Prior hypoglycemia enhances glucose responsiveness in some ventromedial hypothalamic glucosensing neurons.
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.
Kang
Ling
L
Department of Neurology and Neurosciences, New Jersey Medical School, University of Medicine and Dentistry, Newark, New Jersey, USA.
Sanders
Nicole M
NM
Dunn-Meynell
Ambrose A
AA
Gaspers
Larry D
LD
Routh
Vanessa H
VH
Thomas
Andrew P
AP
Levin
Barry E
BE
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*
D007004:Hypoglycemic Agents; D007328:Insulin; D012333:RNA, Messenger; D006593:Hexokinase; D005941:Glucokinase; D017868:Cyclic AMP-Dependent Protein Kinases; D005947:Glucose; D002118:Calcium