Hypothalamic S-nitrosylation contributes to the counter-regulatory response impairment following recurrent hypoglycemia
PLoS ONE. 2013-07-19; 8(7): e68709
DOI: 10.1371/journal.pone.0068709
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1. PLoS One. 2013 Jul 19;8(7):e68709. doi: 10.1371/journal.pone.0068709. Print
2013.
Hypothalamic S-nitrosylation contributes to the counter-regulatory response
impairment following recurrent hypoglycemia.
Fioramonti X(1), Deak A, Deshpande S, Carneiro L, Zhou C, Sayed N, Orban B,
Berlin JR, Pénicaud L, Leloup C, Beuve A, Routh VH.
Author information:
(1)Department of Pharmacology and Physiology, New Jersey Medical School, Newark,
New Jersey, United States of America.
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.
DOI: 10.1371/journal.pone.0068709
PMCID: PMC3716881
PMID: 23894333 [Indexed for MEDLINE]
Conflict of interest statement: Competing Interests: The authors have declared
that no competing interests exist.