Inactivation of the DMH selectively inhibits the ACTH and corticosterone responses to hypoglycemia

Evans, Sean; Wilkinson, Charles W.; Gronbeck, Pam; Bennett, Jennifer L.; Zavosh, Aryana; Taborsky, Gerald J.; Figlewicz, Dianne P.

doi:10.1152/ajpregu.00328.2003

Cited by 24 publications

(25 citation statements)

References 45 publications

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“…We found that staining for GFP-positive neurons was primarily within the VMH with a small amount of spread to the DMH, the latter predominantly via the needle track. The DMH is a glucose-sensing region, however, its chemical inactivation in vivo with lidocaine results in a mild impairment of adrenocorticotrophin hormone (ACTH) and corticosterone response to acute hypoglycemia only (38). In contrast, in the present study, AMPK downregulation in the VMH resulted in reduced epinephrine and glucagon responses to acute hypoglycemia and had no effect on the corticosterone response.…”

Section: Discussioncontrasting

confidence: 75%

Key Role for AMP-Activated Protein Kinase in the Ventromedial Hypothalamus in Regulating Counterregulatory Hormone Responses to Acute Hypoglycemia

et al. 2008

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OBJECTIVE-To examine in vivo in a rodent model the potential role of AMP-activated protein kinase (AMPK) within the ventromedial hypothalamus (VMH) in glucose sensing during hypoglycemia.RESEARCH DESIGN AND METHODS-Using gene silencing technology to selectively downregulate AMPK in the VMH, a key hypothalamic glucose-sensing region, we demonstrate a key role for AMPK in the detection of hypoglycemia. In vivo hyperinsulinemic-hypoglycemic (50 mg dl Ϫ1 ) clamp studies were performed in awake, chronically catheterized Sprague-Dawley rats that had been microinjected bilaterally to the VMH with an adeno-associated viral (AAV) vector expressing a short hairpin RNA for AMPK␣. (ϳ60%) and epinephrine (ϳ40%) responses to acute hypoglycemia. Rats with VMH AMPK downregulation also required more exogenous glucose to maintain the hypoglycemia plateau and showed significant reductions in endogenous glucose production and wholebody glucose uptake. RESULTS-In comparison with control studies, VMH AMPK downregulation resulted in suppressed glucagon CONCLUSIONS-We

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Section: Discussioncontrasting

confidence: 75%

Key Role for AMP-Activated Protein Kinase in the Ventromedial Hypothalamus in Regulating Counterregulatory Hormone Responses to Acute Hypoglycemia

et al. 2008

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“…However, the role of the THPVP may be more complex than originally hypothesized. First, control PBS infusions in SH rats experiencing a single (naive) bout of hypoglycemia had no effect on the neuroendocrine responses, when compared with other data from our laboratory in this model, in subjects with no CNS cannulas (Evans et al, 2001), or identical experimental protocols where cannulas were aimed at the paraventricular or dorsomedial nuclei of the hypothalamus (Evans et al, 2003(Evans et al, , 2004. Likewise, acute LIDO infusions in SH rats had no effect on the neuroendocrine responses.…”

Section: Discussionmentioning

confidence: 82%

“…Prior to performing experiments, animals were familiarized with square acrylic test chambers (∼30 cm×30 cm×30 cm) and the microinjection procedure as described by Evans et al (2003Evans et al ( , 2004. Subsequent to this, the animals were placed in the test chambers for at least 2 h before experimental procedures began.…”

Section: Methodsmentioning

confidence: 99%

“…We observed decreased activation of the paraventricular nucleus of the hypothalamus (PVN) and dorsomedial hypothalamus (DMH) in rats that experienced multiple, vs. a single bout of hypoglycemia. In subsequent studies, we have demonstrated that reversible inactivation of these regions during a single bout of hypoglycemia (SH) resulted in impairments of the sympathoadrenal and HPA axis responses (Evans et al, 2003(Evans et al, , 2004). Thus, decreased medial hypothalamic activation may contribute to the impaired counterregulatory response of recurrent hypoglycemia (RH).…”

Section: Introductionmentioning

confidence: 99%

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Acute THPVP inactivation decreases the glucagon and sympathoadrenal responses to recurrent hypoglycemia

et al. 2008

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The posterior paraventricular nucleus of the thalamus (THPVP) has been identified as a forebrain region that modulates the central nervous system (CNS) response to recurrent experiences of stressors. The THPVP is activated in response to a single (SH) or recurrent (RH) experience of the metabolic stress of hypoglycemia. In this study, we evaluated whether temporary experimental inactivation of the THPVP would modify the neuroendocrine response to SH or RH. Infusion of lidocaine (LIDO) or vehicle had no effect on the neuroendocrine response to SH, comparable to findings with other stressors. THPVP vehicle infusion concomitant with RH resulted in a prevention of the expected impairment of neuroendocrine responses, relative to SH. LIDO infusion with RH resulted in significantly decreased glucagon and sympathoadrenal responses, relative to SH. These results suggest that the THPVP may contribute to the sympathoadrenal stimulation induced by hypoglycemia; and emphasizes that the THPVP is a forebrain region that may contribute to the coordinated CNS response to metabolic stressors.

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“…Moreover, administration of the GABA A receptor antagonist into the VMH did not alter corticosterone responses. This finding suggests that glucagon and epinephrine responses may be primarily regulated through the VMH, whereas activation of the hypothalamo-pituitaryadrenal response to hypoglycemia is mediated through other hypothalamic centers, such as the paraventricular nucleus (46,47).…”

Section: Discussionmentioning

confidence: 99%

Increased GABAergic Tone in the Ventromedial Hypothalamus Contributes to Suppression of Counterregulatory Reponses After Antecedent Hypoglycemia

et al. 2008

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OBJECTIVE-We have previously demonstrated that modulation of ␥-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-QuantitativeRT-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.

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Inactivation of the DMH selectively inhibits the ACTH and corticosterone responses to hypoglycemia

Cited by 24 publications

References 45 publications

Key Role for AMP-Activated Protein Kinase in the Ventromedial Hypothalamus in Regulating Counterregulatory Hormone Responses to Acute Hypoglycemia

Key Role for AMP-Activated Protein Kinase in the Ventromedial Hypothalamus in Regulating Counterregulatory Hormone Responses to Acute Hypoglycemia

Acute THPVP inactivation decreases the glucagon and sympathoadrenal responses to recurrent hypoglycemia

Increased GABAergic Tone in the Ventromedial Hypothalamus Contributes to Suppression of Counterregulatory Reponses After Antecedent Hypoglycemia

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