Article

Type 1 corticotropin-releasing factor receptors in the ventromedial hypothalamus promote hypoglycemia-induced hormonal counterregulation.

Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
AJP Endocrinology and Metabolism (impact factor: 4.75). 10/2007; 293(3):E705-12. DOI:10.1152/ajpendo.00136.2007 pp.E705-12
Source: PubMed

ABSTRACT Type 2 corticotropin-releasing factor (CRF) receptors (CRFR2) within the ventromedial hypothalamus (VMH), a key glucose-sensing region, play a major role in regulating the hormonal counterregulatory responses (CRRs) to acute hypoglycemia. The VMH expresses both subtypes of CRF receptors, CRFR1 and CRFR2. The objective of this study was to examine the role of the CRFR1 receptor in the VMH in the regulation of the CRR to acute hypoglycemia. To compare the hormonal CRR to hypoglycemia, awake and unrestrained Sprague-Dawley rats were bilaterally microinjected to the VMH with either 1) aECF, 2) CRF (1 pmol/side), 3) CRFR1 antagonist Antalarmin (500 pmol/side), or 4) CRF + Antalarmin prior to undergoing a hyperinsulinemic hypoglycemic (2.8 mM) clamp. A second series of studies also incorporated an infusion of [(3)H]glucose to allow the calculation of glucose dynamics. In addition the effect of CRFR1 antagonism in the paraventricular nucleus (PVN) was studied. Activation of VMH CRFR1 increased, whereas inhibition of CRFR1 suppressed hypoglycemia-induced CRRs. Inhibition of VMH CRFR1 also increased peripheral glucose utilization and reduced endogenous glucose production during hypoglycemia, whereas VMH CRF reduced peripheral glucose utilization. In contrast CRFR1 inhibition in the PVN blunted corticosterone but not epinephrine or glucagon CRR to hypoglycemia. In contrast to CRFR2 activation, CRFR1 activation within the VMH amplifies CRRs to acute hypoglycemia. The balance between these two opposing CRFRs in this key glucose-sensing region may play an important role in determining the magnitude of CRRs to acute hypoglycemia.

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Keywords

acute hypoglycemia
 
contrast CRFR1 inhibition
 
CRF receptors
 
CRFR1 activation
 
CRFR1 antagonism
 
CRFR1 receptor
 
CRFR2 activation
 
endogenous glucose production
 
glucagon CRR
 
glucose dynamics
 
hormonal CRR
 
hyperinsulinemic hypoglycemic
 
peripheral glucose utilization
 
second series
 
Type 2 corticotropin-releasing factor
 
unrestrained Sprague-Dawley rats
 
ventromedial hypothalamus
 
VMH amplifies CRRs
 
VMH CRF
 
VMH CRFR1