title: Hypothalamic S-nitrosylation contributes to the counter-regulatory response impairment following recurrent hypoglycemia.
abstract: OBJECTIVE
  Hypoglycemia is a severe side effect of intensive insulin therapy. Recurrent hypoglycemia (RH) impairs the counter-regulatory response (CRR) which restores euglycemia. During hypoglycemia, ventromedial hypothalamus (VMH) production of nitric oxide (NO) and activation of its receptor soluble guanylyl cyclase (sGC) are critical for the CRR. Hypoglycemia also increases brain reactive oxygen species (ROS) production. NO production in the presence of ROS causes protein S-nitrosylation. S-nitrosylation of sGC impairs its function and induces desensitization to NO. We hypothesized that during hypoglycemia, the interaction between NO and ROS increases VMH sGC S-nitrosylation levels and impairs the CRR to subsequent episodes of hypoglycemia. VMH ROS production and S-nitrosylation were quantified following three consecutive daily episodes of insulin-hypoglycemia (RH model). The CRR was evaluated in rats in response to acute insulin-induced hypoglycemia or via hypoglycemic-hyperinsulinemic clamps. Pretreatment with the anti-oxidant N-acetyl-cysteine (NAC) was used to prevent increased VMH S-nitrosylation.
  
  
  RESULTS
  Acute insulin-hypoglycemia increased VMH ROS levels by 49±6.3%. RH increased VMH sGC S-nitrosylation. Increasing VMH S-nitrosylation with intracerebroventricular injection of the nitrosylating agent S-nitroso-L-cysteine (CSNO) was associated with decreased glucagon secretion during hypoglycemic clamp. Finally, in RH rats pre-treated with NAC (0.5% in drinking water for 9 days) hypoglycemia-induced VMH ROS production was prevented and glucagon and epinephrine production was not blunted in response to subsequent insulin-hypoglycemia.
  
  
  CONCLUSIONS
  These data suggest that NAC may be clinically useful in preventing impaired CRR in patients undergoing intensive-insulin therapy.
authors.affiliation: Department of Pharmacology and Physiology, New Jersey Medical School, Newark, New Jersey, United States of America.
authors.forename: Xavier
authors.initials: X
authors.lastname: Fioramonti
authors.forename: Adam
authors.initials: A
authors.lastname: Deak
authors.forename: Srinidhi
authors.initials: S
authors.lastname: Deshpande
authors.forename: Lionel
authors.initials: L
authors.lastname: Carneiro
authors.forename: Chunxue
authors.initials: C
authors.lastname: Zhou
authors.forename: Nazish
authors.initials: N
authors.lastname: Sayed
authors.forename: Branly
authors.initials: B
authors.lastname: Orban
authors.forename: Joshua R
authors.initials: JR
authors.lastname: Berlin
authors.forename: Luc
authors.initials: L
authors.lastname: Pénicaud
authors.forename: Corinne
authors.initials: C
authors.lastname: Leloup
authors.forename: Annie
authors.initials: A
authors.lastname: Beuve
authors.forename: Vanessa H
authors.initials: VH
authors.lastname: Routh
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage; D000818:Animals; D005947:Glucose / Q000378:metabolism; D007003:Hypoglycemia / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D007328:Insulin / Q000009:adverse effects; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D007328:Insulin; D017382:Reactive Oxygen Species; D005947:Glucose; D000111:Acetylcysteine
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