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1.
Nan Fang Yi Ke Da Xue Xue Bao ; 41(9): 1329-1333, 2021 Aug 31.
Artigo em Chinês | MEDLINE | ID: mdl-34658346

RESUMO

OBJECTIVE: To investigate the effect of overexpression of the oncogenic transcription factor ELF4 on proliferation and apoptosis in human insulinoma cells and explore the underlying mechanism. METHODS: A human insulinoma BON cell line with stable overexpression of ELF4 (BON-ELF4 cells) was constructed using a recombinant retrovirus vector and the expression of ELF4 protein was verified using Western blotting. MTT assay was used to assess the proliferation of BON-ELF4 cells and BON-Vector cells, and the cell apoptosis induced by treatment with epirubicin (0.1 µmol/L for 24 h) was analyzed by detecting the expressions of cleaved caspase-8, caspase-9, and PARP using Western blotting. Flow cytometry with Annexin VFITC/PI staining was performed to analyze the numbers of apoptotic BON-Vector or BON-ELF4 cells. The expressions of phosphorylated Akt and total Akt in the cells were detected using Western blotting. RESULTS: BON-ELF4 cell line with stable overexpression of ELF4 was successfully established. ELF4 overexpression significantly promoted the proliferation (P < 0.05) and obviously suppressed epirubicin- induced apoptosis in BON cells, resulting also in significantly reduced expressions of cleaved caspase-8, caspase-9 and PARP (P < 0.05). The results of flow cytometry showed a significantly lower apoptotic rate in BON-ELF4 cells than in BON-Vector cells following epirubicin treatment (6.03% vs 22.90%). The phosphorylation levels of Akt (Thr308 and Ser473) were significantly increased (P < 0.05) while the level of total Akt remained unchanged (P>0.05) in ELF4- overexpressing cells. CONCLUSION: ELF4 overexpression enhances the proliferation and suppresses apoptosis of insulinomas cells by activating Akt signaling.


Assuntos
Proteínas de Ligação a DNA , Insulinoma , Neoplasias Pancreáticas , Fatores de Transcrição , Apoptose , Proliferação de Células , Humanos , Neoplasias Pancreáticas/genética , Proteínas Proto-Oncogênicas c-akt , Transdução de Sinais
2.
Nutrients ; 13(9)2021 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-34578896

RESUMO

Impaired insulin secretion is one of the main causes of type 2 diabetes. Cholesterol accumulation-induced lipotoxicity contributes to impaired insulin secretion in pancreatic beta cells. However, the detailed mechanism in this process remains unclear. In this study, we proved that oxidized low-density lipoprotein (OxLDL) reduced insulin content, decreased PDX-1 expression, and impaired glucose-stimulated insulin secretion (GSIS) in INS-1 cells, which were rescued by addition of high-density lipoprotein (HDL). OxLDL receptors and cholesterol content were increased by OxLDL. Consistently, OxLDL suppressed cholesterol transporter ABCA1 expression and transcription in a dose-dependent and time-dependent manner. Inhibition of MEK by its specific inhibitor, PD98059, altered the effect of OxLDL on ABCA1 transcription and activation of ERK. Next, chromatin immunoprecipitation assay demonstrated that liver X receptor (LXR) could directly bind to ABCA1 promoter and this binding was inhibited by OxLDL. Furthermore, OxLDL decreased the nuclear LXR expression, which was prevented by HDL. LXR-enhanced ABCA1 transcription was suppressed by OxLDL, and the effect was cancelled by mutation of the LXR-binding sites. In summary, our study shows that OxLDL down-regulates ABCA1 expression by MEK/ERK/LXR pathway, leading to cholesterol accumulation in INS-1 cells, which may result in impaired insulin synthesis and GSIS.


Assuntos
Transportador 1 de Cassete de Ligação de ATP/genética , Regulação para Baixo/genética , Insulinoma/genética , Lipoproteínas LDL/genética , Receptores X do Fígado/genética , Sistema de Sinalização das MAP Quinases/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Animais , Células Cultivadas , Regulação para Baixo/fisiologia , Expressão Gênica/genética , Humanos , Insulinoma/metabolismo , Lipoproteínas LDL/metabolismo , Receptores X do Fígado/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Ratos
3.
World J Gastroenterol ; 27(32): 5322-5340, 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34539135

RESUMO

The presence of pancreatic cancer during childhood is extremely rare, and physicians may be tempted to overlook this diagnosis based on age criteria. However, there are primary malignant pancreatic tumors encountered in pediatric patients, such as pancreatoblastoma, and tumors considered benign in general but may present a malignant potential, such as the solid pseudo-papillary tumor, insulinoma, gastrinoma, and vasoactive intestinal peptide secreting tumor. Their early diagnosis and management are of paramount importance since the survival rates tend to differ for various types of these conditions. Many pediatric cancers may present pancreatic metastases, such as renal cell carcinoma, which may evolve with pancreatic metastatic disease even after two or more decades. Several childhood diseases may create a predisposition for the development of pancreatic cancer during adulthood; hence, there is a need for extensive screening strategies and complex programs to facilitate the transition from pediatric to adult healthcare. Nevertheless, genetic studies highlight the fact the specific gene mutations and family aggregations may be correlated with a special predisposition towards pancreatic cancer. This review aims to report the main pancreatic cancers diagnosed during childhood, the most important childhood diseases predisposing to the development of pancreatic malignancies, and the gene mutations associates with pancreatic malignant tumors.


Assuntos
Insulinoma , Neoplasias Pancreáticas , Adulto , Criança , Humanos , Pâncreas , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/terapia , Taxa de Sobrevida
4.
J Med Case Rep ; 15(1): 479, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34583764

RESUMO

BACKGROUND: Insulinomas are rare clinical entities, but concurrent diabetes mellitus is even more uncommon, and the combination is easily missed. Recurrent hypoglycemia could be misconstrued as improved glycemic control. We present an unusual patient with type 2 diabetes and neuroglycopenia, with apparent improved glycemic control due to an insulinoma. CASE PRESENTATION: A 54-year-old mixed ancestry man with a positive family history of type 2 diabetes mellitus was diagnosed with type 2 diabetes mellitus and hypertension 8 years prior to admission. He presented with episodes of abnormal behavior and hypoglycemia. Inappropriately high insulin and C-peptide concentrations were identified at the time of hypoglycemia. Despite poor adherence to his diabetic treatment, he had no target organ damage relating to diabetes, and his hemoglobin A1c (HbA1c) was 5.3%. A diagnosis of insulinoma was made, and he was started on diazoxide, with endoscopic ultrasound revealing a possible lesion in the pancreatic tail measuring 12 mm × 12 mm. A fine-needle aspiration biopsy could not be performed due to overlying splenic arteries and the risk of vascular perforation. An intraoperative ultrasound confirmed a 15 mm × 10 mm tumor in the pancreatic tail, necessitating a partial pancreatectomy and splenectomy, which were curative. A well-differentiated intermediate grade 2 pancreatic neuroendocrine tumor producing insulin was confirmed on histopathology. CONCLUSIONS: Recurrent, progressive hypoglycemia and improved glycemic control in a diabetic, without an alternative explanation, may suggest an insulinoma. Insulinomas that exist with type 1 diabetes mellitus, particularly malignant insulinomas, must have escaped autoimmune attack through lack of autoantigen expression. Computed tomography on its own may be insufficiently sensitive for diagnosis of insulinomas, whereas endoscopic and intraoperative ultrasonography may improve the identification of the culprit lesion.


Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemia , Insulinoma , Neoplasias Pancreáticas , Diabetes Mellitus Tipo 2/complicações , Humanos , Hipoglicemia/etiologia , Insulinoma/cirurgia , Masculino , Pessoa de Meia-Idade , Pancreatectomia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/cirurgia
5.
Eur J Endocrinol ; 185(4): 577-586, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34374651

RESUMO

Objective: Insulinomas are rare functional pancreatic neuroendocrine tumours. As previous data on the long-term prognosis of insulinoma patients are scarce, we studied the morbidity and mortality in the Finnish insulinoma cohort. Design: Retrospective cohort study. Methods: Incidence of endocrine, cardiovascular, gastrointestinal and psychiatric disorders, and cancers was compared in all the patients diagnosed with an insulinoma in Finland during 1980-2010 (n = 79, including two patients with multiple endocrine neoplasia type 1 syndrome), vs 316 matched controls, using the Mantel-Haenszel method. Overall survival was analysed with Kaplan-Meier and Cox regression analyses. Results: The median length of follow-up was 10.7 years for the patients and 12.2 years for the controls. The long-term incidence of atrial fibrillation (rate ratio (RR): 2.07 (95% CI: 1.02-4.22)), intestinal obstruction (18.65 (2.09-166.86)), and possibly breast (4.46 (1.29-15.39) and kidney cancers (RR not applicable) was increased among insulinoma patients vs controls, P < 0.05 for all comparisons. Endocrine disorders and pancreatic diseases were more frequent in the patients during the first year after insulinoma diagnosis, but not later on. The survival of patients with a non-metastatic insulinoma (n = 70) was similar to that of controls, but for patients with distant metastases (n = 9), the survival was significantly impaired (median 3.4 years). Conclusions: The long-term prognosis of patients with a non-metastatic insulinoma is similar to the general population, except for an increased incidence of atrial fibrillation, intestinal obstruction, and possibly breast and kidney cancers. These results need to be confirmed in future studies. Metastatic insulinomas entail a markedly decreased survival.


Assuntos
Insulinoma/epidemiologia , Neoplasias Pancreáticas/epidemiologia , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Comorbidade , Finlândia/epidemiologia , Seguimentos , História do Século XX , História do Século XXI , Humanos , Incidência , Insulinoma/complicações , Insulinoma/diagnóstico , Insulinoma/mortalidade , Pessoa de Meia-Idade , Morbidade , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Fatores de Tempo
6.
J Postgrad Med ; 67(3): 164-167, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34414928

RESUMO

Insulinoma is a rare neuroendocrine tumor originating from hypersecreting beta-cells of islets of Langerhans in the pancreas. We report a case of 72-year-old male, with chronic alcohol abuse, presenting with atypical features like refractory recurrent secondary generalized seizures and behavioral disturbances with increased irritability, initially mistreated as alcohol withdrawal. Detailed history, particularly the relationship of the symptoms with food intake, made us think of other causes of seizures. Fasting biochemical investigations and localizing studies helped clinch the diagnosis. The tumor was localized with the help of endoscopic ultrasonography and whole-body Ga68-DOTANOC PET-CT. The patient was treated conservatively with diazoxide and is doing well on follow-up. The present case report emphasizes the importance of detailed clinical history, more so in atypically presenting cases of refractory seizures. Insulinoma can be medically managed despite surgery being the gold standard curative treatment.


Assuntos
Anti-Hipertensivos/uso terapêutico , Diabetes Mellitus Tipo 2/complicações , Diazóxido/uso terapêutico , Insulinoma/diagnóstico por imagem , Neoplasias Pancreáticas/patologia , Idoso , Alcoolismo , Complicações do Diabetes , Diabetes Mellitus Tipo 2/sangue , Endossonografia , Humanos , Insulinoma/patologia , Insulinoma/cirurgia , Masculino , Compostos Organometálicos/metabolismo , Neoplasias Pancreáticas/cirurgia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Cintilografia , Convulsões/etiologia , Imagem Corporal Total
7.
Int J Med Robot ; 17(6): e2317, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34297475

RESUMO

BACKGROUND: Insulinomas are rare insulin-producing pancreatic neuroendocrine tumours leading to severe episodes of hypoglycaemia. Surgery is the predominant curative therapy. METHODS: We report here the first paediatric case of an insulinoma of the pancreatic body resected completely robotically under ultrasound guidance in a 10-year-old male with multiple endocrine neoplasia type 1. The port set-up was adapted for the narrowed dimensions of the paediatric peritoneal space. We comment on technical key steps for the organ-preserving procedure that was performed in close proximity to critical anatomic structures, with supporting video. Preoperative diagnostics, including endoscopic ultrasound, to determine surgical management are highlighted. RESULTS: Following an uneventful post-operative course, the boy was discharged on day 11 with normalised glucose-metabolism. A pseudocyst developing after 4 weeks was treated with endoscopic stenting. CONCLUSIONS: The applicability of a robotic surgical system in limited space conditions such as found in the paediatric abdominal cavity is demonstrated here for pancreatic surgery.


Assuntos
Insulinoma , Neoplasias Pancreáticas , Procedimentos Cirúrgicos Robóticos , Criança , Humanos , Insulinoma/cirurgia , Masculino , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/cirurgia
8.
Sci Rep ; 11(1): 15014, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294854

RESUMO

Specifying the exact localization of insulinoma remains challenging due to the lack of insulinoma-specific imaging methods. Recently, glucagon-like peptide-1 receptor (GLP-1R)-targeted imaging, especially positron emission tomography (PET), has emerged. Although various radiolabeled GLP-1R agonist exendin-4-based probes with chemical modifications for PET imaging have been investigated, an optimal candidate probe and its scanning protocol remain a necessity. Thus, we investigated the utility of a novel exendin-4-based probe conjugated with polyethylene glycol (PEG) for [18F]FB(ePEG12)12-exendin-4 PET imaging for insulinoma detection. We utilized [18F]FB(ePEG12)12-exendin-4 PET/CT to visualize mouse tumor models, which were generated using rat insulinoma cell xenografts. The probe demonstrated high uptake value on the tumor as 37.1 ± 0.4%ID/g, with rapid kidney clearance. Additionally, we used Pdx1-Cre;Trp53R172H;Rbf/f mice, which developed endogenous insulinoma and glucagonoma, since they enabled differential imaging evaluation of our probe in functional pancreatic neuroendocrine neoplasms. In this model, our [18F]FB(ePEG12)12-exendin-4 PET/CT yielded favorable sensitivity and specificity for insulinoma detection. Sensitivity: 30-min post-injection 66.7%, 60-min post-injection 83.3%, combined 100% and specificity: 30-min post-injection 100%, 60-min post-injection 100%, combined 100%, which was corroborated by the results of in vitro time-based analysis of internalized probe accumulation. Accordingly, [18F]FB(ePEG12)12-exendin-4 is a promising PET imaging probe for visualizing insulinoma.


Assuntos
Radioisótopos de Flúor , Insulinoma/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Insulinoma/patologia , Masculino , Camundongos , Camundongos Transgênicos , Tomografia por Emissão de Pósitrons/métodos , Ratos , Ensaios Antitumorais Modelo de Xenoenxerto
10.
Medicine (Baltimore) ; 100(25): e26382, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160414

RESUMO

RATIONALE: Multiple endocrine neoplasia type 1 (MEN1) is a rare tumor syndrome with an autosomal dominant inheritance, and genetic testing for MEN1 gene is important for both affected individuals and their relatives. We present a 2-person family affected by a germline c.1546dupC MEN1 mutation, and one of them had a full-spectrum of MEN-related endocrine tumors. PATIENT CONCERNS: A female patient aged 32 years presented with jejunal ulcer perforation due to gastrinoma. DIAGNOSES: We conducted genetic analysis and extensive biochemical/radiological evaluation for detecting other endocrine tumors. Multiple pancreatic neuroendocrine tumors (NETs), prolactinoma and primary hyperparathyroidism were diagnosed, and a frame-shift mutation, NM_130799.1:c.1546dupC (p.Arg516Profs∗15), was detected. One daughter of the proband, aged 12 years, had the same mutation for MEN1. INTERVENTION: She underwent pancreatic surgery for pancreatic NETs and total parathyroidectomy for primary hyperparathyroidism. OUTCOMES: After pancreatic surgery, long-term symptoms of epigastric soreness, acid belching, sweating, and palpitation in fasting were improved. Hypercalcemia was improved after parathyroidectomy and she was supplemented with oral calcium and vitamin D. Her daughter showed normal biochemical surveillance until 15 years of age. LESSONS: We report 2 people in a family affected by MEN1 with the heterozygous germline c.1546dupC mutation, a variant that should be surveilled for early development of full-blown MEN1-associated endocrine tumors.


Assuntos
Neoplasia Endócrina Múltipla Tipo 1/diagnóstico , Neoplasias Primárias Múltiplas/diagnóstico , Tumores Neuroendócrinos/diagnóstico , Proteínas Proto-Oncogênicas/genética , Adenoma/diagnóstico , Adenoma/genética , Adenoma/cirurgia , Adulto , Criança , Feminino , Mutação da Fase de Leitura , Gastrinoma/diagnóstico , Gastrinoma/genética , Gastrinoma/cirurgia , Testes Genéticos , Mutação em Linhagem Germinativa , Glucagonoma , Heterozigoto , Humanos , Hiperparatireoidismo Primário/diagnóstico , Hiperparatireoidismo Primário/genética , Hiperparatireoidismo Primário/cirurgia , Insulinoma , Neoplasia Endócrina Múltipla Tipo 1/complicações , Neoplasia Endócrina Múltipla Tipo 1/genética , Neoplasia Endócrina Múltipla Tipo 1/cirurgia , Neoplasias Primárias Múltiplas/genética , Neoplasias Primárias Múltiplas/cirurgia , Tumores Neuroendócrinos/genética , Tumores Neuroendócrinos/cirurgia , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/cirurgia , Neoplasias das Paratireoides/diagnóstico , Neoplasias das Paratireoides/genética , Neoplasias das Paratireoides/cirurgia , Paratireoidectomia , Prolactinoma/diagnóstico , Prolactinoma/genética , Prolactinoma/cirurgia
11.
Am J Physiol Cell Physiol ; 321(2): C247-C256, 2021 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-34106785

RESUMO

The islets of Langerhans of the pancreas are the primary endocrine organ responsible for regulating whole body glucose homeostasis. The use of isolated primary islets for research development and training requires organ resection, careful digestion, and isolation of the islets from nonendocrine tissue. This process is time consuming, expensive, and requires substantial expertise. For these reasons, we sought to develop a more rapidly obtainable and consistent model system with characteristic islet morphology and function that could be employed to train personnel and better inform experiments prior to using isolated rodent and human islets. Immortalized ß cell lines reflect several aspects of primary ß cells, but cell propagation in monolayer cell culture limits their usefulness in several areas of research, which depend on islet morphology and/or functional assessment. In this manuscript, we describe the propagation and characterization of insulinoma pseudo-islets (IPIs) from a rat insulinoma cell line INS832/3. IPIs were generated with an average diameter of 200 µm, consistent with general islet morphology. The rates of oxygen consumption and mitochondrial oxidation-reduction changes in response to glucose and metabolic modulators were similar to isolated rat islets. In addition, the dynamic insulin secretory patterns of IPIs were similar to primary rat islets. Thus, INS832/3-derived IPIs provide a valuable and convenient model for accelerating islet and diabetes research.


Assuntos
Diabetes Mellitus/metabolismo , Insulinoma/metabolismo , Ilhotas Pancreáticas/metabolismo , Pâncreas/metabolismo , Animais , Linhagem Celular , Glucose/metabolismo , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/metabolismo , Consumo de Oxigênio/fisiologia
12.
BMJ Case Rep ; 14(5)2021 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-34011656

RESUMO

A 55-year-old patient had spent 12 years with unexplained seizures, initially diagnosed as epilepsy and then as a psychiatric disorder. When she was admitted with hypoglycaemia, a fasting test was performed showing blood sugar levels as low as 1 mmol/L with symptoms of neuroglycopenia. Insulinoma was suspected and an MRI showed a large tumour in the tail region of the pancreas. A Dodecanetetraacetic acid-Tyr3-octreotate (DOTATATE) positron emission tomography CT indicated no malignancy and showed no signs of metastasis. The patient underwent surgery, leaving her asymptomatic.


Assuntos
Epilepsia , Insulinoma , Neoplasias Pancreáticas , Erros de Diagnóstico , Feminino , Humanos , Insulinoma/diagnóstico por imagem , Insulinoma/cirurgia , Pessoa de Meia-Idade , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia Computadorizada por Raios X
13.
Endocrine ; 74(1): 61-71, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34021851

RESUMO

PURPOSE: An increasing number of studies have shown that insulinoma-associated protein 1 (INSM1) is a robust marker for the diagnosis of gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN). The overall diagnostic accuracy of INSM1 for GEP-NEN remains unclear. The purpose of this study is to estimate the diagnostic value of INSM1 for GEP-NEN through a meta-analysis. METHODS: We searched relevant studies addressing the accuracy of INSM1 in the diagnosis of GEP-NEN from PubMed, Web of Science, Embase, Cochrane Library and China National Knowledge Infrastructure (CNKI) as well as from reference lists since the establishment of the database to January 12, 2021. Pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic (SROC) curves were used to comprehensively evaluate the diagnostic value of INSM1 for GEP-NEN. Statistical analysis was performed by Stata 15.0 and RevMan 5.4. RESULTS: Nine studies with a total of 393 patients were included in the meta-analysis. The meta-analysis results showed that the pooled sensitivity and specificity of INSM1 for the diagnosis of GEP-NEN were 0.99 (95% CI: 0.87-1.00) and 0.96 (95% CI: 0.93-0.98), respectively. The PLR and NLR were 23.3 (95% CI: 13.3-40.8) and 0.01 (95% CI: 0.00-0.14), respectively. The DOR was 380.31 (95% CI: 164.14-881.21), and the area under the curve (AUC) of SROC curve was 0.98 (95% CI: 0.96-0.99). CONCLUSIONS: The results show that INSM1 is an effective marker for the diagnosis of GEP-NEN with high sensitivity and specificity. INSM1 is recommended for clinical application to improve the diagnostic accuracy of GEP-NEN. However, more high-quality studies are needed to confirm these findings.


Assuntos
Insulinoma , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Biomarcadores , Humanos , Tumores Neuroendócrinos/diagnóstico , Neoplasias Pancreáticas/diagnóstico , Proteínas Repressoras , Sensibilidade e Especificidade
14.
N Z Vet J ; 69(4): 234-239, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33944682

RESUMO

AIMS: To compare survival in dogs with recurrent or metastatic insulinomas that were treated with palliative therapy, alone or in combination with toceranib phosphate and to assess tolerability of the combined therapy in dogs. MATERIALS AND METHODS: Dogs diagnosed with insulinoma were retrospectively identified in the records of the Veterinary Teaching Hospital Complutense (Madrid, Spain). Diagnosis of insulinoma was based on clinical signs of hypoglycaemia, concentrations in serum of glucose <3.3 mmol/L and insulin >10 µIU/mL and presence of a pancreatic mass on diagnostic imaging. Dogs were treated surgically or medically, according to clinical stage established by imaging techniques, and monitored with blood and urine analyses monthly and abdominal ultrasonography every 3 months until death. Dogs that presented with metastatic disease at diagnosis or with recurrent hypoglycaemia after surgery were treated, according to the owner's decision, with one of two treatment protocols: palliative therapy alone (control group, n=7: diet, prednisone, famotidine or omeprazole, ±octreotide) or palliative therapy in combination with toceranib (treatment group, n=5; median dose of toceranib 2.52 mg/kg). Overall survival time (OST) and adverse events were compared between the two treatment groups. RESULTS: The OST was longer in the treatment group (median 399, min 125, max 476 days) compared to the control group (median 67, min 23, max 387 days; p=0.042). Dogs in the treatment group had a higher incidence of grade 1-2 gastrointestinal toxicity (diarrhoea) than dogs in the control group (p=0.010). In all cases, gastrointestinal toxicity was solved by temporarily discontinuing toceranib. CONCLUSIONS AND CLINICAL RELEVANCE: The use of toceranib combined with palliative treatment in dogs with suspect metastatic or recurrent insulinomas increased survival time and was adequate tolerated.


Assuntos
Antineoplásicos , Doenças do Cão , Insulinoma , Neoplasias Pancreáticas , Animais , Antineoplásicos/uso terapêutico , Doenças do Cão/tratamento farmacológico , Cães , Hospitais Veterinários , Hospitais de Ensino , Indóis , Insulinoma/veterinária , Cuidados Paliativos , Neoplasias Pancreáticas/veterinária , Pirróis , Estudos Retrospectivos
15.
FASEB J ; 35(5): e21515, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33811688

RESUMO

The conserved endoplasmic reticulum (ER) membrane protein TRAPα (translocon-associated protein, also known as signal sequence receptor 1, SSR1) has been reported to play a critical but unclear role in insulin biosynthesis. TRAPα/SSR1 is one component of a four-protein complex including TRAPß/SSR2, TRAPγ/SSR3, and TRAPδ/SSR4. The TRAP complex topologically has a small exposure on the cytosolic side of the ER via its TRAPγ/SSR3 subunit, whereas TRAPß/SSR2 and TRAPδ/SSR4 function along with TRAPα/SSR1 largely on the luminal side of the ER membrane. Here, we have examined pancreatic ß-cells with deficient expression of either TRAPß/SSR2 or TRAPδ/SSR4, which does not perturb mRNA expression levels of other TRAP subunits, or insulin mRNA. However, deficient protein expression of TRAPß/SSR2 and, to a lesser degree, TRAPδ/SSR4, diminishes the protein levels of other TRAP subunits, concomitant with deficient steady-state levels of proinsulin and insulin. Deficient TRAPß/SSR2 or TRAPδ/SSR4 is not associated with any apparent defect of exocytotic mechanism but rather by a decreased abundance of the proinsulin and insulin that accompanies glucose-stimulated secretion. Amino acid pulse labeling directly establishes that much of the steady-state deficiency of intracellular proinsulin can be accounted for by diminished proinsulin biosynthesis, observed in a pulse-labeling as short as 5 minutes. The proinsulin and insulin levels in TRAPß/SSR2 or TRAPδ/SSR4 null mutant ß-cells are notably recovered upon re-expression of the missing TRAP subunit, accompanying a rebound of proinsulin biosynthesis. Remarkably, overexpression of TRAPα/SSR1 can also suppress defects in ß-cells with diminished expression of TRAPß/SSR2, strongly suggesting that TRAPß/SSR2 is needed to support TRAPα/SSR1 function.


Assuntos
Proteínas de Ligação ao Cálcio/deficiência , Retículo Endoplasmático/metabolismo , Glucose/metabolismo , Insulina/biossíntese , Insulinoma/patologia , Glicoproteínas de Membrana/deficiência , Proinsulina/biossíntese , Receptores Citoplasmáticos e Nucleares/deficiência , Receptores de Peptídeos/deficiência , Animais , Células Cultivadas , Células Secretoras de Insulina/citologia , Insulinoma/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Ratos
16.
Khirurgiia (Mosk) ; (3): 5-10, 2021.
Artigo em Russo | MEDLINE | ID: mdl-33710820

RESUMO

OBJECTIVE: To report own experience in the treatment of patients with proinsulinoma. MATERIAL AND METHODS: There were 10 patients with increased proinsulin production and normal insulin level since 2017. Most of them were young women. RESULTS: Fasting hypoglycemia in all patients was severe (up to 0.7 mmol/l). Clinical picture consisted of typical symptoms similar to those in insulinoma. The main difference in the course of proinsulinoma was the absence of weight gain in 7 patients and rapid weight loss (from 210 to 90 kg within 9 months) in 1 patient. All patients with proinsulinoma underwent surgery. In most cases, minimally aggressive surgery was performed. CONCLUSION: Proinsulinoma is an extremely rare endocrine-active neuroendocrine pancreatic tumor. Differential features of proinsulinoma are the absence of weight gain and normal insulin levels in the presence of hypoglycemia. Surgery is the only radical method of treatment.


Assuntos
Insulinoma , Neoplasias Pancreáticas , Proinsulina/biossíntese , Feminino , Humanos , Hipoglicemia/etiologia , Insulina/análise , Insulinoma/complicações , Insulinoma/diagnóstico , Insulinoma/metabolismo , Insulinoma/cirurgia , Masculino , Pâncreas/metabolismo , Pâncreas/patologia , Pâncreas/cirurgia , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/cirurgia
17.
Medicine (Baltimore) ; 100(13): e25076, 2021 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-33787590

RESUMO

RATIONALE: Ectopic insulinomas are extremely rare and challenging to diagnose for clinicians. Precise preoperative localization is essential to successful treatment. PATIENT CONCERNS: A 23-year-old man presented with a 1-year history of recurrent hypoglycemia. DIAGNOSIS: Examinations in the local hospital did not reveal any pancreatic lesion. After admission, a fasting test and a 5-hour oral glucose tolerance test (OGTT) suggested a diagnosis of endogenous hyperinsulinemic hypoglycemia. Enhanced volume perfusion computed tomography (VPCT) revealed 2 nodules in the tail of the pancreas, a nodule in the gastric antrum, and a nodule in the hilum of the spleen. To differentiate which nodule was responsible for hypoglycemia, we performed 68Ga-Exendin-4 PET/CT and 68Ga-DOTATATE PET/CT which helped to make a conclusive diagnosis that the lesion in the gastric antrum was an ectopic insulinoma. INTERVENTIONS: The patient was cured with minimally invasive laparoscopic resection of the tumor. OUTCOMES: The symptoms were relieved and the blood glucose level remained normal after surgery. CONCLUSIONS: This case shows that 68Gallium-exendin-4 PET/CT is useful for precise localization and thereby successful treatment of insulinoma, especially for occult insulinomas and those derived from an ectopic pancreas.


Assuntos
Coristoma/diagnóstico por imagem , Insulinoma/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Neoplasias Gástricas/diagnóstico por imagem , Coristoma/complicações , Exenatida , Radioisótopos de Gálio , Teste de Tolerância a Glucose , Humanos , Hipoglicemia/diagnóstico por imagem , Hipoglicemia/etiologia , Insulinoma/complicações , Masculino , Compostos Organometálicos , Pâncreas , Antro Pilórico/diagnóstico por imagem , Compostos Radiofarmacêuticos , Recidiva , Adulto Jovem
18.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 43(1): 47-52, 2021 Feb 28.
Artigo em Chinês | MEDLINE | ID: mdl-33663662

RESUMO

Objective To determine the appropriate averaging strategy for pancreatic perfusion datasets to create images for routine reading of insulinoma.Methods Thirty-nine patients undergoing pancreatic perfusion CT in Peking Union Medical College Hospital and diagnosed as insulinoma by pathology were enrolled in this retrospective study.The time-density curve of abdominal aorta calculated by software dynamic angio was used to decide the timings for averaging.Five strategies,by averaging 3,5,7,9 and 11 dynamic scans in perfusion,all including peak enhancement of the abdominal aorta,were investigated in the study.The image noise,pancreas signal-to-noise ratio(SNR),lesion contrast and lesion contrast-to-noise ratio(CNR)were recorded and compared.Besides,overall image quality and insulinoma depiction were also compared.ANOVA and Friedman's test were performed.Results The image noise decreased and the SNR of pancreas increased with the increase in averaging time points(all P<0.001).The lesion contrast(69.81±41.35)averaged from 5 scans showed no significant difference compared with that(72.77±45.25)averaged from 3 scans(P=0.103),both of which were higher than that in other groups(all P≤0.001).The lesion CNRs of the last four groups showed no significant difference(all P>0.99)and were higher than that of the first group(all P<0.05).There was no significant difference in overall image quality among the 5 groups(P=0.977).Conclusions Image averaged from 5 scans showed moderate image noise,pancreas SNR and relatively high lesion contrast and lesion CNR.Therefore,it is advised to be used in image averaging to detect insulinoma.


Assuntos
Insulinoma , Neoplasias Pancreáticas , Meios de Contraste , Humanos , Insulinoma/diagnóstico por imagem , Pâncreas/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Perfusão , Interpretação de Imagem Radiográfica Assistida por Computador , Leitura , Estudos Retrospectivos , Razão Sinal-Ruído
19.
J Endocrinol ; 249(3): 163-175, 2021 05 06.
Artigo em Inglês | MEDLINE | ID: mdl-33764312

RESUMO

The ß-cell response to injury may be as critical for the development of diabetes as the specific insult. In the current study, we used streptozotocin (STZ) to injure the ß-cell in order to study the response with a focus on NFκB. MIN6 cells were exposed to STZ (0.5-8 mM, 0-24h) ±TNFα (100 ng/mL) and ±IκBß siRNA to lower the threshold to NFκB activation. Cell viability was determined by trypan blue exclusion. NFκB activation was determined by the expression of the target genes Nos2 and Cxcl10, localization of the NFκB proteins p65 and p50, and expression and localization of the NFκB inhibitors, IκBß and IκBα. There was no NFκB activation in MIN6 cell exposed to STZ (2 mM) alone. However, knocking down IκBß expression using siRNA resulted in STZ-induced expression of NFκB target genes and increased cell death, while co-incubation with STZ and TNFα enhanced cell death compared to either exposure alone. Adult male IκBß-/- and WT mice were exposed to STZ and monitored for diabetes. The IκBß-/- mice developed hyperglycemia and diabetes more frequently than controls following STZ exposure. Based on these results we conclude that STZ exposure alone does not induce NFκB activity. However, lowering the threshold to NFκB activation by co-incubation with TNFα or lowering IκBß levels by siRNA sensitizes the NFκB response to STZ and results in a higher likelihood of developing diabetes in vivo. Therefore, increasing the threshold to NFκB activation through stabilizing NFκB inhibitory proteins may prevent ß-cell injury and the development of diabetes.


Assuntos
Células Secretoras de Insulina/efeitos dos fármacos , NF-kappa B/metabolismo , Estreptozocina/toxicidade , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Diabetes Mellitus Experimental , Regulação da Expressão Gênica/efeitos dos fármacos , Inativação Gênica , Quinase I-kappa B/genética , Quinase I-kappa B/metabolismo , Células Secretoras de Insulina/metabolismo , Insulinoma/metabolismo , Masculino , Camundongos , Camundongos Knockout , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/metabolismo , Fator de Necrose Tumoral alfa/farmacologia
20.
Endocr Pract ; 27(9): 874-880, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33705973

RESUMO

OBJECTIVE: The clinical significance of the YY1 gene mutation and expression in pancreatic neuroendocrine tumors (PNETs) remains unknown. Therefore, this study aimed to comprehensively analyze the somatic mutation of YY1 in the different subtypes of PNETs. METHODS: A total of 143 PNETs were assessed by Sanger sequencing to identify the somatic mutation of YY1 gene in various subtypes of PNETs. YY1 protein expression was examined in 103 PNETs by immunohistochemical staining and western blot. Gene mutation and its protein expression were correlated with clinicopathologic features. RESULTS: A recurrent mutation (chr14:100743807C>G) in the YY1 gene was identified in 15 of 83 insulinomas (18%) and in only 1 of 60 noninsulinoma PNETs (1.7%) (P = .0045). The YY1 mutation was not found in MEN1-associated insulinomas. The YY1 mutation in insulinomas was correlated with older age and lower serum glucose levels (age, 57 vs 42.5 years, P = .006; blood glucose, 25.2 vs 33.6 mg/dL, P = .008). YY1 protein expression was found in 100 of 103 PNETs, although expression was weaker in metastases than in localized tumors (P = .036). The stronger expression of YY1 protein was associated with favorable disease-free survival of patients with PNETs (log-rank, P = .011; n = 70). Multivariable statistical analysis showed that YY1 protein expression could be an independent predictor of prognosis. CONCLUSION: The hotspot YY1 mutation mostly occurred in insulinomas and rarely in noninsulinoma PNETs. The stronger YY1 protein expression was correlated with the better prognosis of PNETs patients.


Assuntos
Insulinoma , Tumores Neuroendócrinos , Neoplasias Pancreáticas , Fator de Transcrição YY1 , Idoso , Humanos , Pessoa de Meia-Idade , Mutação , Tumores Neuroendócrinos/genética , Neoplasias Pancreáticas/genética , Prognóstico , Fator de Transcrição YY1/genética
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