On all the CT images (14 of 27 patients), there was no detectable lesion on precontrast series; on arterial series in 13 of 14 patients (arterial series has not been done in one patient), lesions enhanced hypervascular in contrast to the rest of the pancreas with a mean enhancement of 147 HU (range 113-248) and 95 HU (range 65-141), respectively. On venous series in 13 of 14 patients (venous series has not been done in one patient), there was an enhanced lesion in contrast to the rest of the pancreas with a mean enhancement of 110 HU (range 91-151) and 86 HU (range 65-137), respectively. Intraoperative ultrasonography was performed in 11 of 27 patients to localize the tumor, which correlated with the results of the mentioned preoperative studies. Tumor size ranged from 9 × 11 to 31 × 37 mm. Enucleation was carried out in 14 patients, Whipple in 5, segmental resection in 3 and left distal pancreatectomy in 5 patients. The mortality rate was 0. Pathological findings were insulinoma or neuroendocrine tumors in 26 of 27 cases. One patient had a pathological finding of chronic pancreatic disease with intraepithelial neoplasia (grade 1A). Conclusion: We conclude that the preoperative localization of insulinoma in clinically suspected patients can be made on the basis of MRI and/or CT studies. A hallmark lesion is hypointense in T(1)-weighted sequences, homogeneously or peripherally hyperintense in T(1)-weighted fat-suppressed contrast-enhanced sequence using MRI (100% of cases) or/and a hypervascular enhanced lesion on arterial (100% of CT studies) and on venous series using CT (66.7% of CT studies). and IAP.

PMID: 22042212 [PubMed - as supplied by publisher]

Endoscopic ultrasound-guided ethanol ablation of a symptomatic sporadic insulinoma.

Fetched: November 4th, 2011, 11:01pm MDT

Endoscopic ultrasound-guided ethanol ablation of a symptomatic sporadic insulinoma.

Endoscopy. 2011 Oct;43 Suppl 2:E328-9

Authors: Vleggaar FP, Bij de Vaate EA, Valk GD, Leguit RJ, Siersema PD

PMID: 22020710 [PubMed - in process]

Binding of abscisic acid to human LANCL2.

Fetched: November 4th, 2011, 11:01pm MDT

Binding of abscisic acid to human LANCL2.

Biochem Biophys Res Commun. 2011 Oct 20;

Authors: Sturla L, Fresia C, Guida L, Grozio A, Vigliarolo T, Mannino E, Millo E, Bagnasco L, Bruzzone S, De Flora A, Zocchi E

Abstract
The phytohormone abscisic acid (ABA) is the central regulator of abiotic stress in plants and plays important roles during plant growth and development. In animal cells, ABA was shown to be an endogenous hormone, acting as a stress signal and stimulating cell functions involved in inflammatory responses and in insulin release. Recently, we demonstrated that Lanthionine synthetase component C-like protein 2 (LANCL2) is required for ABA binding to the plasmamembrane of granulocytes and for the activation of the signaling pathway triggered by ABA in human granulocytes and in rat insulinoma cells. In order to investigate whether ABA activates LANCL2 via direct interaction, we performed specific binding studies on human LANCL2 recombinant protein using different experimental approaches (saturation binding, scintillation proximity assays, dot blot experiments and affinity chromatography). Altogether, results indicate that human recombinant LANCL2 binds ABA directly and provide the first demonstration of ABA binding to a mammalian ABA receptor.

PMID: 22037458 [PubMed - as supplied by publisher]

A genetically engineered human pancreatic β cell line exhibiting glucose-inducible insulin secretion.

Fetched: November 4th, 2011, 11:01pm MDT

A genetically engineered human pancreatic β cell line exhibiting glucose-inducible insulin secretion.

J Clin Invest. 2011 Sep 1;121(9):3589-97

Authors: Ravassard P, Hazhouz Y, Pechberty S, Bricout-Neveu E, Armanet M, Czernichow P, Scharfmann R

Abstract
Despite intense efforts over the past 30 years, human pancreatic β cell lines have not been available. Here, we describe a robust technology for producing a functional human β cell line using targeted oncogenesis in human fetal tissue. Human fetal pancreatic buds were transduced with a lentiviral vector that expressed SV40LT under the control of the insulin promoter. The transduced buds were then grafted into SCID mice so that they could develop into mature pancreatic tissue. Upon differentiation, the newly formed SV40LT-expressing β cells proliferated and formed insulinomas. The resulting β cells were then transduced with human telomerase reverse transcriptase (hTERT), grafted into other SCID mice, and finally expanded in vitro to generate cell lines. One of these cell lines, EndoC-βH1, expressed many β cell-specific markers without any substantial expression of markers of other pancreatic cell types. The cells secreted insulin when stimulated by glucose or other insulin secretagogues, and cell transplantation reversed chemically induced diabetes in mice. These cells represent a unique tool for large-scale drug discovery and provide a preclinical model for cell replacement therapy in diabetes. This technology could be generalized to generate other human cell lines when the cell type-specific promoter is available.

PMID: 21865645 [PubMed - indexed for MEDLINE]

Rare Cancer News & Clinical Trials » Pancreas

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Pancreas (69 unread)

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