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

    Dov, Avital / Abramovitch, Eva / Warwar, Nasim / Nesher, Rafael

    Endocrinology

    2007  Volume 149, Issue 2, Page(s) 741–748

    Abstract: cAMP activates multiple signal pathways, crucial for the pancreatic beta-cells function and survival and is a major potentiator of insulin release. A family of phosphodiesterases (PDEs) terminate the cAMP signals. We examined the expression of PDEs in ... ...

    Abstract cAMP activates multiple signal pathways, crucial for the pancreatic beta-cells function and survival and is a major potentiator of insulin release. A family of phosphodiesterases (PDEs) terminate the cAMP signals. We examined the expression of PDEs in rat beta-cells and their role in the regulation of insulin response. Using RT-PCR and Western blot analyses, we identified PDE3A, PDE3B, PDE4B, PDE4D, and PDE8B in rat islets and in INS-1E cells and several possible splice variants of these PDEs. Specific depletion of PDE3A with small interfering (si) RNA (siPDE3A) led to a small (67%) increase in the insulin response to glucose in INS-1E cells but not rat islets. siPDE3A had no effect on the glucagon-like peptide-1 (10 nmol/liter) potentiated insulin response in rat islets. Depletion in PDE8B levels in rat islets using similar technology (siPDE8B) increased insulin response to glucose by 70%, the potentiation being of similar magnitude during the first and second phase insulin release. The siPDE8B-potentiated insulin response was further increased by 23% when glucagon-like peptide-1 was included during the glucose stimulus. In conclusion, PDE8B is expressed in a small number of tissues unrelated to glucose or fat metabolism. We propose that PDE8B, an 3-isobutyl-1-methylxanthine-insensitive cAMP-specific phosphodiesterase, could prove a novel target for enhanced insulin response, affecting a specific pool of cAMP involved in the control of insulin granule trafficking and exocytosis. Finally, we discuss evidence for functional compartmentation of cAMP in pancreatic beta-cells.
    MeSH term(s) 3',5'-Cyclic-AMP Phosphodiesterases/genetics ; 3',5'-Cyclic-AMP Phosphodiesterases/metabolism ; Animals ; Cell Line, Tumor ; Cyclic Nucleotide Phosphodiesterases, Type 3/genetics ; Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/physiopathology ; Gene Expression Regulation, Enzymologic/drug effects ; Gene Expression Regulation, Enzymologic/physiology ; Glucagon-Like Peptide 1/metabolism ; Glucagon-Like Peptide 1/pharmacology ; Glucose/metabolism ; Glucose/pharmacology ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/cytology ; Insulin-Secreting Cells/enzymology ; Insulin-Secreting Cells/metabolism ; Insulinoma ; Male ; Pancreatic Neoplasms ; Rats ; Rats, Wistar
    Chemical Substances Insulin ; Glucagon-Like Peptide 1 (89750-14-1) ; 3',5'-Cyclic-AMP Phosphodiesterases (EC 3.1.4.17) ; Cyclic Nucleotide Phosphodiesterases, Type 3 (EC 3.1.4.17) ; PDE8A protein, rat (EC 3.1.4.17) ; Pde3a protein, rat (EC 3.1.4.17) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2007-11-08
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 427856-2
    ISSN 1945-7170 ; 0013-7227
    ISSN (online) 1945-7170
    ISSN 0013-7227
    DOI 10.1210/en.2007-0968
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: PKCepsilon mediates glucose-regulated insulin production in pancreatic beta-cells.

    Warwar, Nasim / Dov, Avital / Abramovitch, Eva / Wu, Ren / Jmoudiak, Marina / Haber, Esther / Cerasi, Erol / Nesher, Rafael

    Biochimica et biophysica acta

    2008  Volume 1783, Issue 10, Page(s) 1929–1934

    Abstract: Endocrine cells produce large amounts of one or more peptides. The post-translational control of selective production of a single protein is often unknown. We used 3 unrelated approaches to diminish PKCepsilon in rat islets to evaluate its role in ... ...

    Abstract Endocrine cells produce large amounts of one or more peptides. The post-translational control of selective production of a single protein is often unknown. We used 3 unrelated approaches to diminish PKCepsilon in rat islets to evaluate its role in preferential glucose-mediated insulin production. Transfection with siRNA (siR-PKCepsilon) or expression of inactive PKCepsilon (PKCepsilon-KD) resulted in a significant reduction in insulin response to glucose (16.7 mmol/l). Glucose stimulation resulted in concentration of PKCepsilon in the perinuclear region, an area known to be rich in ER-Golgi systems, associated with insulin-containing structures. ss'COP1 (RACK2) is the anchoring protein for PKCepsilon. Glucose-stimulated proinsulin production was diminished by 50% in islets expressing PKCepsilon-KD, and 60% in islets expressing RACK2 binding protein (epsilonV1-2); total protein biosynthesis was not affected. In islets expressing epsilonV1-2, a chase period following glucose stimulus resulted in a reduced proinsulin conversion to mature insulin. We propose that PKCepsilon plays a specific role in mediating the glucose-signal into insulin production: binding to ss'COP1 localizes the activated enzyme to the RER where it modulates the shuttling of proinsulin to the TGN. Subsequently the enzyme may be involved in anterograde trafficking of the prohormone or in its processing within the TGN.
    MeSH term(s) Animals ; Base Sequence ; Cells, Cultured ; Enzyme Activation ; Gene Expression Regulation, Enzymologic ; Glucose/pharmacology ; Insulin/biosynthesis ; Insulin/metabolism ; Insulin Secretion ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Male ; Protein Kinase C-epsilon/genetics ; Protein Kinase C-epsilon/metabolism ; Protein Transport ; Rats ; Rats, Wistar ; Signal Transduction
    Chemical Substances Insulin ; Protein Kinase C-epsilon (EC 2.7.11.13) ; Glucose (IY9XDZ35W2)
    Language English
    Publishing date 2008-04-29
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 60-7
    ISSN 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650 ; 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    ISSN (online) 1879-2596 ; 1879-260X ; 1872-8006 ; 1879-2642 ; 1879-2618 ; 1879-2650
    ISSN 0006-3002 ; 0005-2728 ; 0005-2736 ; 0304-4165 ; 0167-4838 ; 1388-1981 ; 0167-4889 ; 0167-4781 ; 0304-419X ; 1570-9639 ; 0925-4439 ; 1874-9399
    DOI 10.1016/j.bbamcr.2008.04.007
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Uc I Zs.247: Show issues Location:
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