title: Blocking NMDA receptor signaling does not decrease hormonal counterregulation to hypoglycemia in humans.
abstract: In animals, blocking of glutamate signaling at the N-methyl-D-aspartate (NMDA) receptor reduces the neuroendocrine counterregulation to hypoglycemia. Hence, it has been proposed that increased excitatory glutamatergic input to the hypothalamus signals enforced central nervous energy demand under conditions of reduced supply. We examined the effect of the NMDA receptor antagonist memantine on hypoglycemia counterregulation in healthy humans. Hypoglycemic clamp experiments were performed in 10 healthy men after oral administration of 20 mg memantine and placebo. Counterregulatory hormones were measured during baseline and a clamp period of 120 min with hypoglycemia of 2.4 mmol/l lasting for 50 min. In addition, symptoms related to glycemic changes were assessed. Unexpectedly, the counterregulatory responses to hypoglycemia of adrenocorticotropin, cortisol and epinephrine were not decreased but tended to be increased by memantine, while norepinephrine and growth hormone were not affected. Glucagon levels were increased by memantine treatment during baseline and throughout the hypoglycemic period. After memantine administration, subjects also experienced more neuroglycopenic symptoms during hypoglycemia, whereas differences in autonomic symptoms did not reach significance. Contrasting with findings in animals, blocking the NMDA receptor does not decrease the counterregulatory responses to hypoglycemia in humans. Our data do not support the view that in humans, enhanced glutamate signaling during hypoglycemia supports the satisfaction of increased central nervous energy demands by enforcing hormonal counterregulation.
authors.affiliation: Department of Internal Medicine I, University of Luebeck, Ratzeburger Allee 160, 23538 Luebeck, Germany. Isabel.Pais@uk-sh.de
authors.forename: Isabel
authors.initials: I
authors.lastname: Pais
authors.forename: Christian
authors.initials: C
authors.lastname: Hubold
authors.forename: Manfred
authors.initials: M
authors.lastname: Hallschmid
authors.forename: Sebastian
authors.initials: S
authors.lastname: Letterer
authors.forename: Kerstin
authors.initials: K
authors.lastname: Oltmanns
authors.forename: Bernd
authors.initials: B
authors.lastname: Schultes
authors.forename: Jan
authors.initials: J
authors.lastname: Born
authors.forename: Achim
authors.initials: A
authors.lastname: Peters
mesh_terms: D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000328:Adult; D004311:Double-Blind Method; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D025461:Feedback, Physiological / Q000187:drug effects*; D005934:Glucagon / Q000378:metabolism; D015309:Glucose Clamp Technique; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism / Q000503:physiopathology*; D007328:Insulin / Q000008:administration & dosage; D008297:Male; D008559:Memantine / Q000494:pharmacology*; D010919:Placebos; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D055815:Young Adult
chemical_list: D018691:Excitatory Amino Acid Antagonists; D007328:Insulin; D010919:Placebos; D016194:Receptors, N-Methyl-D-Aspartate; D000324:Adrenocorticotropic Hormone; D005934:Glucagon; D008559:Memantine; D006854:Hydrocortisone