Hypothalamic S-nitrosylation contributes to the counter-regulatory response impairment following recurrent hypoglycemia.

Details

Serval ID
serval:BIB_053839061DA4
Type
Article: article from journal or magazin.
Collection
Publications
Title
Hypothalamic S-nitrosylation contributes to the counter-regulatory response impairment following recurrent hypoglycemia.
Journal
Plos One
Author(s)
Fioramonti X., Deak A., Deshpande S., Carneiro L., Zhou C., Sayed N., Orban B., Berlin J.R., Pénicaud L., Leloup C., Beuve A., Routh V.H.
ISSN
1932-6203 (Electronic)
ISSN-L
1932-6203
Publication state
Published
Issued date
2013
Volume
8
Number
7
Pages
e68709
Language
english
Notes
Publication types: in OA
Abstract
AIMS: 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.
CONCLUSION: These data suggest that NAC may be clinically useful in preventing impaired CRR in patients undergoing intensive-insulin therapy.
Keywords
Acetylcysteine/administration & dosage, Animals, Glucose/metabolism, Hypoglycemia/chemically induced, Hypoglycemia/metabolism, Hypothalamus/drug effects, Hypothalamus/metabolism, Insulin/adverse effects, Male, Neurons/drug effects, Neurons/metabolism, Rats, Reactive Oxygen Species/metabolism
Pubmed
Open Access
Yes
Create date
20/10/2015 13:21
Last modification date
20/08/2019 12:27
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