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Pathophysiology

Blockade of GABAA Receptors in the Ventromedial Hypothalamus Further Stimulates Glucagon and Sympathoadrenal but Not the Hypothalamo-Pituitary-Adrenal Response to Hypoglycemia

  1. Owen Chan,
  2. Wanling Zhu,
  3. Yuyan Ding,
  4. Rory J. McCrimmon and
  5. Robert S. Sherwin
  1. From the Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut
  1. Address correspondence and reprint requests to Dr. Robert S. Sherwin, Yale University School of Medicine, Department of Internal Medicine, Section of Endocrinology, 300 Cedar St., TAC S141, New Haven, CT 06519-1612. E-mail: robert.sherwin{at}yale.edu
Diabetes 2006 Apr; 55(4): 1080-1087. https://doi.org/10.2337/diabetes.55.04.06.db05-0958
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  • FIG. 1.
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    FIG. 1.

    Representative picture of a coronal rat brain section depicting the typical position of microinjection probes. In the left panel, the ball indicates the end of the guide cannula and the small bar indicates the 1-mm extension of the microinjection needle.

  • FIG. 2.
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    FIG. 2.

    Plasma glucose concentrations of rats receiving the artificial ECF vehicle (control; n = 8), the GABA antagonist bicuculline methiodide (n = 8), and the GABA agonist muscimol (n = 10) during the hyperinsulinemic-hypoglycemic glucose clamp.

  • FIG. 3.
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    FIG. 3.

    Average plasma insulin concentrations (A) and glucose infusion rates (B) during the final 90 minutes of the hypoglycemic clamp for rats receiving the artificial ECF vehicle (control; n = 8), the GABA antagonist bicuculline methiodide (n = 8), and the GABA agonist muscimol (n = 10). Results are presented as means ± SE. *P < 0.05 vs. controls.

  • FIG. 4.
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    FIG. 4.

    Plasma glucose responses during the hypoglycemic clamp for rats receiving the artificial ECF vehicle (control; n = 8), the GABA antagonist bicuculline methiodide (n = 8), or the GABA agonist muscimol (n = 10). Results are presented as means ± SE. *P < 0.04 vs. controls; †P < 0.05 vs. controls.

  • FIG. 5.
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    FIG. 5.

    Epinephrine (A) and norepinephrine (B) responses during the hypoglycemic clamp for rats receiving the artificial ECF vehicle (control; n = 8), the GABA antagonist bicuculline methiodide (n = 8), and the GABA agonist muscimol (n = 10). Results are presented as means ± SE. *P < 0.001 vs. controls; †P < 0.05 vs. controls.

  • FIG. 6.
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    FIG. 6.

    Plasma cortisone concentrations during the hypoglycemic clamp for rats receiving the artificial ECF vehicle (control; n = 8), the GABA antagonist bicuculline methiodide (n = 8), or the GABA agonist muscimol (n = 10). Results are presented as means ± SE.

  • FIG. 7.
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    FIG. 7.

    Plasma glucose concentrations of rats receiving the artificial ECF vehicle (control; n = 5) and the GABA agonist muscimol (n = 6) during the hyperinsulinemic-euglycemic glucose clamp.

  • FIG. 8.
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    FIG. 8.

    Plasma glucagon responses during the euglycemic clamp for rats receiving the artificial ECF vehicle (control; n = 5) and the GABA agonist muscimol (n = 6). Results are presented as means ± SE.

  • FIG. 9.
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    FIG. 9.

    Epinephrine (A) and norepinephrine (B) responses during the euglycemic clamp for rats receiving the artificial ECF vehicle (control; n = 5) and the GABA agonist muscimol (n = 6). Results are presented as means ± SE.

  • FIG. 10.
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    FIG. 10.

    Plasma corticosterone concentrations during the hypoglycemic clamp for rats receiving the artificial ECF vehicle (control; n = 5) and the GABA agonist muscimol (n = 6). Results are presented as means ± SE.

Tables

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  • TABLE 1

    Baseline hormone concentrations for the hypoglycemic clamp study

    ControlBicucullineMuscimol
    n8810
    Body weight (g)334 ± 7330 ± 8334 ± 14
    Plasma glucose (mmol/l)6.3 ± 0.16.1 ± 0.26.2 ± 0.2
    Corticosterone (ng/ml)63 ± 1489 ± 2367 ± 30
    Glucagon (ng/l)39 ± 537 ± 244 ± 5
    Epinephrine (pg/ml)87 ± 2795 ± 3551 ± 14
    Norepinephrine (pg/ml)87 ± 32112 ± 18121 ± 14
    Insulin (μU/ml)11 ± 518 ± 1010 ± 2
    • Data are means ± SE.

  • TABLE 2

    Baseline hormone concentrations for the euglycemic clamp study

    ControlMuscimol
    n56
    Body weight (g)338 ± 7314 ± 1
    Plasma glucose (mmol/l)5.8 ± 0.25.9 ± 0.5
    Corticosterone (ng/ml)29 ± 344 ± 6
    Glucagon (ng/l)38 ± 541 ± 12
    Epinephrine (pg/ml)52 ± 161 ± 24
    Norepinephrine (pg/ml)75 ± 1680 ± 19
    Insulin (μU/ml)28 ± 910 ± 4
    • Data are means ± SE.

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Blockade of GABAA Receptors in the Ventromedial Hypothalamus Further Stimulates Glucagon and Sympathoadrenal but Not the Hypothalamo-Pituitary-Adrenal Response to Hypoglycemia
Owen Chan, Wanling Zhu, Yuyan Ding, Rory J. McCrimmon, Robert S. Sherwin
Diabetes Apr 2006, 55 (4) 1080-1087; DOI: 10.2337/diabetes.55.04.06.db05-0958

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Blockade of GABAA Receptors in the Ventromedial Hypothalamus Further Stimulates Glucagon and Sympathoadrenal but Not the Hypothalamo-Pituitary-Adrenal Response to Hypoglycemia
Owen Chan, Wanling Zhu, Yuyan Ding, Rory J. McCrimmon, Robert S. Sherwin
Diabetes Apr 2006, 55 (4) 1080-1087; DOI: 10.2337/diabetes.55.04.06.db05-0958
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