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Bahou K, Achour Y, Ilahiane M, Sekkat H, Bakali Y, Mhamdi Alaoui M, Raiss M, Sabbah F, Hrora A. Diagnosis and management of benign secreting pancreatic insulinoma: What's new? 4 case report. Rare Tumors 2025; 17:20363613241313409. [PMID: 39790868 PMCID: PMC11713962 DOI: 10.1177/20363613241313409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Accepted: 12/19/2024] [Indexed: 01/12/2025] Open
Abstract
Introduction and importance: Even though insulinoma is the most frequent neuroendocrine tumor, it represents only 2% of pancreatic 2% of all pancreatic neoplasms. Diagnosis is relatively simple, and surgery after accurate determination of the tumors location within the pancreas is the cornerstone of its treatment. Case presentation: We herein report 4 patients undergoing various surgeries for benign secreting insulinomas, after extensive radiological and endoscopic exploration. Clinical discussion: Diagnosis is relatively simple relying on clinical and biological criteria, it must be followed by an extensive and accurate preoperative determination of the tumors localization. The laparoscopic tumoral enucleation is the treatment of choice for small isolated tumors, but open surgery still has its indications. Conclusion: Pancreatic insulinoma is a rare neuroendocrine tumor that can be life-threatening due to hypoglycemic manifestations. The diagnosis is based on clinical and biological criteria. echo endoscopy and to a lesser extent radiological exploration can precisely determine the tumors location. Laparoscopic surgical enucleation of the tumor remains the preferred curative treatment.
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Affiliation(s)
- Khawla Bahou
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Youssef Achour
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Mehdi Ilahiane
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Hamza Sekkat
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Younes Bakali
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Mouna Mhamdi Alaoui
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Mohammed Raiss
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Farid Sabbah
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
| | - Abdelmalek Hrora
- Digestive Surgical Department C, Ibn Sina University Hospital, Rabat, Morocco
- Faculty of Medicine and Pharmacy, Mohammed V University in Rabat, Rabat, Morocco
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Larsen AR, Brusgaard K, Christesen HT, Detlefsen S. Genotype-histotype-phenotype correlations in hyperinsulinemic hypoglycemia. Histol Histopathol 2024; 39:817-844. [PMID: 38305063 DOI: 10.14670/hh-18-709] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2024]
Abstract
Hyperinsulinemic hypoglycemia (HH) of pancreatic origin includes congenital hyperinsulinism (CHI), insulinoma, insulinomatosis, and adult-onset non-insulinoma persistent hyperinsulinemic hypoglycemia syndrome (NI-PHHS). In this review, we describe the genotype-histotype-phenotype correlations in HH and their therapeutic implications. CHI can occur from birth or later on in life. Histologically, diffuse CHI shows diffuse beta cell hypertrophy with a few giant nuclei per islet of Langerhans, most frequently caused by loss-of-function mutations in ABCC8 or KCNJ11. Focal CHI is histologically characterized by focal adenomatous hyperplasia consisting of confluent hyperplastic islets, caused by a paternal ABCC8/KCNJ11 mutation combined with paternal uniparental disomy of 11p15. CHI in Beckwith-Wiedemann syndrome is caused by mosaic changes in the imprinting region 11p15.4-11p15.5, leading to segmental or diffuse overgrowth of endocrine tissue in the pancreas. Morphological mosaicism of pancreatic islets is characterized by occurence of hyperplastic (type 1) islets in one or a few lobules and small (type 2) islets in the entire pancreas. Other rare genetic causes of CHI show less characteristic or unspecific histology. HH with a predominant adult onset includes insulinomas, which are pancreatic insulin-producing endocrine neoplasms, in some cases with metastatic potential. Insulinomas occur sporadically or as part of multiple endocrine neoplasia type 1 due to MEN1 mutations. MAFA mutations may histologically lead to insulinomatosis with insulin-producing neuroendocrine microadenomas or neuroendocrine neoplasms. NI-PHHS is mainly seen in adults and shows slight histological changes in some patients, which have been defined as major and minor criteria. The genetic cause is unknown in most cases. The diagnosis of HH, as defined by genetic, histological, and phenotypic features, has important implications for patient management and outcome.
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Affiliation(s)
- Annette Rønholt Larsen
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
- Steno Diabetes Center, Odense University Hospital, Odense, Denmark
| | - Klaus Brusgaard
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
- Steno Diabetes Center, Odense University Hospital, Odense, Denmark
| | - Henrik Thybo Christesen
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
- Steno Diabetes Center, Odense University Hospital, Odense, Denmark
| | - Sönke Detlefsen
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
- Odense Pancreas Center (OPAC), Odense University Hospital, Odense, Denmark
- Department of Pathology, Odense University Hospital, Odense, Denmark.
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Mo S, Wang Y, Wu W, Zhao H, Jiang H, Qin S. Identifying target ion channel-related genes to construct a diagnosis model for insulinoma. Front Genet 2023; 14:1181307. [PMID: 37772258 PMCID: PMC10523017 DOI: 10.3389/fgene.2023.1181307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Accepted: 08/25/2023] [Indexed: 09/30/2023] Open
Abstract
Background: Insulinoma is the most common functional pancreatic neuroendocrine tumor (PNET) with abnormal insulin hypersecretion. The etiopathogenesis of insulinoma remains indefinable. Based on multiple bioinformatics methods and machine learning algorithms, this study proposed exploring the molecular mechanism from ion channel-related genes to establish a genetic diagnosis model for insulinoma. Methods: The mRNA expression profile dataset of GSE73338 was applied to the analysis, which contains 17 insulinoma samples, 63 nonfunctional PNET (NFPNET) samples, and four normal islet samples. Differently expressed ion channel-related genes (DEICRGs) enrichment analyses were performed. We utilized the protein-protein interaction (PPI) analysis and machine learning of LASSO and support vector machine-recursive feature elimination (SVM-RFE) to identify the target genes. Based on these target genes, a nomogram diagnostic model was constructed and verified by a receiver operating characteristic (ROC) curve. Moreover, immune infiltration analysis, single-gene gene set enrichment analysis (GSEA), and gene set variation analysis (GSVA) were executed. Finally, a drug-gene interaction network was constructed. Results: We identified 29 DEICRGs, and enrichment analyses indicated they were primarily enriched in ion transport, cellular ion homeostasis, pancreatic secretion, and lysosome. Moreover, the PPI network and machine learning recognized three target genes (MCOLN1, ATP6V0E1, and ATP4A). Based on these target genes, we constructed an efficiently predictable diagnosis model for identifying insulinomas with a nomogram and validated it with the ROC curve (AUC = 0.801, 95% CI 0.674-0.898). Then, single-gene GSEA analysis revealed that these target genes had a significantly positive correlation with insulin secretion and lysosome. In contrast, the TGF-beta signaling pathway was negatively associated with them. Furthermore, statistically significant discrepancies in immune infiltration were revealed. Conclusion: We identified three ion channel-related genes and constructed an efficiently predictable diagnosis model to offer a novel approach for diagnosing insulinoma.
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Affiliation(s)
- Shuangyang Mo
- Gastroenterology Department, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, Liuzhou, China
- Gastroenterology Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yingwei Wang
- Gastroenterology Department, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, Liuzhou, China
| | - Wenhong Wu
- Gastroenterology Department, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, Liuzhou, China
| | - Huaying Zhao
- Gastroenterology Department, Liuzhou People’s Hospital Affiliated to Guangxi Medical University, Liuzhou, China
| | - Haixing Jiang
- Gastroenterology Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Shanyu Qin
- Gastroenterology Department, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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4
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Marx M, Trosic-Ivanisevic T, Caillol F, Demartines N, Schoepfer A, Pesenti C, Ratone JP, Robert M, Giovannini M, Godat S. EUS-guided radiofrequency ablation for pancreatic insulinoma: experience in 2 tertiary centers. Gastrointest Endosc 2022; 95:1256-1263. [PMID: 34902374 DOI: 10.1016/j.gie.2021.11.045] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 11/30/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS Insulinoma is the most frequent functional neuroendocrine tumor of the pancreas, and preserving surgery is the treatment of choice. EUS-guided radiofrequency ablation (EUS-RFA) is a novel and promising technique that induces tissue necrosis of localized lesions. This article presents a preliminary clinical experience in treating pancreatic insulinomas <2 cm by EUS-RFA, focusing on safety and efficacy. METHODS The clinical course of patients with pancreatic insulinoma treated by EUS-RFA at 2 tertiary referral centers was analyzed. RESULTS Between November 2017 and December 2020, 7 patients were included (6 women; mean age, 66 years). EUS-RFA was feasible in all patients with immediate hypoglycemia relief after only 1 single treatment session; 6 of 7 achieved complete response by cross-sectional imaging and remained asymptomatic (median follow-up, 21 months; range, 3-38). Three patients had minor adverse events. One elderly patient developed a large retrogastric collection 15 days after treatment and died 1 month after EUS-RFA. CONCLUSIONS Management of pancreatic neuroendocrine tumors <2 cm by EUS-RFA seems to be effective with an acceptable safety profile. However, further evidence focusing on long-term survival and recurrence is needed.
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Affiliation(s)
- Mariola Marx
- Division of Gastroenterology, Paoli Calmettes Institute, Marseille, France
| | | | - Fabrice Caillol
- Division of Gastroenterology, Paoli Calmettes Institute, Marseille, France
| | | | - Alain Schoepfer
- Division of Gastroenterology and Hepatology, CHUV, Lausanne, Switzerland
| | - Christian Pesenti
- Division of Gastroenterology, Paoli Calmettes Institute, Marseille, France
| | | | - Maxime Robert
- Division of Gastroenterology and Hepatology, CHUV, Lausanne, Switzerland
| | - Marc Giovannini
- Division of Gastroenterology, Paoli Calmettes Institute, Marseille, France
| | - Sébastien Godat
- Division of Gastroenterology and Hepatology, CHUV, Lausanne, Switzerland
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Ryaboshapkina M, Saitoski K, Hamza GM, Jarnuczak AF, Pechberty S, Berthault C, Sengupta K, Underwood CR, Andersson S, Scharfmann R. Characterization of the Secretome, Transcriptome, and Proteome of Human β Cell Line EndoC-βH1. Mol Cell Proteomics 2022; 21:100229. [PMID: 35378291 PMCID: PMC9062487 DOI: 10.1016/j.mcpro.2022.100229] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Revised: 02/26/2022] [Accepted: 03/27/2022] [Indexed: 11/28/2022] Open
Abstract
Early diabetes research is hampered by limited availability, variable quality, and instability of human pancreatic islets in culture. Little is known about the human β cell secretome, and recent studies question translatability of rodent β cell secretory profiles. Here, we verify representativeness of EndoC-βH1, one of the most widely used human β cell lines, as a translational human β cell model based on omics and characterize the EndoC-βH1 secretome. We profiled EndoC-βH1 cells using RNA-seq, data-independent acquisition, and tandem mass tag proteomics of cell lysate. Omics profiles of EndoC-βH1 cells were compared to human β cells and insulinomas. Secretome composition was assessed by data-independent acquisition proteomics. Agreement between EndoC-βH1 cells and primary adult human β cells was ∼90% for global omics profiles as well as for β cell markers, transcription factors, and enzymes. Discrepancies in expression were due to elevated proliferation rate of EndoC-βH1 cells compared to adult β cells. Consistently, similarity was slightly higher with benign nonmetastatic insulinomas. EndoC-βH1 secreted 783 proteins in untreated baseline state and 3135 proteins when stressed with nontargeting control siRNA, including known β cell hormones INS, IAPP, and IGF2. Further, EndoC-βH1 secreted proteins known to generate bioactive peptides such as granins and enzymes required for production of bioactive peptides. EndoC-βH1 secretome contained an unexpectedly high proportion of predicted extracellular vesicle proteins. We believe that secretion of extracellular vesicles and bioactive peptides warrant further investigation with specialized proteomics workflows in future studies.
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Affiliation(s)
- Maria Ryaboshapkina
- Translational Science and Experimental Medicine, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
| | - Kevin Saitoski
- Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France
| | - Ghaith M Hamza
- Discovery Sciences, AstraZeneca, Boston, Massachusetts, USA; Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, New Hampshire, USA
| | - Andrew F Jarnuczak
- Quantitative Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Séverine Pechberty
- Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France
| | - Claire Berthault
- Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France
| | - Kaushik Sengupta
- Alliance Management, Business Development, Licensing and Strategy, Biopharmaceuticals R&D, Astra Zeneca, Gothenburg, Sweden
| | - Christina Rye Underwood
- Bioscience Metabolism, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Cambridge, United Kingdom
| | - Shalini Andersson
- Oligonucleotide Discovery, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Raphael Scharfmann
- Université de Paris, Institut Cochin, INSERM U1016, CNRS UMR 8104, Paris, France
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6
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Lim WY, Lee H, Cho YS. Identification of genetic variants for blood insulin level in sex-stratified Korean population and evaluation of the causal relationship between blood insulin level and polycystic ovary syndrome. Genes Genomics 2021; 43:1105-1117. [PMID: 34304350 DOI: 10.1007/s13258-021-01134-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2021] [Accepted: 06/24/2021] [Indexed: 01/06/2023]
Abstract
BACKGROUND Blood insulin level is an important risk factor for numerous disorders. Individual blood insulin level is known to be substantially influenced by genetic factors. Several genetic association studies identified a number of genetic variants for blood insulin level, but none of them was from a sex-stratified population. OBJECTIVE This study aimed to identify male- and female-specific genetic variants related to blood insulin level and to evaluate the causal relationship between blood insulin level and polycystic ovary syndrome (PCOS) that is likely caused by high insulin in Korean women. METHODS A genome-wide association study was conducted to identify genetic variants influencing blood insulin level in males (N = 4183) and females (N = 4659) in the Korean population. Two-sample Mendelian randomization (MR) analysis was used to investigate the causal effects of the insulin variants identified from GWAS on PCOS in Korean women. Genetic association data for PCOS were obtained from a PCOS study cohort (946 cases, 976 controls) in Ewha Womans University Hospital. RESULTS GWAS linear regression analysis identified 13 female-specific SNPs and 13 male-specific SNPs showing suggestive associations (P < 10-5) with blood insulin level. The results from two-sample MR analysis using the GWAS variants for PCOS indicated that genetically determined insulin level was not associated with the risk of PCOS in Korean women. CONCLUSION This study identified sex-specific genetic variants showing associations with insulin for the first time in East Asian populations. In addition, MR analysis using variants discovered from Korean women revealed that genetically determined high level of insulin is not the cause of PCOS.
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Affiliation(s)
- Woo Young Lim
- Department of Biomedical Science, Hallym University, Chuncheon, Gangwon-do, 24252, Republic of Korea
| | - Hyejin Lee
- Department of Internal Medicine, Ewha Womans University School of Medicine, Seoul, Republic of Korea
| | - Yoon Shin Cho
- Department of Biomedical Science, Hallym University, Chuncheon, Gangwon-do, 24252, Republic of Korea.
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7
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Hu R, Zhu X, Yuan M, Ho KH, Kaverina I, Gu G. Microtubules and Gαo-signaling modulate the preferential secretion of young insulin secretory granules in islet β cells via independent pathways. PLoS One 2021; 16:e0241939. [PMID: 34292976 PMCID: PMC8297875 DOI: 10.1371/journal.pone.0241939] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 06/15/2021] [Indexed: 12/24/2022] Open
Abstract
For sustainable function, each pancreatic islet β cell maintains thousands of insulin secretory granules (SGs) at all times. Glucose stimulation induces the secretion of a small portion of these SGs and simultaneously boosts SG biosynthesis to sustain this stock. The failure of these processes, often induced by sustained high-insulin output, results in type 2 diabetes. Intriguingly, young insulin SGs are more likely secreted during glucose-stimulated insulin secretion (GSIS) for unknown reasons, while older SGs tend to lose releasability and be degraded. Here, we examine the roles of microtubule (MT) and Gαo-signaling in regulating the preferential secretion of young versus old SGs. We show that both MT-destabilization and Gαo inactivation results in more SGs localization near plasma membrane (PM) despite higher levels of GSIS and reduced SG biosynthesis. Intriguingly, MT-destabilization or Gαo-inactivation results in higher secretion probabilities of older SGs, while combining both having additive effects on boosting GSIS. Lastly, Gαo inactivation does not detectably destabilize the β-cell MT network. These findings suggest that Gαo and MT can modulate the preferential release of younger insulin SGs via largely parallel pathways.
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Affiliation(s)
- Ruiying Hu
- Department of Cell and Developmental Biology, The Program of Developmental Biology and the Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, United States of America
| | - Xiaodong Zhu
- Department of Cell and Developmental Biology, The Program of Developmental Biology and the Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, United States of America
| | - Mingyang Yuan
- Department of Cell and Developmental Biology, The Program of Developmental Biology and the Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, United States of America
| | - Kung-Hsien Ho
- Department of Cell and Developmental Biology, The Program of Developmental Biology and the Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, United States of America
| | - Irina Kaverina
- Department of Cell and Developmental Biology, The Program of Developmental Biology and the Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, United States of America
| | - Guoqiang Gu
- Department of Cell and Developmental Biology, The Program of Developmental Biology and the Center for Stem Cell Biology, Vanderbilt University, Nashville, TN, United States of America
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Using the Secretion Ratios of Insulin and C-peptide During the 2-h Oral Glucose Tolerance Test to Diagnose Insulinoma. Dig Dis Sci 2021; 66:1533-1539. [PMID: 32529519 DOI: 10.1007/s10620-020-06379-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2020] [Accepted: 05/30/2020] [Indexed: 02/05/2023]
Abstract
BACKGROUND Insulinoma, owing to the low incidence and small volume of the tumor, is often undiagnosed. The 72-h fast test is centered on diagnosing insulinoma; however, it cannot be performed on outpatients. Our aim was to evaluate the results of a 3-h oral glucose tolerance test (3-h OGTT) for insulinoma diagnosis. METHODS Thirty-seven patients with insulinoma were enrolled for comparison with 42 control subjects. All patients underwent 3-h OGTT with measurements of insulin and C-peptide. The secretion ratios of insulin and C-peptide at 1, 2, and 3 h were calculated by comparison with their values at 0 h. We used logistic regression analysis to establish the predictive models and compared the diagnostic efficiency by receiver operating characteristic analysis. RESULTS The fasting insulin and C-peptide levels of insulinoma patients were both higher; however, the concentrations at 1 h and 2 h were both lower (P < 0.05). The levels at 3 h were not significantly different (P > 0.05). Our final logistic regression model was constructed as follows: logit (P) = 8.305 - 0.441 × insulin 2 h/0 h ratio - 1.679 × C-peptide 1 h/0 h ratio. A cutoff value of > 0.351 showed the highest diagnostic accuracy, with an area under the curve of 0.97, a sensitivity of 86.5%, and a specificity of 95.2%. CONCLUSIONS The 2-h/0-h insulin ratio, as well as the 1-h/0-h C-peptide ratio, has high diagnostic efficiency for insulinoma. The 2-h OGTT can be an alternative test for diagnosing insulinoma in outpatient settings.
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9
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Senica K, Tomazic A, Skvarca A, Kolenc Peitl P, Mikolajczak R, Hubalewska-Dydejczyk A, Lezaic L. Superior Diagnostic Performance of the GLP-1 Receptor Agonist [Lys 40(AhxHYNIC-[ 99mTc]/EDDA)NH 2]-Exendin-4 over Conventional Imaging Modalities for Localization of Insulinoma. Mol Imaging Biol 2020; 22:165-172. [PMID: 31098984 DOI: 10.1007/s11307-019-01372-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
PURPOSE Insulinomas are the most common functioning neuroendocrine neoplasms of the pancreas, typically diagnosed due to characteristic symptoms. In the vast majority, the treatment is surgical and curative, requiring accurate localization of the tumour; conventional imaging, including somatostatin receptor molecular imaging, is negative in up to 10 % of cases. Recently, labelled glucagon-like peptide receptor (GLP-1R) analogues were introduced as a sensitive diagnostic method for localization of insulinomas. The aim of this study was to assess the diagnostic accuracy of a Tc-99m-labelled GLP-1R agonist [Lys40(AhxHYNIC-[99mTc]EDDA)NH2]-exendin-4 for localization of occult insulinoma. PROCEDURES Eight patients (all females; age range 35-75 years) with biochemically proven insulinoma and with negative or inconclusive conventional imaging (consisting of somatostatin receptor scintigraphy, computed tomography, endoscopic ultrasound and magnetic resonance imaging) were enrolled. Whole-body single-photon emission tomography/computed tomography (SPECT/CT) imaging was performed 4 h post-injection of 740 MBq of [Lys40(AhxHYNIC-[99mTc]EDDA)NH2]-exendin-4. Surgical treatment was performed based on imaging findings. Histology of the removed lesions and biochemical and clinical symptom resolution was considered as the gold standard for analysis of the imaging results. RESULTS Focal uptake of [Lys40(AhxHYNIC-[99mTc]EDDA)NH2]-exendin-4 was found in all patients, leading to successful removal of the offending lesion and complete biochemical and symptomatic resolution. Histological analysis confirmed insulinoma in all included patients. CONCLUSIONS [Lys40(AhxHYNIC-[99mTc]EDDA)NH2]-exendin-4 SPECT/CT appears to be an excellent molecular imaging method for preoperative localization of an occult insulinoma, surpassing conventional imaging methods. If routinely available, it could be considered as a method of choice due to its favorable combination of imaging characteristics.
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Affiliation(s)
- Katra Senica
- Department of Nuclear Medicine, University Medical Centre Ljubljana, Zaloska 7, 1525, Ljubljana, Slovenia
| | - Ales Tomazic
- Department of Abdominal Surgery, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Ales Skvarca
- Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia
| | - Petra Kolenc Peitl
- Department of Nuclear Medicine, University Medical Centre Ljubljana, Zaloska 7, 1525, Ljubljana, Slovenia
| | - Renata Mikolajczak
- Radioisotope Centre POLATOM, National Centre for Nuclear Research, Otwock, Poland
| | | | - Luka Lezaic
- Department of Nuclear Medicine, University Medical Centre Ljubljana, Zaloska 7, 1525, Ljubljana, Slovenia.
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10
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Maggio I, Mollica V, Brighi N, Lamberti G, Manuzzi L, Ricci AD, Campana D. The functioning side of the pancreas: a review on insulinomas. J Endocrinol Invest 2020; 43:139-148. [PMID: 31368049 DOI: 10.1007/s40618-019-01091-w] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2019] [Accepted: 07/24/2019] [Indexed: 12/19/2022]
Abstract
PURPOSE Insulinomas are a rare type of neuroendocrine tumors, originating in the pancreas, difficult to diagnose and to treat. Due to its rarity, insulinomas are a not well-known pathological entity; thus, the diagnostic process is frequently a medical challenge with many possible differential diagnoses. The diagnostic process varies between non-invasive procedures, such as the fasting test or imaging techniques, and invasive ones. Insulinomas are rarely malignant, but the glycemic imbalance correlated with this tumor can frequently alter the quality of life of the patients and the consequent hypoglycemia can be extremely dangerous. Moreover, insulinomas can be associated with different genetic syndromes, such as Multiple Endocrine Neoplasia 1, accompanied by other specific symptoms. There are many different treatment strategies, depending on the need to control symptoms or control diseases progression, the only curative one being surgery. METHODS AND RESULTS We reviewed the evidences present in the literature on insulinomas and reported its main clinical characteristics and management strategies. CONCLUSION The aim of this review of the literature is to present the current knowledge on insulinomas, exploring the main clinical characteristics, the diagnostic tools, and the therapeutic strategies.
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Affiliation(s)
- I Maggio
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - V Mollica
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - N Brighi
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
- NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - G Lamberti
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - L Manuzzi
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - A D Ricci
- Department of Experimental, Diagnostic and Specialty Medicine, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy
| | - D Campana
- NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.
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11
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Karatug Kacar A, Bahadori F, Kepekci Tekkeli SE, Topcu G, Bolkent S. Investigation of cell death mechanism and activity of esculetin-loaded PLGA nanoparticles on insulinoma cells in vitro. ACTA ACUST UNITED AC 2020; 72:592-606. [PMID: 31978266 DOI: 10.1111/jphp.13228] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 12/13/2019] [Accepted: 12/17/2019] [Indexed: 01/03/2023]
Abstract
AIM The purpose of this study was to prepare targeted cancer therapy formulation against insulinoma INS-1 cells and to study its effect on cell death with related mechanisms in vitro. METHODS Polylactide-co-glycolide (PLGA) nano-micelles were used for preparation of esculetin nano-formulation (nano-esculetin). The cells were treated with nano-esculetin and free esculetin. Apoptotic and necrotic cell death percentages, cell proliferation, ATP and GTP reductions and insulin levels were investigated on insulinoma INS-1 cells for both free and nano-esculetin formulations. RESULTS About 50 mg of PLGA was able to carry 20 mg esculetin in 20 ml of formulation. The obtained optimized formulation was 150 nm, with 92% encapsulation efficiency and a slow-release behaviour was observed during release studies. Nano-esculetin bearing 25, 50 and 100 μg esculetin and free esculetin in equivalent doses successfully decreased cell viability. The prevailing cell death mechanism was necrosis. Along with cell proliferation, intracellular insulin and the ratio of ATP and GTP were decreased even with 12.5, 25 and 50 μg esculetin bearing nano-formulation and its equivalent free esculetin. CONCLUSIONS The results revealed that esculetin is able to show its anti-tumor afficacy after loading to PLGA nano-micelles and nano-encapsulation intensifies its cytotoxic activity in vitro. Current study shows that esculetin and its nano formulations are promising agents in treatment of insulinoma.
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Affiliation(s)
- Ayse Karatug Kacar
- Department of Biology, Faculty of Science, Istanbul University, Istanbul, Turkey
| | - Fatemeh Bahadori
- Department of Pharmaceutical Biotechnology, Faculty of Pharmacy, Bezmialem Vakif University, Istanbul, Turkey
| | | | - Gulacti Topcu
- Department of Pharmacognosy, Faculty of Pharmacy, Bezmialem Vakif University, Istanbul, Turkey
| | - Sehnaz Bolkent
- Department of Biology, Faculty of Science, Istanbul University, Istanbul, Turkey
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12
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Al-Kassar A, Al-Shdaifat A. Iatrogenic occult infection causing hypoglycemia in a teenage female. Ann Saudi Med 2019; 39:359-361. [PMID: 31580708 PMCID: PMC6832324 DOI: 10.5144/0256-4947.2019.359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2018] [Accepted: 10/24/2018] [Indexed: 11/26/2022] Open
Abstract
Hypoglycemia is a clinically significant disorder with a wide variety of underlying causes. We report an unusual case of hypoglycemic episodes caused by an iatrogenic infection in a 17-year-old white female who presented to our emergency department complaining of 2-3 episodes of syncope per week in the previous year, which started after an appendectomy in 2016. She was hypoglycemic and a vague painless abdominal mass was found upon palpation. An abdominal CT revealed a large, well-defined heterogeneous lesion. The excised mass was surrounded by pieces of gauze that had remained in her abdomen since the appendectomy. An asymptomatic infection was the cause of her hypoglycemic episodes. After antibiotic therapy, the abdominal symptoms resolved within the first week and at follow up at 6 months after surgery, her glucose level was back to normal. This is the first reported case of iatrogenic occult infection with episodic hypoglycemia as a cardinal feature. This case illustrates that infection should remain in the differential diagnosis although cardinal signs are absent. SIMILAR CASES PUBLISHED: 0.
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Affiliation(s)
- Anwar Al-Kassar
- From the Faculty of Medicine, College of Medicine, Hashemite University, Zarqa, Jordan
| | - Amjad Al-Shdaifat
- From the Faculty of Medicine, College of Medicine, Hashemite University, Zarqa, Jordan
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13
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Egorov AV, Lezhinskiy DV, Vasilyev IA, Musaev GK, Parnova VA. [Choice of surgical approach to insulin-producing pancreatic tumors]. Khirurgiia (Mosk) 2019:41-45. [PMID: 31464273 DOI: 10.17116/hirurgia201908141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
AIM To determine the optimal surgical approach to insulin-producing pancreatic tumors via an analysis of early postoperative results. MATERIAL AND METHODS There were 134 patients with insulin-producing pancreatic tumors followed by organic hyperinsulinism who have undergone surgery in the faculty-based surgical clinic of the Sechenov First Moscow State Medical University for the period 1990-2017. Patients were divided into three groups depending on type of surgical intervention. Surgical procedure was determined after comprehensive preoperative and intraoperative examination including intraoperative ultrasound. RESULTS Incidence of postoperative complications was 32.8%. Ten (7.5%) patients required redo surgical interventions. Overall postoperative mortality was 4.5%. The best immediate results were observed in patients undergoing distal pancreatectomy. There was a correlation between incidence of early postoperative complications and tumor location depth in the enucleation group. CONCLUSION Enucleation is advisable for insulinoma of pancreatic head or uncinated process, as well as superficial tumors of the left half of the pancreas. Distal pancreatectomy is indicated for deep tumors of the left half of the pancreas. Indications for pancreatoduodenectomy are individual.
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Affiliation(s)
- A V Egorov
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - D V Lezhinskiy
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - I A Vasilyev
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - G Kh Musaev
- Sechenov First Moscow State Medical University, Moscow, Russia
| | - V A Parnova
- Sechenov First Moscow State Medical University, Moscow, Russia
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14
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Hopper AD, Jalal M, Munir A. Recent advances in the diagnosis and management of pancreatic neuroendocrine tumours. Frontline Gastroenterol 2019; 10:269-274. [PMID: 31290854 PMCID: PMC6583562 DOI: 10.1136/flgastro-2018-101006] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Revised: 09/12/2018] [Accepted: 09/14/2018] [Indexed: 02/06/2023] Open
Abstract
The incidence of pancreatic neuroendocrine tumours (PNET) is rising mainly due to the increased use of cross-sectional imaging. Although many PNETs are asymptomatic and non-functioning, the overall 5-year survival is still less than 50%. In this article, we review the advances in diagnosis, classification and staging of PNET that have evolved with the development of new cross-sectional imaging methods and biopsy techniques. With accurate classification, evidence-based, individualised prognostic outcomes and treatments are able to be given which are also discussed.
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Affiliation(s)
- Andrew D Hopper
- Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| | - Mustafa Jalal
- Department of Gastroenterology, Royal Hallamshire Hospital, Sheffield, UK
| | - Alia Munir
- Department of Endocrinology, Royal Hallamshire Hospital, Sheffield, UK
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15
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Challis BG, Powlson AS, Casey RT, Pearson C, Lam BY, Ma M, Pitfield D, Yeo GSH, Godfrey E, Cheow HK, Chatterjee VK, Carroll NR, Shaw A, Buscombe JR, Simpson HL. Adult-onset hyperinsulinaemic hypoglycaemia in clinical practice: diagnosis, aetiology and management. Endocr Connect 2017; 6:540-548. [PMID: 28784625 PMCID: PMC5597976 DOI: 10.1530/ec-17-0076] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2017] [Accepted: 08/07/2017] [Indexed: 01/04/2023]
Abstract
OBJECTIVE In adults with hyperinsulinaemic hypoglycaemia (HH), in particular those with insulinoma, the optimal diagnostic and management strategies remain uncertain. Here, we sought to characterise the biochemical and radiological assessment, and clinical management of adults with HH at a tertiary centre over a thirteen-year period. DESIGN Clinical, biochemical, radiological and histological data were reviewed from all confirmed cases of adult-onset hyperinsulinaemic hypoglycaemia at our centre between 2003 and 2016. In a subset of patients with stage I insulinoma, whole-exome sequencing of tumour DNA was performed. RESULTS Twenty-nine patients were identified (27 insulinoma, including 6 subjects with metastatic disease; 1 pro-insulin/GLP-1 co-secreting tumour; 1 activating glucokinase mutation). In all cases, hypoglycaemia (glucose ≤2.2 mmol/L) was achieved within 48 h of a supervised fast. At fast termination, subjects with stage IV insulinoma had significantly higher insulin, C-peptide and pro-insulin compared to those with insulinoma staged I-IIIB. Preoperative localisation of insulinoma was most successfully achieved with EUS. In two patients with inoperable, metastatic insulinoma, peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE rapidly restored euglycaemia and lowered fasting insulin. Finally, in a subset of stage I insulinoma, whole-exome sequencing of tumour DNA identified the pathogenic Ying Yang-1 (YY1) somatic mutation (c.C1115G/p.T372R) in one tumour, with all tumours exhibiting a low somatic mutation burden. CONCLUSION Our study highlights, in particular, the utility of the 48-h fast in the diagnosis of insulinoma, EUS for tumour localisation and the value of PRRT therapy in the treatment of metastatic disease.
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Affiliation(s)
- Benjamin G Challis
- Metabolic Research LaboratoriesWellcome Trust-MRC Institute of Metabolic Science, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK
- Wolfson Diabetes and Endocrine CentreAddenbrooke's Hospital, Cambridge, UK
- IMED Biotech UnitClinical Discovery Unit, AstraZeneca, UK
| | - Andrew S Powlson
- Metabolic Research LaboratoriesWellcome Trust-MRC Institute of Metabolic Science, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK
- Wolfson Diabetes and Endocrine CentreAddenbrooke's Hospital, Cambridge, UK
| | - Ruth T Casey
- Wolfson Diabetes and Endocrine CentreAddenbrooke's Hospital, Cambridge, UK
| | - Carla Pearson
- Wolfson Diabetes and Endocrine CentreAddenbrooke's Hospital, Cambridge, UK
| | - Brian Y Lam
- Metabolic Research LaboratoriesWellcome Trust-MRC Institute of Metabolic Science, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK
| | - Marcella Ma
- Metabolic Research LaboratoriesWellcome Trust-MRC Institute of Metabolic Science, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK
| | - Deborah Pitfield
- Wolfson Diabetes and Endocrine CentreAddenbrooke's Hospital, Cambridge, UK
| | - Giles S H Yeo
- Metabolic Research LaboratoriesWellcome Trust-MRC Institute of Metabolic Science, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK
| | - Edmund Godfrey
- Department of RadiologyAddenbrooke's Hospital, Cambridge, UK
| | - Heok K Cheow
- Department of RadiologyAddenbrooke's Hospital, Cambridge, UK
- Department of Nuclear MedicineAddenbrooke's Hospital, Cambridge, UK
| | - V Krishna Chatterjee
- Metabolic Research LaboratoriesWellcome Trust-MRC Institute of Metabolic Science, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK
- Wolfson Diabetes and Endocrine CentreAddenbrooke's Hospital, Cambridge, UK
| | | | - Ashley Shaw
- Department of RadiologyAddenbrooke's Hospital, Cambridge, UK
| | - John R Buscombe
- Department of RadiologyAddenbrooke's Hospital, Cambridge, UK
- Department of Nuclear MedicineAddenbrooke's Hospital, Cambridge, UK
| | - Helen L Simpson
- Department of Diabetes and EndocrinologyUCLH NHS Foundation Trust, London, UK
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16
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Kimura H, Matsuda H, Ogawa Y, Fujimoto H, Toyoda K, Fujita N, Arimitsu K, Hamamatsu K, Yagi Y, Ono M, Inagaki N, Saji H. Development of 111In-labeled exendin(9-39) derivatives for single-photon emission computed tomography imaging of insulinoma. Bioorg Med Chem 2017; 25:1406-1412. [PMID: 28089587 DOI: 10.1016/j.bmc.2016.12.051] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Revised: 12/28/2016] [Accepted: 12/31/2016] [Indexed: 10/20/2022]
Abstract
Insulinoma is a tumor derived from pancreatic β-cells, and the resulting hyperinsulinemia leads to characteristic hypoglycemia. Recent studies have reported the frequent overexpression of glucagon-like peptide-1 receptor (GLP-1R) in human insulinomas, suggesting that the binding of a radiolabeled compound to GLP-1R is useful for the imaging of such tumors. Exendin(9-39), a fragment peptide of exendin-3 and -4, binds GLP-1R with high affinity and acts as an antagonist. Accordingly, radiolabeled exendin(9-39) derivatives have also been investigated as insulinoma imaging probes that might be less likely to induce hypoglycemia. In this study, we synthesized a novel indium-111 (111In)-benzyl-diethylenetriaminepentaacetic acid (111In-BnDTPA)-conjugated exendin(9-39), 111In-BnDTPA-exendin(9-39), and evaluated its utility as a probe for the SPECT imaging of insulinoma. natIn-BnDTPA-exendin(9-39) exhibited a high affinity for GLP-1R (IC50=2.5nM), stability in plasma, and a specific activity that improved following reactions with a solvent and solubilizer. Regarding the in vivo biodistribution of 111In-BnDTPA-exendin(9-39) in INS-1 tumor-bearing mice, high uptake levels were observed in tumors (14.6%ID/g at 15min), with corresponding high tumor-to-blood (T/B), tumor-to-muscle (T/M), and tumor-to-pancreas (T/P) ratios (T/B=2.55, T/M=22.7, T/P=2.7 at 1h). The pre-administration of excess nonradioactive exendin(9-39) significantly reduced accumulation in both the tumor and pancreas (76% and 68% inhibition, respectively) at 1h after 111In-BnDTPA-exendin(9-39) injection, indicating that the GLP-1R mediated a majority of 111In-BnDTPA-exendin(9-39) uptake in the tumor and pancreas. Finally, 111In-BnDTPA-exendin(9-39) SPECT/CT studies in mice yielded clear images of tumors at 30min post-injection. These results suggest that 111In-BnDTPA-exendin(9-39) could be a useful SPECT molecular imaging probe for the detection and exact localization of insulinomas.
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Affiliation(s)
- Hiroyuki Kimura
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan.
| | - Hirokazu Matsuda
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Research & Development Division, Arkray, Inc., Yousuien-nai, 59 Gansuin-cho, Kamigyo-ku, Kyoto 602-0008, Japan
| | - Yu Ogawa
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Hiroyuki Fujimoto
- Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Kentaro Toyoda
- Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Naotaka Fujita
- Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Kenji Arimitsu
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan
| | - Keita Hamamatsu
- Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Yusuke Yagi
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan; Department of Analytical and Bioinorganic Chemistry, Kyoto Pharmaceutical University, 5 Nakauchi-cho, Misasagi, Yamashina-ku, Kyoto 607-8414, Japan
| | - Masahiro Ono
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan
| | - Nobuya Inagaki
- Department of Diabetes and Clinical Nutrition, Kyoto University Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606-8507, Japan
| | - Hideo Saji
- Department of Patho-Functional Bioanalysis, Kyoto University Graduate School of Pharmaceutical Sciences, 46-29, Yoshida Shimoadachi-cho, Sakyo-ku, Kyoto 606-8501, Japan.
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Antonakis PT, Ashrafian H, Martinez-Isla A. Pancreatic insulinomas: Laparoscopic management. World J Gastrointest Endosc 2015; 7:1197-1207. [PMID: 26566426 PMCID: PMC4639741 DOI: 10.4253/wjge.v7.i16.1197] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 06/22/2015] [Accepted: 09/07/2015] [Indexed: 02/05/2023] Open
Abstract
Insulinomas are rare pancreatic neuroendocrine tumors that are most commonly benign, solitary, and intrapancreatic. Uncontrolled insulin overproduction from the tumor produces neurological and adrenergic symptoms of hypoglycemia. Biochemical diagnosis is confirmed by the presence of Whipple’s triad, along with corroborating measurements of blood glucose, insulin, proinsulin, C-peptide, β-hydroxybutyrate, and negative tests for hypoglycemic agents during a supervised fasting period. This is accompanied by accurate preoperative localization using both invasive and non-invasive imaging modalities. Following this, careful preoperative planning is required, with the ensuing procedure being preferably carried out laparoscopically. An integral part of the laparoscopic approach is the application of laparoscopic intraoperative ultrasound, which is indispensable for accurate intraoperative localization of the lesion in the pancreatic region. The extent of laparoscopic resection is dependent on preoperative and intraoperative findings, but most commonly involves tumor enucleation or distal pancreatectomy. When performed in an experienced surgical unit, laparoscopic resection is associated with minimal mortality and excellent long-term cure rates. Furthermore, this approach confers equivalent safety and efficacy rates to open resection, while improving cosmesis and reducing hospital stay. As such, laparoscopic resection should be considered in all cases of benign insulinoma where adequate surgical expertise is available.
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18
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Henquin JC, Nenquin M, Guiot Y, Rahier J, Sempoux C. Human Insulinomas Show Distinct Patterns of Insulin Secretion In Vitro. Diabetes 2015; 64:3543-53. [PMID: 26116696 DOI: 10.2337/db15-0527] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2015] [Accepted: 06/20/2015] [Indexed: 11/13/2022]
Abstract
Insulinomas are β-cell tumors that cause hypoglycemia through inappropriate secretion of insulin. Characterization of the in vitro dynamics of insulin secretion by perifused fragments of 10 human insulinomas permitted their subdivision into three functional groups with similar insulin content. Group A (four patients with fasting and/or postprandial hypoglycemic episodes) showed qualitatively normal responses to glucose, leucine, diazoxide, tolbutamide, and extracellular CaCl2 omission or excess. The effect of glucose was concentration dependent, but, compared with normal islets, insulin secretion was excessive in both low- and high-glucose conditions. Group B (three patients with fasting hypoglycemic episodes) was mainly characterized by large insulin responses to 1 mmol/L glucose, resulting in very high basal secretion rates that were inhibited by diazoxide and restored by tolbutamide but were not further augmented by other agents except for high levels of CaCl2. Group C (three patients with fasting hypoglycemic episodes) displayed very low rates of insulin secretion and virtually no response to stimuli (including high CaCl2 concentration) and inhibitors (CaCl2 omission being paradoxically stimulatory). In group B, the presence of low-Km hexokinase-I in insulinoma β-cells (not in adjacent islets) was revealed by immunohistochemistry. Human insulinomas thus show distinct, though not completely heterogeneous, defects in insulin secretion that are attributed to the undue expression of hexokinase-I in 3 of 10 patients.
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Affiliation(s)
- Jean-Claude Henquin
- Unit of Endocrinology and Metabolism, Faculty of Medicine, University of Louvain, Brussels, Belgium
| | - Myriam Nenquin
- Unit of Endocrinology and Metabolism, Faculty of Medicine, University of Louvain, Brussels, Belgium
| | - Yves Guiot
- Department of Pathology, University Clinics Saint Luc, Faculty of Medicine, University of Louvain, Brussels, Belgium
| | - Jacques Rahier
- Department of Pathology, University Clinics Saint Luc, Faculty of Medicine, University of Louvain, Brussels, Belgium
| | - Christine Sempoux
- Department of Pathology, University Clinics Saint Luc, Faculty of Medicine, University of Louvain, Brussels, Belgium
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19
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Nakamura Y, Matsushita A, Katsuno A, Yamahatsu K, Sumiyoshi H, Mizuguchi Y, Uchida E. Clinical outcomes of 15 consecutive patients who underwent laparoscopic insulinoma resection: The usefulness of monitoring intraoperative blood insulin during laparoscopic pancreatectomy. Asian J Endosc Surg 2015; 8:303-9. [PMID: 25869736 DOI: 10.1111/ases.12187] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2015] [Revised: 02/16/2015] [Accepted: 02/25/2015] [Indexed: 01/29/2023]
Abstract
BACKGROUND Insulinoma is a very serious functional tumor. Surgeons should confirm complete resection of insulinomas before completing the operation, even in laparoscopic surgery. METHODS Between August 2007 and September 2014, 15 consecutive patients with biochemical evidence of an insulinoma underwent laparoscopic pancreatectomy. Intraoperatively, a peripheral arterial blood sample was taken, and insulin was measured by quick insulin assay. Insulin levels were determined before anesthesia induction, every 30 min thereafter, and every 30 min for at least 1 h after tumor resection to confirm insulin levels did not increase before surgery was completed. RESULTS All 15 patients (3 men and 12 women, average age 57.2 years) successfully underwent laparoscopic resection. One patient had two tumors, and the remaining 14 patients had one tumor each (three in the head, five in the body, and eight in the tail of the pancreas). Preoperative localization and regionalization studies identified the tumor correctly through CT (12/15 [80.0%]), MRI (9/12 [75.0%]), angiography (11/13 [84.6%]), endoscopic ultrasonography (7/10 [70.0%]), and selective arterial calcium injection (14/14 [100%]). Intraoperative ultrasonography detected 13 of 15 tumors (86.7%), and intraoperative blood insulin monitoring confirmed the complete resection of 16 of 16 tumors (100%). All patients were discharged with normal insulin levels and have been followed up for 3-88 months. There has been no recurrence of symptoms in any patients and none has died. CONCLUSION Complete removal of an insulinoma can be reliably predicted by intraoperative blood insulin monitoring even in laparoscopic pancreatectomies.
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Affiliation(s)
- Yoshiharu Nakamura
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Akira Matsushita
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Akira Katsuno
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Kazuya Yamahatsu
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Hiroki Sumiyoshi
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Yoshiaki Mizuguchi
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
| | - Eiji Uchida
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo, Japan
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20
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Liu J, Zhang CW, Hong DF, Wu J, Yang HG, Chen Y, Zhao DJ, Zhang YH. Laparoscope resection of retroperitoneal ectopic insulinoma: A rare case. World J Gastroenterol 2015; 21:4413-4418. [PMID: 25892896 PMCID: PMC4394107 DOI: 10.3748/wjg.v21.i14.4413] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2014] [Revised: 12/25/2014] [Accepted: 01/21/2015] [Indexed: 02/06/2023] Open
Abstract
Ectopic insulinoma is a very rare and dormant tumor. Here we report the case of a 79-year-old female who presented with repeated episodes of hypoglycemia and was diagnosed with insulinoma based on laboratory and imaging examinations. Computed tomography and positron emission tomography revealed a tumor in the retroperitoneum under and left of the hepatoduodenal ligament, which was resected successfully using a laparoscopic approach. Pathologic results revealed an ectopic insulinoma, which was confirmed immunohistochemically. Ectopic insulinomas are accompanied by hypoglycemia that can be misdiagnosed as drug- or disease-induced. These tumors are difficult to diagnose and locate, particularly in atypical cases or for very small tumors. Synthetic or targeted examinations, including low blood glucose, elevated insulin, proinsulin, and C-peptide levels, 48-h fasting tests, and relevant imaging methods should be considered for suspected cases of insulinoma. Surgery is the treatment of choice for patients with insulinoma, and laparoscopic resection is a feasible and effective method for select ectopic insulinoma cases.
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21
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Doi R. Determinants of surgical resection for pancreatic neuroendocrine tumors. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2015; 22:610-7. [PMID: 25773163 DOI: 10.1002/jhbp.224] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 01/14/2015] [Indexed: 12/14/2022]
Abstract
Pancreatic neuroendocrine tumors (pNETs) include functioning and non-functional tumors. Functioning tumors consist of tumors that produce a variety of hormones and their clinical effects. Therefore, determinants of resection of pNETs should be discussed for each group of tumors. Less than 10% of insulinomas are malignant, therefore more than 90% of the cases can be cured by surgical resection. Lymphadenectomy is generally not necessary in insulinoma operation. If preoperative localization of the insulinoma is completed, enucleation from the pancreatic body or tail, and distal pancreatectomy can be performed safely by laparoscopy. When preoperative localization of a sporadic insulinoma is not confirmed, surgical exploration is needed. Intraoperative localization of a tumor, intraoperative insulin sampling and frozen section are required. The crucial purpose of surgical resection is to control inappropriate insulin secretion by removing all insulinomas. Gastrinomas are usually located in the duodenum or pancreas, which secrete gastrin and cause Zollinger-Ellison syndrome (ZES). Duodenal gastrinomas are usually small, therefore they are not seen on preoperative imaging studies or endoscopic ultrasound, and can be found only at surgery if a duodenotomy is performed. In addition, lymph node metastasis is found in 40-60% of cases. Therefore, the experienced surgeons should direct operation for gastrinomas. Surgical exploration with duodenotomy should be performed at a laparotomy. Other functioning pNETs can occur in the pancreas or in other locations. Curative resection is always recommended whenever possible after optimal symptomatic control of the clinical syndrome by medical treatment. Indications for surgery depend on clinical symptom control, tumor size, location, extent, malignancy and presence of metastasis. A lot of non-functioning pNETs are found incidentally according to the quality improvement of imaging techniques. Localized, small, malignant non-functioning pNETs should be operated on aggressively, while in possibly benign tumors smaller than 2 cm the surgical risk-benefit ratio should be carefully weighted. Surgical liver resection is generally proposed in curative intent to all patients with operable metastases from G1 or G2 pNET. The benefits of surgical resection of liver metastases have been demonstrated in terms of overall survival and quality of life. Complete resection is associated with better long-term survival.
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Affiliation(s)
- Ryuichiro Doi
- Department of Surgery, Otsu Red Cross Hospital, 1-1-35 Nagara, Otsu, Shiga, 520-8511, Japan
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Montravers F, Arnoux JB, Ribeiro MJ, Kerrou K, Nataf V, Galmiche L, Aigrain Y, Bellanné-Chantelot C, Saint-Martin C, Ohnona J, Balogova S, Huchet V, Michaud L, Talbot JN, de Lonlay P. Strengths and limitations of using 18fluorine-fluorodihydroxyphenylalanine PET/CT for congenital hyperinsulinism. Expert Rev Endocrinol Metab 2014; 9:477-485. [PMID: 30736210 DOI: 10.1586/17446651.2014.949240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
18fluorine-fluorodihydroxyphenylalanine (FDOPA) PET/CT is currently the first-line imaging technique to distinguish between focal and diffuse forms of congenital hyperinsulinism (CHI) and to accurately localize focal forms. However, this technique has a number of limitations, mainly the very small size of focal forms or inversely a very large focal form mimicking a diffuse form, and misinterpretation of physiologic uptake masking hot spots or inversely mimicking focal forms. The other limitation is the limited availability of the radiopharmaceutical. FDOPA PET/CT has no recognized competitor to date among the available morphologic and functional imaging techniques. Other potential approaches using specific tracers for positron emission tomography (PET) are discussed, using radiopharmaceuticals specific for β cell mass or targeting somatostatin receptors. These radiopharmaceuticals can be labeled with gallium-68, a PET emitter readily available in PET centers equipped with 68Ge/68Ga generators.
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Affiliation(s)
- Françoise Montravers
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Jean-Baptiste Arnoux
- b Centre de référence des maladies héréditaires du métabolisme de l'enfant, et l'adulte, AP-HP Hôpital Necker-Enfants Malades, Université Paris Descartes, Paris, France
| | - Maria-Joao Ribeiro
- c Service de médecine nucléaire, CHRU, Université François Rabelais, INSERM U930, Tours, France
| | - Khaldoun Kerrou
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Valérie Nataf
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Louise Galmiche
- d Service d'anatomo-pathologie, AP-HP Hôpital Necker-Enfants Malades, Université Paris Descartes, Paris, France
| | - Yves Aigrain
- b Centre de référence des maladies héréditaires du métabolisme de l'enfant, et l'adulte, AP-HP Hôpital Necker-Enfants Malades, Université Paris Descartes, Paris, France
| | - Christine Bellanné-Chantelot
- e Département de génétique, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Cécile Saint-Martin
- e Département de génétique, AP-HP Groupe Hospitalier Pitié-Salpétrière, Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Jessica Ohnona
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Sona Balogova
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
- f Department of nuclear medicine, Comenius University and St. Elisabeth Institute, Bratislava, Slovakia
| | - Virginie Huchet
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Laure Michaud
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Jean-Noël Talbot
- a Service de médecine nucléaire, Hôpital Tenon, AP-HP and Université Pierre et Marie Curie-Paris 6, Paris, France
| | - Pascale de Lonlay
- b Centre de référence des maladies héréditaires du métabolisme de l'enfant, et l'adulte, AP-HP Hôpital Necker-Enfants Malades, Université Paris Descartes, Paris, France
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Soós Z, Czégeni A, Salamon F, Salamon M, Kenessey I, Folyovich A, Tihanyi T, Winkler G. [A case of glucose-sensitive insulinoma accompanied by slightly elevated serum insulin levels and persisting convulsions after the surgically removed neuroendocrine tumor]. Orv Hetil 2013; 154:69-73. [PMID: 23291205 DOI: 10.1556/oh.2013.29522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Insul(in)oma is a usually solitary or, in some cases, multifocal tumor of pancreatic beta cells. It may be a component of multiple endocrine neoplasia type 1. or von Hippel-Lindau syndrome. In typical forms the diagnosis - based on the Whipple triad - is simple, however, it may be difficult to recognize in cases with near normal or only slightly elevated serum insulin levels, as well as in patients with known convulsive episodes. With the case presentation of an 81-year-old woman the authors draw attention to the pitfalls of the correct diagnosis. A special feature of the presented case is that convulsions persisted after surgical removal of the pancreatic neuroendocrine tumor verified with functional and imaging methods. Recurrent or residual tumor was not found, and morphological damage of the brain was absent. In the background of the continuing convulsions cerebrovascular alterations as well as the cytotoxic effect of the hypoglycemia-induced excessive glutamate production can be postulated.
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Affiliation(s)
- Zsuzsanna Soós
- Szent János Kórház II. Belgyógyászat-Diabetológia Budapest Diós árok 1-3. 1125
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24
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Knigge U, Hansen CP. Surgery for GEP-NETs. Best Pract Res Clin Gastroenterol 2012; 26:819-31. [PMID: 23582921 DOI: 10.1016/j.bpg.2012.12.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Accepted: 12/27/2012] [Indexed: 01/31/2023]
Abstract
Surgery is the only treatment that may cure the patient with gastroentero-pancreatic (GEP) neuroendocrine tumours (NET) and neuroendocrine carcinomas (NEC) and should always be considered as first line treatment if R0/R1 resection can be achieved. The surgical and interventional procedures for GEP-NET are accordingly described below. Life-long follow-up should be performed in almost all patients at a specialized NET center.
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Affiliation(s)
- Ulrich Knigge
- Department of Gastrointestinal Surgery C, Neuroendocrine Tumor Centre of Excellence, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
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25
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Vascular pancreatic lesions: spectrum of imaging findings of malignant masses and mimics with pathologic correlation. ACTA ACUST UNITED AC 2012; 38:802-17. [DOI: 10.1007/s00261-012-9954-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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26
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Abstract
OBJECTIVES Adenosine triphosphate-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) are 2 important cholesterol transporters in human pancreatic β-cells. The aim of this study was to investigate their alteration in insulinomas and their potential associations with abnormal insulin secretion in these patients. METHODS Six patients with insulinoma and 6 healthy controls were recruited. Lipid profiles and glucose metabolism were measured. Insulin content, ABCA1, and ABCG1 in insulinomas and the adjacent islets of the 6 patients with insulinoma were detected by immunohistochemistry or immunofluorescence. RESULTS Plasma total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglyceride were comparable between the controls and the patients with insulinoma. Fasting glucose was less than 2.8 mmol/L, and insulin release index was greater than 0.3 in each patient. Serum insulin fell extremely, and blood glucose reached the reference range within an hour after the cutting of the tumors in 2 patients with insulinoma. Adenosine triphosphate-binding cassette transporter G1 increased in insulinomas compared with the adjacent islets. However, ABCA1 was detected neither in the adjacent islets nor in insulinomas. Adenosine triphosphate-binding cassette transporter G1 expression in insulinomas was significantly associated with fasting insulin level and insulin release index. CONCLUSIONS Increased ABCG1 may contribute to insulin hypersecretion in insulinomas. In contrast, the undetectable ABCA1 in insulinomas may reflect a negative feedback in insulin secretion in these patients.
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27
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Jensen RT, Cadiot G, Brandi ML, de Herder WW, Kaltsas G, Komminoth P, Scoazec JY, Salazar R, Sauvanet A, Kianmanesh R. ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms: functional pancreatic endocrine tumor syndromes. Neuroendocrinology 2012; 95:98-119. [PMID: 22261919 PMCID: PMC3701449 DOI: 10.1159/000335591] [Citation(s) in RCA: 369] [Impact Index Per Article: 28.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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28
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Castermans D, Somers I, Kriel J, Louwet W, Wera S, Versele M, Janssens V, Thevelein JM. Glucose-induced posttranslational activation of protein phosphatases PP2A and PP1 in yeast. Cell Res 2012; 22:1058-77. [PMID: 22290422 PMCID: PMC3367521 DOI: 10.1038/cr.2012.20] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The protein phosphatases PP2A and PP1 are major regulators of a variety of cellular processes in yeast and other eukaryotes. Here, we reveal that both enzymes are direct targets of glucose sensing. Addition of glucose to glucose-deprived yeast cells triggered rapid posttranslational activation of both PP2A and PP1. Glucose activation of PP2A is controlled by regulatory subunits Rts1, Cdc55, Rrd1 and Rrd2. It is associated with rapid carboxymethylation of the catalytic subunits, which is necessary but not sufficient for activation. Glucose activation of PP1 was fully dependent on regulatory subunits Reg1 and Shp1. Absence of Gac1, Glc8, Reg2 or Red1 partially reduced activation while Pig1 and Pig2 inhibited activation. Full activation of PP2A and PP1 was also dependent on subunits classically considered to belong to the other phosphatase. PP2A activation was dependent on PP1 subunits Reg1 and Shp1 while PP1 activation was dependent on PP2A subunit Rts1. Rts1 interacted with both Pph21 and Glc7 under different conditions and these interactions were Reg1 dependent. Reg1-Glc7 interaction is responsible for PP1 involvement in the main glucose repression pathway and we show that deletion of Shp1 also causes strong derepression of the invertase gene SUC2. Deletion of the PP2A subunits Pph21 and Pph22, Rrd1 and Rrd2, specifically enhanced the derepression level of SUC2, indicating that PP2A counteracts SUC2 derepression. Interestingly, the effect of the regulatory subunit Rts1 was consistent with its role as a subunit of both PP2A and PP1, affecting derepression and repression of SUC2, respectively. We also show that abolished phosphatase activation, except by reg1Δ, does not completely block Snf1 dephosphorylation after addition of glucose. Finally, we show that glucose activation of the cAMP-PKA (protein kinase A) pathway is required for glucose activation of both PP2A and PP1. Our results provide novel insight into the complex regulatory role of these two major protein phosphatases in glucose regulation.
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Affiliation(s)
- Dries Castermans
- Laboratory of Molecular Cell Biology, Institute of Botany and Microbiology, KULeuven, Belgium
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29
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Michelsen NV, Brusgaard K, Tan Q, Thomassen M, Hussain K, Christesen HT. Investigation of Archived Formalin-Fixed Paraffin-Embedded Pancreatic Tissue with Whole-Genome Gene Expression Microarray. ACTA ACUST UNITED AC 2011. [DOI: 10.5402/2011/275102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The use of formalin-fixed, paraffin-embedded (FFPE) tissue overcomes the most prominent issues related to research on relatively rare diseases: limited sample size, availability of control tissue, and time frame. The use of FFPE pancreatic tissue in GEM may be especially challenging due to its very high amounts of ribonucleases compared to other tissues/organs. In choosing pancreatic tissue, we therefore indirectly address the applicability of other FFPE tissues to gene expression microarray (GEM). GEM was performed on archived, routinely fixed, FFPE pancreatic tissue from patients with congenital hyperinsulinism (CHI), insulinoma, and deceased age-appropriate neonates, using whole-genome arrays. Although ribonuclease-rich, we obtained biologically relevant and disease-specific, significant genes; cancer-related genes; genes involved in (a) the regulation of insulin secretion and synthesis, (b) amino acid metabolism, and (c) calcium ion homeostasis. These results should encourage future research and GEM studies on FFPE tissue from the invaluable biobanks available at the departments of pathology worldwide.
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Affiliation(s)
- Nete V. Michelsen
- Department of Clinical Genetics, Odense University Hospital, Sdr Boulevard 29, 5000 Odense C, Denmark
| | - Klaus Brusgaard
- Department of Clinical Genetics, Odense University Hospital, Sdr Boulevard 29, 5000 Odense C, Denmark
| | - Qihua Tan
- Department of Clinical Genetics, Odense University Hospital, Sdr Boulevard 29, 5000 Odense C, Denmark
| | - Mads Thomassen
- Department of Clinical Genetics, Odense University Hospital, Sdr Boulevard 29, 5000 Odense C, Denmark
| | - Khalid Hussain
- Great Ormond Street Children’s Hospital NHS Trust and Institute of Child Health, London WC1N 1EH, UK
| | - Henrik T. Christesen
- H.C. Andersen Children’s Hospital, Odense University Hospital, Sdr Boulevard 29, 5000 Odense C, Denmark
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Li CJ, Zhou HL, Li J, Yao HT, Su R, Li WP. Roles of sulfonylurea receptor 1 and multidrug resistance protein 1 in modulating insulin secretion in human insulinoma. Hepatobiliary Pancreat Dis Int 2011; 10:88-94. [PMID: 21269941 DOI: 10.1016/s1499-3872(11)60013-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Sulfonylurea receptor 1 (SUR1) and multidrug resistance protein 1 (MRP1) are two prominent members of multidrug resistance proteins associated with insulin secretion. The aims of this study were to investigate their expression in insulinomas and their sole and synergistic effects in modulating abnormal insulin secretion. METHODS Fasting glucose, insulin and C-peptide were measured in 11 insulinoma patients and 11 healthy controls. Prolonged oral glucose tolerance tests were performed in 6 insulinoma patients. Insulin content, SUR1 and MRP1 were detected in 11 insulinoma patients by immunohistochemistry. SUR1 and MRP1 were also detected in 6 insulinoma patients by immunofluorescence. RESULTS Insulinoma patients presented the typical demonstrations of Whipple's triad. Fasting glucose of each insulinoma patient was lower than 2.8 mmol/L, and simultaneous insulin and C-peptide were increased in insulinoma patients. Prolonged oral glucose tolerance tests showed that insulin secretion in insulinoma patients were also stimulated by high glucose. Immunohistochemistry and immunofluorescence staining showed that SUR1 increased, but MRP1 decreased in insulinoma compared with the adjacent islets. CONCLUSIONS The hypersecretion of insulin in insulinomas might be, at least partially, due to the enrichment of SUR1. In contrast, MRP1, which is down-regulated in insulinomas, might reflect a negative feedback in insulin secretion.
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Affiliation(s)
- Cheng-Jiang Li
- Department of Endocrinology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
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