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  • 1
    Online Resource
    Online Resource
    Leptin modulates β cell expression of IL-1 receptor antagonist and release of IL-1β in human islets
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 21 ( 2004-05-25), p. 8138-8143
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 21 ( 2004-05-25), p. 8138-8143
    Abstract: High concentrations of glucose induce β cell production of IL-1β, leading to impaired β cell function and apoptosis in human pancreatic islets. IL-1 receptor antagonist (IL-1Ra) is a naturally occurring antagonist of IL-1β and protects cultured human islets from glucotoxicity. Therefore, the balance of IL-1β and IL-1Ra may play a crucial role in the pathogenesis of diabetes. In the present study, we observed expression of IL-1Ra in human pancreatic β cells of nondiabetic individuals, which was decreased in tissue sections of type 2 diabetic patients. In vitro , chronic exposure of human islets to leptin, a hormone secreted by adipocytes, decreased β cell production of IL-1Ra and induced IL-1β release from the islet preparation, leading to impaired β cell function, caspase-3 activation, and apoptosis. Exogenous addition of IL-1Ra protected cultured human islets from the deleterious effects of leptin. Antagonizing IL-1Ra by introduction of small interfering RNA to IL-1Ra into human islets led to caspase-3 activation, DNA fragmentation, and impaired β cell function. Moreover, siIL-1Ra enhanced glucose-induced β cell apoptosis. These findings demonstrate expression of IL-1Ra in the human β cell, providing localized protection against leptin- and glucose-induced islet IL-1β.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0305683101
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2004
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 2
    Online Resource
    Online Resource
    Differential expression of E-cadherin at the surface of rat β-cells as a marker of functional heterogeneity
    Bioscientifica ; 2007
    In:  Journal of Endocrinology Vol. 194, No. 1 ( 2007-07), p. 21-29
    Details
    In: Journal of Endocrinology, Bioscientifica, Vol. 194, No. 1 ( 2007-07), p. 21-29
    Abstract: The aim of this study was to assess whether the expression of E-cadherin at the surface of rat β-cells is regulated by insulin secretagogues and correlates with insulin secretion. When cultured under standard conditions, virtually all β-cells expressed E-cadherin observed by immunofluorescence, but heterogeneous staining was observed. Using fluorescence-activated cell sorting (FACS), two β-cell sub-populations were sorted: one that was poorly labeled (‘ECad-low’) and another that was highly labeled (‘ECad-high’). After 1-h stimulation with 16.7 mM glucose, insulin secretion (reverse hemolytic plaque assay) from individual ECad-high β-cells was higher than that from ECad-low β-cells. Ca 2+ -dependent β-cell aggregation was increased at 16.7 mM glucose when compared with 2.8 mM glucose. E-cadherin at the surface of β-cells was increased after 18 h at 11.1 and 22.2 mM glucose when compared with 2.8 mM glucose, with the greatest increase at 22.2 mM glucose + 0.5 mM isobutylmethylxanthine (IBMX). While no labeling was detected on freshly trypsinized cells, the proportion of stained cells increased in a time-dependent manner during culture for 1, 3, and 24 h. This recovery was faster when cells were incubated at 16.7 vs 2.8 mM glucose. Cycloheximide inhibited expression of E-cadherin at 2.8 mM glucose, but not at 16.7 mM, while depolymerization of actin by either cytochasin B or latrunculin B increased surface E-cadherin at low glucose. In conclusion, these results show that expression of E-cadherin at the surface of islet β-cells is controlled by secretagogues including glucose, correlates with insulin secretion, and can serve as a surface marker of β-cell function.
    Type of Medium: Online Resource
    ISSN: 0022-0795 , 1479-6805
    URL: Article
    DOI: 10.1677/JOE-06-0169
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2007
    detail.hit.zdb_id: 1474892-7
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  • 3
    Online Resource
    Online Resource
    Blockade of β1 Integrin–Laminin-5 Interaction Affects Spreading and Insulin Secretion of Rat β-Cells Attached on Extracellular Matrix
    American Diabetes Association ; 2006
    In:  Diabetes Vol. 55, No. 5 ( 2006-05-01), p. 1413-1420
    Details
    In: Diabetes, American Diabetes Association, Vol. 55, No. 5 ( 2006-05-01), p. 1413-1420
    Abstract: When attached on a matrix produced by a rat bladder carcinoma cell line (804G matrix), rat pancreatic β-cells spread in response to glucose and secrete more insulin compared with cells attached on poly-l-lysine. The aim of this study was to determine whether laminin-5 and its corresponding cell receptor β1 integrin are implicated in these phenomena. By using specific blocking antibodies, we demonstrated that laminin-5 is the component present in 804G matrix responsible for the effect of 804G matrix on β-cell function and spreading. When expression of two well-known laminin-5 ligands, β1 and β4 integrin, was assessed by Western blot and RT-PCR, only the β1 integrin was detected in β-cells. Anti–β1 integrin antibody reduced the spreading of β-cells on 804G matrix. Blockade of the interaction between β1 integrins and laminin-5 resulted in a reduction in glucose-stimulated insulin secretion. Blocking anti–β1 integrin antibody also inhibited focal adhesion kinase phosphorylation induced by 804G matrix. In conclusion, anti–β1 integrin and –laminin-5 antibodies interfere with spreading of β-cells, resulting in decreased insulin secretion in response to glucose. Our findings indicate that outside-in signaling via engagement of β1 integrins by laminin-5 is an important component of normal β-cell function.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db05-1388
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2006
    detail.hit.zdb_id: 1501252-9
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  • 4
    Online Resource
    Online Resource
    Extracellular Matrix Protects Pancreatic β-Cells Against Apoptosis
    American Diabetes Association ; 2004
    In:  Diabetes Vol. 53, No. 8 ( 2004-08-01), p. 2034-2041
    Details
    In: Diabetes, American Diabetes Association, Vol. 53, No. 8 ( 2004-08-01), p. 2034-2041
    Abstract: We have shown previously that culture of β-cells on matrix derived from 804G cells and rich in laminin-5 improves their function. The purpose of this study was to investigate whether this matrix protects β-cells against apoptosis and to elucidate signaling pathways involved. Matrix protected sorted rat β-cells against apoptosis under standard conditions (11.2 mmol/l glucose, 10% serum), after serum deprivation (1% serum), and in response to interleukin-1β (IL-1β; 2 ng/ml), compared with control (poly-l-lysine [pLL]). Caspase-8 activity was reduced in cells cultured on matrix, whereas focal adhesion kinase (FAK), protein kinase B (PKB, or Akt), and extracellular signal–regulated kinase (ERK) phosphorylation was augmented. Treatment (4 h) with an anti-β1 integrin antibody, with the ERK pathway inhibitor PD98059, and/or with the phosphatidylinositol 3-kinase inhibitor LY294002 augmented cell death on 804G matrix but not on pLL. In long-term assays (48 h), PD98059 but not LY294002 drastically augmented cell death on 804G matrix but did so to a lesser extent on pLL. The protein inhibitor of nuclear factor-κB (IκBα) was overexpressed in cells cultured 18 h on matrix with partial blockade by PD98059. In summary, this study provides evidence for activation of signaling pathways and gene expression by extracellular matrix leading to improved β-cell survival.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.53.8.2034
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2004
    detail.hit.zdb_id: 1501252-9
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  • 5
    Online Resource
    Online Resource
    Increased Intracellular Calcium Is Required for Spreading of Rat Islet β-Cells on Extracellular Matrix
    American Diabetes Association ; 2001
    In:  Diabetes Vol. 50, No. 5 ( 2001-05-01), p. 1039-1046
    Details
    In: Diabetes, American Diabetes Association, Vol. 50, No. 5 ( 2001-05-01), p. 1039-1046
    Abstract: Rat islet β-cells spread in response to glucose when attached on the matrix produced by a rat bladder carcinoma cell line (804G). Furthermore, in a mixed population of cells, it has been observed previously that spread cells secrete more insulin acutely in response to glucose, compared with cells that remain rounded. These results suggest bi-directional signaling between the islet β-cell and the extracellular matrix. In the present study, the role of increased intracellular free Ca2+ concentration [Ca2+]i as an intracellular step linking glucose stimulation and β-cell spreading (inside-out signaling) was investigated. Purified rat β-cells were attached to this matrix and incubated under various conditions known to affect [Ca2+] i. The effect of glucose on β-cell spreading was mimicked by 25 mmol/l KCl (which induces calcium influx) and inhibited by diazoxide (which impairs depolarization and calcium entry) and by the l-type Ca2+ channel blocker SR-7037. When a 24-h incubation at 16.7 glucose was followed by 24 h at 2.8 mmol/l, β-cells that had first spread regained a round phenotype. In the presence of thapsigargin, spreading progressed throughout the experiment, suggesting that capture of calcium by the endoplasmic reticulum is involved in the reversibility of spreading previously induced by glucose. Spreading was still observed in degranulated β-cells and in botulinum neurotoxin E–expressing β-cells when exocytosis was prevented. In summary, the results indicate that increased [Ca2+]i is required for the glucose-induced spreading of β-cells on 804G matrix and that it is not a consequence of exocytotic processes that follow elevation of [Ca2+] i.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.50.5.1039
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2001
    detail.hit.zdb_id: 1501252-9
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  • 6
    Online Resource
    Online Resource
    Cell-type, allelic, and genetic signatures in the human pancreatic beta cell transcriptome
    Cold Spring Harbor Laboratory ; 2013
    In:  Genome Research Vol. 23, No. 9 ( 2013-09), p. 1554-1562
    Details
    In: Genome Research, Cold Spring Harbor Laboratory, Vol. 23, No. 9 ( 2013-09), p. 1554-1562
    Abstract: Elucidating the pathophysiology and molecular attributes of common disorders as well as developing targeted and effective treatments hinges on the study of the relevant cell type and tissues. Pancreatic beta cells within the islets of Langerhans are centrally involved in the pathogenesis of both type 1 and type 2 diabetes. Describing the differentiated state of the human beta cell has been hampered so far by technical (low resolution microarrays) and biological limitations (whole islet preparations rather than isolated beta cells). We circumvent these by deep RNA sequencing of purified beta cells from 11 individuals, presenting here the first characterization of the human beta cell transcriptome. We perform the first comparison of gene expression profiles between beta cells, whole islets, and beta cell depleted islet preparations, revealing thus beta-cell–specific expression and splicing signatures. Further, we demonstrate that genes with consistent increased expression in beta cells have neuronal-like properties, a signal previously hypothesized. Finally, we find evidence for extensive allelic imbalance in expression and uncover genetic regulatory variants (eQTLs) active in beta cells. This first molecular blueprint of the human beta cell offers biological insight into its differentiated function, including expression of key genes associated with both major types of diabetes.
    Type of Medium: Online Resource
    ISSN: 1088-9051
    URL: Article
    DOI: 10.1101/gr.150706.112
    RVK:
    XA 10000
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2013
    detail.hit.zdb_id: 1483456-X
    SSG: 12
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  • 7
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    Online Resource
    The Fas pathway is involved in pancreatic β cell secretory function
    Proceedings of the National Academy of Sciences ; 2007
    In:  Proceedings of the National Academy of Sciences Vol. 104, No. 8 ( 2007-02-20), p. 2861-2866
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 104, No. 8 ( 2007-02-20), p. 2861-2866
    Abstract: Pancreatic β cell mass and function increase in conditions of enhanced insulin demand such as obesity. Failure to adapt leads to diabetes. The molecular mechanisms controlling this adaptive process are unclear. Fas is a death receptor involved in β cell apoptosis or proliferation, depending on the activity of the caspase-8 inhibitor FLIP. Here we show that the Fas pathway also regulates β cell secretory function. We observed impaired glucose tolerance in Fas-deficient mice due to a delayed and decreased insulin secretory pattern. Expression of PDX-1, a β cell-specific transcription factor regulating insulin gene expression and mitochondrial metabolism, was decreased in Fas-deficient β cells. As a consequence, insulin and ATP production were severely reduced and only partly compensated for by increased β cell mass. Up-regulation of FLIP enhanced NF-κB activity via NF-κB-inducing kinase and RelB. This led to increased PDX-1 and insulin production independent of changes in cell turnover. The results support a previously undescribed role for the Fas pathway in regulating insulin production and release.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0611487104
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2007
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    Activation of NF-κB by Extracellular Matrix Is Involved in Spreading and Glucose-stimulated Insulin Secretion of Pancreatic Beta Cells
    Elsevier BV ; 2005
    In:  Journal of Biological Chemistry Vol. 280, No. 34 ( 2005-08), p. 30630-30637
    Details
    In: Journal of Biological Chemistry, Elsevier BV, Vol. 280, No. 34 ( 2005-08), p. 30630-30637
    Type of Medium: Online Resource
    ISSN: 0021-9258
    URL: Article
    DOI: 10.1074/jbc.M502493200
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2005
    detail.hit.zdb_id: 2141744-1
    detail.hit.zdb_id: 1474604-9
    SSG: 12
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  • 9
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    Online Resource
    Role of the Rho-ROCK (Rho-Associated Kinase) Signaling Pathway in the Regulation of Pancreatic β-Cell Function
    The Endocrine Society ; 2009
    In:  Endocrinology Vol. 150, No. 5 ( 2009-05-01), p. 2072-2079
    Details
    In: Endocrinology, The Endocrine Society, Vol. 150, No. 5 ( 2009-05-01), p. 2072-2079
    Abstract: Extracellular matrix has a beneficial impact on β-cell spreading and function, but the underlying signaling pathways have yet to be fully elucidated. In other cell types, Rho, a well-characterized member of the family of Rho GTPases, and its effector Rho-associated kinase (ROCK), play an important role as downstream mediators of outside in signaling from extracellular matrix. Therefore, a possible role of the Rho-ROCK pathway in β-cell spreading, actin cytoskeleton dynamics, and function was investigated. Rho was inhibited using a new cell-permeable version of C3 transferase, whereas the activity of ROCK was repressed using the specific ROCK inhibitors H-1152 and Y-27632. Inhibition of Rho and of ROCK increased spreading and improved both short-term and prolonged glucose-stimulated insulin secretion but had no impact on basal secretion. Inhibition of this pathway led to a depolymerization of the actin cytoskeleton. Furthermore, the impact of the inhibition of ROCK on stimulated insulin secretion was acute and reversible, suggesting that rapid signaling such as phosphorylation is involved. Finally, quantification of the activity of RhoA indicated that the extracellular matrix represses RhoA activity. Overall these results show for the first time that the Rho-ROCK signaling pathway contributes to the stabilization of the actin cytoskeleton and inhibits glucose-stimulated insulin secretion in primary pancreatic β-cells. Furthermore, they indicate that inhibition of this pathway might be one of the mechanisms by which the extracellular matrix exerts its beneficial effects on pancreatic β-cell function.
    Type of Medium: Online Resource
    ISSN: 0013-7227 , 1945-7170
    URL: Article
    DOI: 10.1210/en.2008-1135
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2009
    detail.hit.zdb_id: 2011695-0
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