Continuous hypothalamic KATP channel activation blunts glucose counter-regulation in vivo in rats and supresses KATP conductance in vitro

Craig Beall (Lead / Corresponding author), Elizabeth Haythorne (Lead / Corresponding author), Xiaoning Fan, Qingyou Du, Sofija Jovanovic, Robert Sherwin, Michael L J Ashford, Rory McCrimmon (Lead / Corresponding author)

    Research output: Contribution to journalArticle

    1 Citation (Scopus)

    Abstract


    Aims/hypothesis

    Acute systemic delivery of the sulfonylurea receptor (SUR)-1-specific ATP-sensitive K+ channel (KATP) opener, NN414, has been reported to amplify glucose counter-regulatory responses (CRRs) in rats exposed to hypoglycaemia. Thus, we determined whether continuous NN414 could prevent hypoglycaemia-induced defective counter-regulation.
    Methods

    Chronically catheterised male Sprague–Dawley rats received a continuous infusion of NN414 into the third ventricle for 8 days after implantation of osmotic minipumps. Counter-regulation was examined by hyperinsulinaemic–hypoglycaemic clamp on day 8 after three episodes of insulin-induced hypoglycaemia (recurrent hypoglycaemia [RH]) on days 5, 6 and 7. In a subset of rats exposed to RH, NN414 infusion was terminated on day 7 to wash out NN414 before examination of counter-regulation on day 8. To determine whether continuous NN414 exposure altered KATP function, we used the hypothalamic glucose-sensing GT1-7 cell line, which expresses the SUR-1-containing KATP channel.
    Results

    Continuous exposure to NN414 in the setting of RH increased, rather than decreased, the glucose infusion rate (GIR), as exemplified by attenuated adrenaline (epinephrine) secretion. Termination of NN414 on day 7 with subsequent washout for 24 h partially diminished the GIR. The same duration of exposure of GT1-7 cells to NN414 substantially reduced KATP conductance, which was also reversed on washout of the agonist. The suppression of KATP current was not associated with reduced channel subunit mRNA or protein levels.
    Conclusions/interpretation

    These data indicate that continuous KATP activation results in suppressed CRRs to hypoglycaemia in vivo, which in vitro is associated with the reversible conversion of KATP into a stable inactive state.
    Original languageEnglish
    Pages (from-to)2088-2092
    Number of pages5
    JournalDiabetologia
    Volume56
    Issue number9
    DOIs
    Publication statusPublished - Sep 2013

    Fingerprint

    KATP Channels
    Hypoglycemia
    Glucose
    Sulfonylurea Receptors
    Epinephrine
    Third Ventricle
    In Vitro Techniques
    Adenosine Triphosphate
    Insulin
    Cell Line
    Messenger RNA

    Keywords

    • hypoglycaemia
    • ATP-sensitive K+ channel (KATP channel)
    • HYPOTHALAMIC NEURONS

    Cite this

    Beall, Craig ; Haythorne, Elizabeth ; Fan, Xiaoning ; Du, Qingyou ; Jovanovic, Sofija ; Sherwin, Robert ; Ashford, Michael L J ; McCrimmon, Rory. / Continuous hypothalamic KATP channel activation blunts glucose counter-regulation in vivo in rats and supresses KATP conductance in vitro. In: Diabetologia. 2013 ; Vol. 56, No. 9. pp. 2088-2092.
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    abstract = "Aims/hypothesisAcute systemic delivery of the sulfonylurea receptor (SUR)-1-specific ATP-sensitive K+ channel (KATP) opener, NN414, has been reported to amplify glucose counter-regulatory responses (CRRs) in rats exposed to hypoglycaemia. Thus, we determined whether continuous NN414 could prevent hypoglycaemia-induced defective counter-regulation.MethodsChronically catheterised male Sprague–Dawley rats received a continuous infusion of NN414 into the third ventricle for 8 days after implantation of osmotic minipumps. Counter-regulation was examined by hyperinsulinaemic–hypoglycaemic clamp on day 8 after three episodes of insulin-induced hypoglycaemia (recurrent hypoglycaemia [RH]) on days 5, 6 and 7. In a subset of rats exposed to RH, NN414 infusion was terminated on day 7 to wash out NN414 before examination of counter-regulation on day 8. To determine whether continuous NN414 exposure altered KATP function, we used the hypothalamic glucose-sensing GT1-7 cell line, which expresses the SUR-1-containing KATP channel.ResultsContinuous exposure to NN414 in the setting of RH increased, rather than decreased, the glucose infusion rate (GIR), as exemplified by attenuated adrenaline (epinephrine) secretion. Termination of NN414 on day 7 with subsequent washout for 24 h partially diminished the GIR. The same duration of exposure of GT1-7 cells to NN414 substantially reduced KATP conductance, which was also reversed on washout of the agonist. The suppression of KATP current was not associated with reduced channel subunit mRNA or protein levels.Conclusions/interpretationThese data indicate that continuous KATP activation results in suppressed CRRs to hypoglycaemia in vivo, which in vitro is associated with the reversible conversion of KATP into a stable inactive state.",
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    Continuous hypothalamic KATP channel activation blunts glucose counter-regulation in vivo in rats and supresses KATP conductance in vitro. / Beall, Craig (Lead / Corresponding author); Haythorne, Elizabeth (Lead / Corresponding author); Fan, Xiaoning; Du, Qingyou; Jovanovic, Sofija; Sherwin, Robert; Ashford, Michael L J; McCrimmon, Rory (Lead / Corresponding author).

    In: Diabetologia, Vol. 56, No. 9, 09.2013, p. 2088-2092.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Continuous hypothalamic KATP channel activation blunts glucose counter-regulation in vivo in rats and supresses KATP conductance in vitro

    AU - Beall, Craig

    AU - Haythorne, Elizabeth

    AU - Fan, Xiaoning

    AU - Du, Qingyou

    AU - Jovanovic, Sofija

    AU - Sherwin, Robert

    AU - Ashford, Michael L J

    AU - McCrimmon, Rory

    PY - 2013/9

    Y1 - 2013/9

    N2 - Aims/hypothesisAcute systemic delivery of the sulfonylurea receptor (SUR)-1-specific ATP-sensitive K+ channel (KATP) opener, NN414, has been reported to amplify glucose counter-regulatory responses (CRRs) in rats exposed to hypoglycaemia. Thus, we determined whether continuous NN414 could prevent hypoglycaemia-induced defective counter-regulation.MethodsChronically catheterised male Sprague–Dawley rats received a continuous infusion of NN414 into the third ventricle for 8 days after implantation of osmotic minipumps. Counter-regulation was examined by hyperinsulinaemic–hypoglycaemic clamp on day 8 after three episodes of insulin-induced hypoglycaemia (recurrent hypoglycaemia [RH]) on days 5, 6 and 7. In a subset of rats exposed to RH, NN414 infusion was terminated on day 7 to wash out NN414 before examination of counter-regulation on day 8. To determine whether continuous NN414 exposure altered KATP function, we used the hypothalamic glucose-sensing GT1-7 cell line, which expresses the SUR-1-containing KATP channel.ResultsContinuous exposure to NN414 in the setting of RH increased, rather than decreased, the glucose infusion rate (GIR), as exemplified by attenuated adrenaline (epinephrine) secretion. Termination of NN414 on day 7 with subsequent washout for 24 h partially diminished the GIR. The same duration of exposure of GT1-7 cells to NN414 substantially reduced KATP conductance, which was also reversed on washout of the agonist. The suppression of KATP current was not associated with reduced channel subunit mRNA or protein levels.Conclusions/interpretationThese data indicate that continuous KATP activation results in suppressed CRRs to hypoglycaemia in vivo, which in vitro is associated with the reversible conversion of KATP into a stable inactive state.

    AB - Aims/hypothesisAcute systemic delivery of the sulfonylurea receptor (SUR)-1-specific ATP-sensitive K+ channel (KATP) opener, NN414, has been reported to amplify glucose counter-regulatory responses (CRRs) in rats exposed to hypoglycaemia. Thus, we determined whether continuous NN414 could prevent hypoglycaemia-induced defective counter-regulation.MethodsChronically catheterised male Sprague–Dawley rats received a continuous infusion of NN414 into the third ventricle for 8 days after implantation of osmotic minipumps. Counter-regulation was examined by hyperinsulinaemic–hypoglycaemic clamp on day 8 after three episodes of insulin-induced hypoglycaemia (recurrent hypoglycaemia [RH]) on days 5, 6 and 7. In a subset of rats exposed to RH, NN414 infusion was terminated on day 7 to wash out NN414 before examination of counter-regulation on day 8. To determine whether continuous NN414 exposure altered KATP function, we used the hypothalamic glucose-sensing GT1-7 cell line, which expresses the SUR-1-containing KATP channel.ResultsContinuous exposure to NN414 in the setting of RH increased, rather than decreased, the glucose infusion rate (GIR), as exemplified by attenuated adrenaline (epinephrine) secretion. Termination of NN414 on day 7 with subsequent washout for 24 h partially diminished the GIR. The same duration of exposure of GT1-7 cells to NN414 substantially reduced KATP conductance, which was also reversed on washout of the agonist. The suppression of KATP current was not associated with reduced channel subunit mRNA or protein levels.Conclusions/interpretationThese data indicate that continuous KATP activation results in suppressed CRRs to hypoglycaemia in vivo, which in vitro is associated with the reversible conversion of KATP into a stable inactive state.

    KW - hypoglycaemia

    KW - ATP-sensitive K+ channel (KATP channel)

    KW - HYPOTHALAMIC NEURONS

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