ATP-Sensitive K+ Channels Regulate the Release of GABA in the Ventromedial Hypothalamus During Hypoglycemia

  • Owen Chan
    Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut
  • Marcus Lawson
    Department of Animal Sciences, University of Illinois at Urbana, Champaign, Urbana, Illinois
  • Wanling Zhu
    Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut
  • Joseph Lee Beverly
    Department of Animal Sciences, University of Illinois at Urbana, Champaign, Urbana, Illinois
  • Robert S. Sherwin
    Department of Internal Medicine, Section of Endocrinology, Yale University School of Medicine, New Haven, Connecticut

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<jats:p>OBJECTIVE—To determine whether alterations in counterregulatory responses to hypoglycemia through the modulation of ATP-sensitive K+ channels (KATP channels) in the ventromedial hypothalamus (VMH) are mediated by changes in GABAergic inhibitory tone in the VMH, we examined whether opening and closing KATP channels in the VMH alter local GABA levels and whether the effects of modulating KATP channel activity within the VMH can be reversed by local modulation of GABA receptors.</jats:p> <jats:p>RESEARCH DESIGN AND METHODS—Rats were cannulated and bilateral guide cannulas inserted to the level of the VMH. Eight days later, the rats received a VMH microinjection of either 1) vehicle, 2) the KATP channel opener diazoxide, 3) the KATP channel closer glybenclamide, 4) diazoxide plus the GABAA receptor agonist muscimol, or 5) glybenclamide plus the GABAA receptor antagonist bicuculline methiodide (BIC) before performance of a hypoglycemic clamp. Throughout, VMH GABA levels were measured using microdialysis.</jats:p> <jats:p>RESULTS—As expected, diazoxide suppressed glucose infusion rates and increased glucagon and epinephrine responses, whereas glybenclamide raised glucose infusion rates in conjunction with reduced glucagon and epinephrine responses. These effects of KATP modulators were reversed by GABAA receptor agonism and antagonism, respectively. Microdialysis revealed that VMH GABA levels decreased 22% with the onset of hypoglycemia in controls. Diazoxide caused a twofold greater decrease in GABA levels, and glybenclamide increased VMH GABA levels by 57%.</jats:p> <jats:p>CONCLUSIONS—Our data suggests that KATP channels within the VMH may modulate the magnitude of counterregulatory responses by altering release of GABA within that region.</jats:p>

収録刊行物

  • Diabetes

    Diabetes 56 (4), 1120-1126, 2007-04-01

    American Diabetes Association

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