Format

Send to

Choose Destination
Diabetes. 2011 May;60(5):1582-9. doi: 10.2337/db10-1579. Epub 2011 Mar 16.

Increased GABAergic output in the ventromedial hypothalamus contributes to impaired hypoglycemic counterregulation in diabetic rats.

Author information

1
Section of Endocrinology, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, USA. owen.chan@yale.edu

Abstract

OBJECTIVE:

Impaired glucose counterregulation during hypoglycemia is well documented in patients with type 1 diabetes; however, the molecular mechanisms underlying this defect remain uncertain. We reported that the inhibitory neurotransmitter γ-aminobutyric acid (GABA), in a crucial glucose-sensing region within the brain, the ventromedial hypothalamus (VMH), plays an important role in modulating the magnitude of the glucagon and epinephrine responses to hypoglycemia and investigated whether VMH GABAergic tone is altered in diabetes and therefore might contribute to defective counterregulatory responses.

RESEARCH DESIGN AND METHODS:

We used immunoblots to measure GAD(65) protein (a rate-limiting enzyme in GABA synthesis) and microdialysis to measure extracellular GABA levels in the VMH of two diabetic rat models, the diabetic BB rat and the streptozotocin (STZ)-induced diabetic rat, and compared them with nondiabetic controls.

RESULTS:

Both diabetic rat models exhibited an ~50% increase in GAD(65) protein as well as a twofold increase in VMH GABA levels compared with controls under baseline conditions. Moreover, during hypoglycemia, VMH GABA levels did not change in the diabetic animals, whereas they significantly declined in nondiabetic animals. As expected, glucagon responses were absent and epinephrine responses were attenuated in diabetic rats compared with their nondiabetic control counterparts. The defective counterregulatory response in STZ-diabetic animals was restored to normal with either local blockade of GABA(A) receptors or knockdown of GAD(65) in the VMH.

CONCLUSIONS:

These data suggest that increased VMH GABAergic inhibition is an important contributor to the absent glucagon response to hypoglycemia and the development of counterregulatory failure in type 1 diabetes.

PMID:
21411513
PMCID:
PMC3292334
DOI:
10.2337/db10-1579
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center