6533b86efe1ef96bd12cac3d
RESEARCH PRODUCT
Hypothalamic S-Nitrosylation Contributes to the Counter-Regulatory Response Impairment following Recurrent Hypoglycemia
Branly OrbanJoshua R. BerlinLionel CarneiroAnnie BeuveChunxue ZhouLuc PénicaudC. LeloupAdam DeakNazish SayedSrinidhi DeshpandeXavier FioramontiXavier FioramontiVanessa H. Routhsubject
Central Nervous SystemMaleespèce active de l'oxygènemedicine.medical_treatmentlcsh:Medicinechemistry.chemical_compoundEndocrinology0302 clinical medicineDesensitization (telecommunications)Insulinhypothalamuslcsh:ScienceNeurons0303 health sciencesMultidisciplinaryStatisticsNeurochemistryOrvostudományokAnimal Models[ SDV.MHEP.EM ] Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism[SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism3. Good healthEpinephrineHomeostatic MechanismsAlimentation et NutritionMedicineNeurochemicalshypoglycémieResearch Articlediabètemedicine.drugmedicine.medical_specialtyRecurrent hypoglycemiamonoxide d'azoteinsulino-thérapie intensiveNeurophysiologyBiostatisticsHypoglycemiaKlinikai orvostudományokNitric OxideGlucagonNitric oxide03 medical and health sciencesModel OrganismsInternal medicinemedicineFood and NutritionAnimalscontre-régulationBiologyNutrition030304 developmental biologyDiabetic EndocrinologyEndocrine Physiologybusiness.industryInsulinlcsh:Rneurone sensible au glucosenutritional and metabolic diseasesmonoxide d'azote;espèce active de l'oxygène;S-nitrosylation;hypoglycémie;neurone sensible au glucose;hypothalamus;contre-régulation;diabète;insulino-thérapie intensiveDiabetes Mellitus Type 1NeuroendocrinologyDiabetes Mellitus Type 2medicine.diseaseHypoglycemiaS-nitrosylationAcetylcysteineRatsGlucoseEndocrinologychemistryMetabolic DisordersRatlcsh:QReactive Oxygen SpeciesbusinessSoluble guanylyl cyclaseMathematics030217 neurology & neurosurgeryNeurosciencedescription
http://www.ncbi.nlm.nih.gov/pubmed/23894333; International audience; 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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2013-07-01 | PLoS ONE |