title: EphA5-EphrinA5 interactions within the ventromedial hypothalamus influence counterregulatory hormone release and local glutamine/glutamate balance during hypoglycemia.
abstract: 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 overexpression 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.
authors.affiliation: Department of Internal Medicine and Endocrinology, Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Szepietowska
authors.forename: Wanling
authors.initials: W
authors.lastname: Zhu
authors.forename: Jan
authors.initials: J
authors.lastname: Czyzyk
authors.forename: Tore
authors.initials: T
authors.lastname: Eid
authors.forename: Robert S
authors.initials: RS
authors.lastname: Sherwin
mesh_terms: D000818:Animals; D001786:Blood Glucose; D036386:Ephrin-A5 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D004837:Epinephrine / Q000097:blood / Q000378:metabolism; D005786:Gene Expression Regulation; D005934:Glucagon / Q000097:blood / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D018698:Glutamic Acid / Q000378:metabolism*; D005973:Glutamine / Q000378:metabolism*; D007003:Hypoglycemia / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D036123:Receptor, EphA5 / Q000235:genetics / Q000378:metabolism*; D014697:Ventromedial Hypothalamic Nucleus / Q000187:drug effects* / Q000378:metabolism
chemical_list: D001786:Blood Glucose; D036386:Ephrin-A5; D007328:Insulin; D005973:Glutamine; D018698:Glutamic Acid; D005934:Glucagon; D036123:Receptor, EphA5; D005947:Glucose; D009638:Norepinephrine; D004837:Epinephrine