Antecedent Hindbrain Glucoprivation Does Not Impair the Counterregulatory Response to Hypoglycemia

Abstract

Recurrent hypoglycemia impairs hormonal counterregulatory responses (CRRs) to further bouts of hypoglycemia. The hypothalamus and hindbrain are both critical for sensing hypoglycemia and triggering CRRs. Hypothalamic glucose sensing sites are implicated in the pathogenesis of defective CRRs; however, the contribution of hindbrain glucose sensing has not been elucidated. Using a rat model, we compared the effect of antecedent glucoprivation targeting hindbrain or hypothalamic glucose sensing sites with the effect of antecedent recurrent hypoglycemia on CRR to hypoglycemia induced 24 h later. Recurrent hypoglycemia decreased sympathoadrenal (1,470 ± 325 vs. 3,811 ± 540 pg/ml in controls [t = 60 min], P = 0.001) and glucagon secretion (222 ± 43 vs. 494 ± 56 pg/ml in controls [t = 60]), P = 0.003) in response to hypoglycemia. Antecedent 5-thio-glucose (5TG) injected into the hindbrain did not impair sympathoadrenal (3,806 ± 344 pg/ml [t = 60]) or glucagon (513 ± 56 pg/ml [t = 60]) responses to subsequent hypoglycemia. However, antecedent 5TG delivered into the third ventricle was sufficient to blunt CRRs to hypoglycemia. These results show that hindbrain glucose sensing is not involved in the development of defective CRRs. However, neural substrates surrounding the third ventricle are particularly sensitive to glucoprivic stimulation and may contribute importantly to the development of defective CRRs.There is a long history of anatomical and pharmacological evidence supporting the role of both the hypothalamus (6–14) and hindbrain (15–18) in glucose sensing and in the initiation of hormonal CRRs. Although there is evidence supporting the role of the hypothalamus, in particular the ventromedial nucleus, in the development of defective hypoglycemic CRRs (10,19–21), the contribution of hindbrain glucose sensing mechanisms is unknown. Given their anatomical differences and the fact that hindbrain glucoreceptors can function independently from the hypothalamus (16), recurrent hypoglycemic stimulation may differentially affect these two distinct glucose sensing brain regions. In the present study, we adapted our recurrent hypoglycemia rat model, which results in significant deficits in hormonal CRRs (22), to identify the contribution of a hindbrain glucose sensing site (17) in defective CRRs. We compared the effect of antecedent 5-thio-glucose (5TG), delivered into the hindbrain or third ventricle, with the effect of antecedent recurrent hypoglycemia on hormonal CRRs to subsequent hypoglycemia. We hypothesized that either antecedent hindbrain or third ventricular glucoprivation would impair CRRs to subsequent hypoglycemia. As expected, antecedent third ventricular glucoprivation, similar to recurrent hypoglycemia, blunted hormonal CRRs to subsequent hypoglycemia. In marked contrast, antecedent glucoprivation localized to a caudal hindbrain glucose sensing site did not impair hypoglycemia CRRs. Therefore, the hindbrain does not appear to be vulnerable to the central nervous system's adaptive mechanisms that impair CRRs under conditions of recurrent