Type 1 corticotropin-releasing factor receptors in the ventromedial hypothalamus promote hypoglycemia-induced hormonal counterregulation.
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.
Article: Influence of insulin in the ventromedial hypothalamus on pancreatic glucagon secretion in vivo.[show abstract] [hide abstract]
ABSTRACT: Insulin released by the beta-cell is thought to act locally to regulate glucagon secretion. The possibility that insulin might also act centrally to modulate islet glucagon secretion has received little attention. Initially the counterregulatory response to identical hypoglycemia was compared during intravenous insulin and phloridzin infusion in awake chronically catheterized nondiabetic rats. To explore whether the disparate glucagon responses seen were in part due to changes in ventromedial hypothalamus (VMH) exposure to insulin, bilateral guide cannulas were inserted to the level of the VMH and 8 days later rats received a VMH microinjection of either 1) anti-insulin affibody, 2) control affibody, 3) artificial extracellular fluid, 4) insulin (50 microU), 5) insulin receptor antagonist (S961), or 6) anti-insulin affibody plus a gamma-aminobutyric acid A (GABA(A)) receptor agonist muscimol, prior to a hypoglycemic clamp or under baseline conditions. As expected, insulin-induced hypoglycemia produced a threefold increase in plasma glucagon. However, the glucagon response was fourfold to fivefold greater when circulating insulin did not increase, despite equivalent hypoglycemia and C-peptide suppression. In contrast, epinephrine responses were not altered. The phloridzin-hypoglycemia induced glucagon increase was attenuated (40%) by VMH insulin microinjection. Conversely, local VMH blockade of insulin amplified glucagon twofold to threefold during insulin-induced hypoglycemia. Furthermore, local blockade of basal insulin levels or insulin receptors within the VMH caused an immediate twofold increase in fasting glucagon levels that was prevented by coinjection to the VMH of a GABA(A) receptor agonist. Together, these data suggest that insulin's inhibitory effect on alpha-cell glucagon release is in part mediated at the level of the VMH under both normoglycemic and hypoglycemic conditions.Diabetes 03/2010; 59(6):1521-7. · 8.29 Impact Factor
Article: The medial amygdalar nucleus: a novel glucose-sensing region that modulates the counterregulatory response to hypoglycemia.[show abstract] [hide abstract]
ABSTRACT: To determine whether the medial amygdalar nucleus (MAN) represents a novel brain glucose-sensing region involved in the detection of hypoglycemia and generation of a counterregulatory hormone response. Fura-2 calcium imaging was used to assess glucose responsivity in neurons isolated from the MAN and single-cell real-time reverse transcription PCR used to examine gene expression within glucose-responsive neurons. In vivo studies with local MAN perfusion of the glucoprivic agent, 2-deoxyglucose (2-DG), under normal and hypoglycemic conditions and also after MAN lesioning with ibotenic acid, were used to examine the functional role of MAN glucose sensors. In addition, retrograde neuronal tracer studies were used to examine reciprocal pathways between the MAN and the ventromedial hypothalamus (VMH). The MAN contains a population of glucose-sensing neurons (13.5%), which express glucokinase, and the selective urocortin 3 (UCN3) receptor CRH-R2, but not UCN3 itself. Lesioning the MAN suppressed, whereas 2-DG infusion amplified, the counterregulatory response to hyperinsulinemic hypoglycemia in vivo. However, 2-DG infusion to the MAN or VMH under normoglycemic conditions had no systemic effect. The VMH is innervated by UCN3 neurons that arise mainly from the MAN, and ∼1/3 of MAN UCN3 neurons are active during mild hypoglycemia. The MAN represents a novel limbic glucose-sensing region that contains characteristic glucokinase-expressing glucose-sensing neurons that respond directly to manipulations of glucose availability both in vitro and in vivo. Moreover, UCN3 neurons may provide feedback inhibitory regulation of the counterregulatory response through actions within the VMH and the MAN.Diabetes 10/2010; 59(10):2646-52. · 8.29 Impact Factor
Article: Hypoglycemia in type 1 diabetes.Diabetes 10/2010; 59(10):2333-9. · 8.29 Impact Factor