Mice deficient in GEM GTPase show abnormal glucose homeostasis due to defects in beta-cell calcium handling

Jenny E Gunton, Mary Sisavanh, Rebecca A Stokes, Jon Satin, Leslie S Satin, Min Zhang, Sue M Liu, Weikang Cai, Kim Cheng, Gregory J Cooney, D Ross Laybutt, Trina So, Juan-Carlos Molero, Shane T Grey, Douglas A Andres, Michael S Rolph, Charles R Mackay

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    Abstract

    AIMS AND HYPOTHESIS: Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo. METHODS: Gem-deficient mice were generated and their metabolic phenotype characterised by in vivo testing of glucose tolerance, insulin tolerance and insulin secretion. Calcium flux was measured in isolated islets. RESULTS: Gem-deficient mice were glucose intolerant and had impaired glucose stimulated insulin secretion. Furthermore, the islets of Gem-deficient mice exhibited decreased free calcium responses to glucose and the calcium oscillations seen upon glucose stimulation were smaller in amplitude and had a reduced frequency. CONCLUSIONS: These results suggest that Gem plays an important role in normal beta-cell function by regulation of calcium signalling.
    Original languageEnglish
    Article numbere39462
    Number of pages9
    JournalPLoS ONE
    Volume7
    Issue number6
    DOIs
    Publication statusPublished - 2012

    Cite this

    Gunton, Jenny E ; Sisavanh, Mary ; Stokes, Rebecca A ; Satin, Jon ; Satin, Leslie S ; Zhang, Min ; Liu, Sue M ; Cai, Weikang ; Cheng, Kim ; Cooney, Gregory J ; Laybutt, D Ross ; So, Trina ; Molero, Juan-Carlos ; Grey, Shane T ; Andres, Douglas A ; Rolph, Michael S ; Mackay, Charles R. / Mice deficient in GEM GTPase show abnormal glucose homeostasis due to defects in beta-cell calcium handling. In: PLoS ONE. 2012 ; Vol. 7, No. 6.
    @article{cc93ce4e087a45ea9575d2efbe3a9e3f,
    title = "Mice deficient in GEM GTPase show abnormal glucose homeostasis due to defects in beta-cell calcium handling",
    abstract = "AIMS AND HYPOTHESIS: Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo. METHODS: Gem-deficient mice were generated and their metabolic phenotype characterised by in vivo testing of glucose tolerance, insulin tolerance and insulin secretion. Calcium flux was measured in isolated islets. RESULTS: Gem-deficient mice were glucose intolerant and had impaired glucose stimulated insulin secretion. Furthermore, the islets of Gem-deficient mice exhibited decreased free calcium responses to glucose and the calcium oscillations seen upon glucose stimulation were smaller in amplitude and had a reduced frequency. CONCLUSIONS: These results suggest that Gem plays an important role in normal beta-cell function by regulation of calcium signalling.",
    author = "Gunton, {Jenny E} and Mary Sisavanh and Stokes, {Rebecca A} and Jon Satin and Satin, {Leslie S} and Min Zhang and Liu, {Sue M} and Weikang Cai and Kim Cheng and Cooney, {Gregory J} and Laybutt, {D Ross} and Trina So and Juan-Carlos Molero and Grey, {Shane T} and Andres, {Douglas A} and Rolph, {Michael S} and Mackay, {Charles R}",
    year = "2012",
    doi = "10.1371/journal.pone.0039462",
    language = "English",
    volume = "7",
    journal = "PLoS ONE",
    issn = "1932-6203",
    publisher = "Public Library of Science",
    number = "6",

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    Gunton, JE, Sisavanh, M, Stokes, RA, Satin, J, Satin, LS, Zhang, M, Liu, SM, Cai, W, Cheng, K, Cooney, GJ, Laybutt, DR, So, T, Molero, J-C, Grey, ST, Andres, DA, Rolph, MS & Mackay, CR 2012, 'Mice deficient in GEM GTPase show abnormal glucose homeostasis due to defects in beta-cell calcium handling', PLoS ONE, vol. 7, no. 6, e39462. https://doi.org/10.1371/journal.pone.0039462

    Mice deficient in GEM GTPase show abnormal glucose homeostasis due to defects in beta-cell calcium handling. / Gunton, Jenny E; Sisavanh, Mary; Stokes, Rebecca A; Satin, Jon; Satin, Leslie S; Zhang, Min; Liu, Sue M; Cai, Weikang; Cheng, Kim; Cooney, Gregory J; Laybutt, D Ross; So, Trina; Molero, Juan-Carlos; Grey, Shane T; Andres, Douglas A; Rolph, Michael S; Mackay, Charles R.

    In: PLoS ONE, Vol. 7, No. 6, e39462, 2012.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Mice deficient in GEM GTPase show abnormal glucose homeostasis due to defects in beta-cell calcium handling

    AU - Gunton, Jenny E

    AU - Sisavanh, Mary

    AU - Stokes, Rebecca A

    AU - Satin, Jon

    AU - Satin, Leslie S

    AU - Zhang, Min

    AU - Liu, Sue M

    AU - Cai, Weikang

    AU - Cheng, Kim

    AU - Cooney, Gregory J

    AU - Laybutt, D Ross

    AU - So, Trina

    AU - Molero, Juan-Carlos

    AU - Grey, Shane T

    AU - Andres, Douglas A

    AU - Rolph, Michael S

    AU - Mackay, Charles R

    PY - 2012

    Y1 - 2012

    N2 - AIMS AND HYPOTHESIS: Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo. METHODS: Gem-deficient mice were generated and their metabolic phenotype characterised by in vivo testing of glucose tolerance, insulin tolerance and insulin secretion. Calcium flux was measured in isolated islets. RESULTS: Gem-deficient mice were glucose intolerant and had impaired glucose stimulated insulin secretion. Furthermore, the islets of Gem-deficient mice exhibited decreased free calcium responses to glucose and the calcium oscillations seen upon glucose stimulation were smaller in amplitude and had a reduced frequency. CONCLUSIONS: These results suggest that Gem plays an important role in normal beta-cell function by regulation of calcium signalling.

    AB - AIMS AND HYPOTHESIS: Glucose-stimulated insulin secretion from beta-cells is a tightly regulated process that requires calcium flux to trigger exocytosis of insulin-containing vesicles. Regulation of calcium handling in beta-cells remains incompletely understood. Gem, a member of the RGK (Rad/Gem/Kir) family regulates calcium channel handling in other cell types, and Gem over-expression inhibits insulin release in insulin-secreting Min6 cells. The aim of this study was to explore the role of Gem in insulin secretion. We hypothesised that Gem may regulate insulin secretion and thus affect glucose tolerance in vivo. METHODS: Gem-deficient mice were generated and their metabolic phenotype characterised by in vivo testing of glucose tolerance, insulin tolerance and insulin secretion. Calcium flux was measured in isolated islets. RESULTS: Gem-deficient mice were glucose intolerant and had impaired glucose stimulated insulin secretion. Furthermore, the islets of Gem-deficient mice exhibited decreased free calcium responses to glucose and the calcium oscillations seen upon glucose stimulation were smaller in amplitude and had a reduced frequency. CONCLUSIONS: These results suggest that Gem plays an important role in normal beta-cell function by regulation of calcium signalling.

    UR - http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3386271/pdf/pone.0039462.pdf

    U2 - 10.1371/journal.pone.0039462

    DO - 10.1371/journal.pone.0039462

    M3 - Article

    VL - 7

    JO - PLoS ONE

    JF - PLoS ONE

    SN - 1932-6203

    IS - 6

    M1 - e39462

    ER -