title: Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons.
abstract: Antecedent insulin-induced hypoglycemia (IIH) reduces adrenomedullary responses (AMR) to subsequent bouts of hypoglycemia. The ventromedial hypothalamus [VMH: arcuate (ARC) + ventromedial nuclei] contains glucosensing neurons, which are thought to be mediators of these AMR. Since type 1 diabetes mellitus often begins in childhood, we used juvenile (4- to 5-wk-old) rats to demonstrate that a single bout of IIH (5 U/kg sc) reduced plasma glucose by 24% and peak epinephrine by 59% 1 day later. This dampened AMR was associated with 46% higher mRNA for VMH glucokinase, a key mediator of neuronal glucosensing. Compared with neurons from saline-injected rats, ventromedial nucleus glucose-excited neurons from insulin-injected rats demonstrated a leftward shift in their glucose responsiveness (EC50 = 0.45 and 0.10 mmol/l for saline and insulin, respectively, P = 0.05) and a 31% higher maximal activation by glucose (P = 0.05), although this maximum occurred at a higher glucose concentration (saline, 0.7 vs. insulin, 1.5 mmol/l). Although EC50 values did not differ, ARC glucose-excited neurons had 19% higher maximal activation, which occurred at a lower glucose concentration in insulin- than saline-injected rats (saline, 2.5 vs. insulin, 1.5 mmol/l). In addition, ARC glucose-inhibited neurons from insulin-injected rats were maximally inhibited at a fivefold lower glucose concentration (saline, 2.5 vs. insulin, 0.5 mmol/l), although this inhibition declined at >0.5 mmol/l glucose. These data suggest that the increased VMH glucokinase after IIH may contribute to the increased responsiveness of VMH glucosensing neurons to glucose and the associated blunting of the AMR.
authors: Department of Neurology and Neurosciences, New Jersey Medical School, University of Medicine and Dentistry, Newark, New Jersey, USA.
authors: Ling
authors: L
authors: Kang
authors: Nicole M
authors: NM
authors: Sanders
authors: Ambrose A
authors: AA
authors: Dunn-Meynell
authors: Larry D
authors: LD
authors: Gaspers
authors: Vanessa H
authors: VH
authors: Routh
authors: Andrew P
authors: AP
authors: Thomas
authors: Barry E
authors: BE
authors: Levin
mesh_terms: D000313:Adrenal Medulla / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000502:physiology; D005941:Glucokinase / Q000096:biosynthesis / Q000235:genetics; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology*; D006593:Hexokinase / Q000096:biosynthesis / Q000235:genetics; D007003:Hypoglycemia / Q000139:chemically induced / Q000503:physiopathology*; D007004:Hypoglycemic Agents; D007328:Insulin; D008297:Male; D009474:Neurons / Q000187:drug effects*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014697:Ventromedial Hypothalamic Nucleus / Q000166:cytology / Q000187:drug effects / Q000503:physiopathology*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D012333:RNA, Messenger; D006593:Hexokinase; D005941:Glucokinase; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose; D002118:Calcium