Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2008 May;57(5):1363-70.
doi: 10.2337/db07-1559. Epub 2008 Mar 28.

Increased GABAergic tone in the ventromedial hypothalamus contributes to suppression of counterregulatory responses after antecedent hypoglycemia

Owen Chan  1 , Haiying Cheng, Raimund Herzog, Daniel Czyzyk, Wanling Zhu, Ajin Wang, Rory J McCrimmon, Margretta R Seashore, Robert S Sherwin
Affiliations

Increased GABAergic tone in the ventromedial hypothalamus contributes to suppression of counterregulatory responses after antecedent hypoglycemia

Owen Chan et al. Diabetes. 2008 May.

Abstract

Objective: We have previously demonstrated that modulation of gamma-aminobutyric acid (GABA) inhibitory tone in the ventromedial hypothalamus (VMH), an important glucose-sensing region in the brain, modulates the magnitude of glucagon and sympathoadrenal responses to hypoglycemia. In the current study, we examined whether increased VMH GABAergic tone may contribute to suppression of counterregulatory responses after recurrent hypoglycemia.

Research design and methods: To test this hypothesis, we quantified expression of the GABA synthetic enzyme, glutamic acid decarboxylase (GAD), in the VMH of control and recurrently hypoglycemic rats. Subsequently, we used microdialysis and microinjection techniques to assess changes in VMH GABA levels and the effects of GABA(A) receptor blockade on counterregulatory responses to a standardized hypoglycemic stimulus.

Results: Quantitative RT-PCR and immunoblots in recurrently hypoglycemic animals revealed that GAD(65) mRNA and protein were increased 33 and 580%, respectively. Basal VMH GABA concentrations were more than threefold higher in recurrently hypoglycemic animals. Furthermore, whereas VMH GABA levels decreased in both control and recurrently hypoglycemic animals with the onset of hypoglycemia, the fall was not significant in recurrently hypoglycemic rats. During hypoglycemia, recurrently hypoglycemic rats exhibited a 49-63% reduction in glucagon and epinephrine release. These changes were reversed by delivery of a GABA(A) receptor antagonist to the VMH.

Conclusions: Our data suggest that recurrent hypoglycemia increases GABAergic inhibitory tone in the VMH and that this, in turn, suppresses glucagon and sympathoadrenal responses to subsequent bouts of acute hypoglycemia. Thus, hypoglycemia-associated autonomic failure may be due in part to a relative excess of the inhibitory neurotransmitter, GABA, within the VMH.

PubMed Disclaimer

Figures

FIG. 1
FIG. 1
Quantitative RT-PCR assessment of GAD65, GAD67, and GABAA receptor (GABAA-R) mRNA expression in the VMH of recurrently hypoglycemic animals (n = 6) compared with recurrent saline controls (n = 6) and expressed as fold change versus control levels. *P < 0.01 vs. controls; †P < 0.01 vs. controls.
FIG. 2
FIG. 2
Representative images and densitometric analyses of immunoblots for GAD65 (left panels) and GAD67 (right panels) protein in the VMH (top) and cortex (bottom) of control (n = 4–7) and recurrently hypoglycemic (n = 4–7) animals. Data are represented as relative optical density expressed as a ratio over β-actin levels. Results are presented as means ± SE. *P < 0.001 vs. controls.
FIG. 3
FIG. 3
Average extracellular GABA concentrations in microdialysate samples collected from control (n = 17) and recurrently hypoglycemic (RH; n = 17) animals during the baseline period (□) and during the 90-min hypoglycemic clamping period (■). *P < 0.02 vs. control basal. #P < 0.01 vs. control basal. §P < 0.01 vs. control hypoglycemia. †P < 0.04 vs. control basal. P = 0.36 for RH basal vs. RH hypoglycemia. Data are presented as means ± SE.
FIG. 4
FIG. 4
Plasma glucose concentrations of normal saline controls (Control; n = 8), recurrently hypoglycemic animals (RH; n = 8), and recurrently hypoglycemic animals receiving the GABAA receptor antagonist bicuculline methiodide (RH + BMI; n = 6) during the hyperinsulinemic-hypoglycemic glucose clamp.
FIG. 5
FIG. 5
Average plasma insulin (A) concentrations and glucose infusion rates (B) during the final 90 min of the hypoglycemic clamp in normal saline controls (n = 8), recurrently hypoglycemic animals (RH; n = 8), and recurrently hypoglycemic animals receiving the GABAA receptor antagonist bicuculline methiodide (RH + BMI; n = 6). Results are presented as means ± SE. *P < 0.05 vs. controls.
FIG. 6
FIG. 6
Plasma glucagon (A) and epinephrine (B) responses during the hypoglycemic clamp in normal saline controls (n = 8), recurrently hypoglycemic animals (RH; n = 8), and recurrently hypoglycemic animals receiving the GABAA receptor antagonist bicuculline methiodide (RH + BMI; n = 6). Results are presented as means ± SE. *P < 0.03 vs. controls. †P < 0.001 vs. controls.
FIG. 7
FIG. 7
Peak plasma corticosterone concentrations during the hypoglycemic clamp in normal saline controls (n = 8), recurrently hypoglycemic animals (RH; n = 8), and recurrently hypoglycemic animals receiving the GABAA receptor antagonist bicuculline methiodide (RH + BMI; n = 6). Results are presented as means ± SE.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977–986. - PubMed
    1. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33) Lancet. 1998;352:837–853. - PubMed
    1. Cryer PE. Hypoglycaemia: the limiting factor in the glycaemic management of type I and type II diabetes. Diabetologia. 2002;45:937–948. - PubMed
    1. Dagogo-Jack SE, Craft S, Cryer PE. Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus: recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. J Clin Invest. 1993;91:819–828. - PMC - PubMed
    1. Segel SA, Paramore DS, Cryer PE. Hypoglycemia-associated autonomic failure in advanced type 2 diabetes. Diabetes. 2002;51:724–733. - PubMed

Publication types