Hypothalamic S-Nitrosylation Contributes to the Counter-Regulatory Response Impairment following Recurrent HypoglycemiaReport as inadecuate

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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.


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.


These data suggest that NAC may be clinically useful in preventing impaired CRR in patients undergoing intensive-insulin therapy.

Author: Xavier Fioramonti , Adam Deak , Srinidhi Deshpande, Lionel Carneiro, Chunxue Zhou, Nazish Sayed, Branly Orban, Joshua R. Berlin,

Source: http://plos.srce.hr/


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