EphA5-EphrinA5 Interactions Within the Ventromedial Hypothalamus Influence Counterregulatory Hormone Release and Local Glutamine/Glutamate Balance During Hypoglycemia

Yale University School of Medicine, Department of Internal Medicine and Endocrinology, New Haven, Connecticut.
Diabetes (Impact Factor: 8.1). 12/2012; 62(4). DOI: 10.2337/db12-0982
Source: PubMed


Activation of β-cell EphA5 receptors by its ligand ephrinA5 from adjacent β-cells has been reported to decrease insulin secretion during hypoglycemia. Given the similarities between islet and ventromedial hypothalamus (VMH) glucose sensing, we tested the hypothesis that the EphA5/ephrinA5 system might function within the VMH during hypoglycemia to stimulate counterregulatory hormone release as well. Counterregulatory responses and glutamine/glutamate concentrations in the VMH were assessed during a hyperinsulinemic hypoglycemic glucose clamp study in chronically catheterized awake male Sprague-Dawley rats that received an acute VMH microinjection of ephrinA5-Fc, chronic VMH knockdown, or over-expression of ephrinA5 using an adenoassociated viral construct. Local stimulation of VMH EphA5 receptors by ephrinA5-Fc or ephrinA5 overexpression increased, whereas knockdown of VMH ephrinA5 reduced counterregulatory responses during hypoglycemia. Overexpression of VMH ephrinA5 transiently increased local glutamate concentrations, whereas ephrinA5 knockdown produced profound suppression of VMH interstitial fluid glutamine concentrations in the basal state and during hypoglycemia. Changes in ephrinA5/EphA5 interactions within the VMH, a key brain glucose-sensing region, act in concert with islets to restore glucose homeostasis during acute hypoglycemia, and its effect on counterregulation may be mediated by changes in glutamate/glutamine cycling.

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Available from: Barbara Szepietowska
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    ABSTRACT: Hypoglycemia produces complex neural and hormonal responses that restore glucose levels to normal. Glucose, metabolic substrates and their transporters, neuropeptides and neurotransmitters alter the firing rate of glucose-sensing neurons in the ventromedial hypothalamus (VMH); these monitor energy status and regulate the release of neurotransmitters that instigate a suitable counter-regulatory response. Under normal physiological conditions, these mechanisms maintain blood glucose concentrations within narrow margins. However, antecedent hypoglycemia and diabetes can lead to adaptations within the brain that impair counter-regulatory responses. Clearly, the mechanisms employed to detect and regulate the response to hypoglycemia, and the pathophysiology of defective counter-regulation in diabetes, are complex and need to be elucidated to permit the development of therapies that prevent or reduce the risk of hypoglycemia.
    No preview · Article · Sep 2013 · Trends in Endocrinology and Metabolism
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    ABSTRACT: Hypoglycemia stimulates counterregulatory hormone release to restore euglycemia. This protective response is diminished by recurrent hypoglycemia, limiting the benefits of intensive insulin treatment in patients with diabetes. Previously we have reported that EphA5 receptor-ephrinA5 interactions within the ventromedial hypothalamus (VMH) influence counterregulatory hormone responses during acute hypoglycemia in non-diabetic rats. In this study we examined whether recurrent hypoglycemia alters the capacity of the ephrinA5 ligand to activate VMH EphA5 receptors, and if so whether these changes could contribute to pathogenesis of defective glucose counterregulation in response to a standard hypoglycemic stimulus. The expression of ephrinA5, but not EphA5 receptors within the VMH was found to be reduced by antecedent recurrent hypoglycemia. In addition, there was an increase in the number of synaptic connections as well as reduced astroglial synaptic coverage. Activation of VMH EphA5 receptors via targeted microinjection of ephrinA5-Fc prior to hyperinsulinemic hypoglycemic clamp study caused a reduction in the glucose infusion rate in non-diabetic rats exposed to recurrent hypoglycemia. The increase in the counterregulatory response to insulin- induced hypoglycemia was associated with a 150% increase in glucagon release (p<0.001). These data suggest that changes in ephrinA5/EphA5 interactions and synaptic plasticity within the VMH, a key brain glucose-sensing region, may contribute to the impairment in glucagon secretion and counterregulatory responses caused by recurrent hypoglycemia.
    Full-text · Article · Nov 2013 · Diabetes
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