3-nitrotyrosine and Hypoglycemia

It has been reported that hyperglycemia following hypoglycemia produces an ischemia-reperfusion-like effect in type 1 diabetes. In this study the possibility that GLP-1 has a protective effect on this phenomenon has been tested.. 15 type 1 diabetic patients underwent to five experiments: a period of two hours of hypoglycemia followed by two hours of normo-glycemia or hyperglycemia with the concomitant infusion of GLP-1 or vitamin C or both. At baseline, after 2 and 4 hours, glycemia, plasma nitrotyrosine, plasma 8-iso prostaglandin F2alpha, sCAM-1a, IL-6 and flow mediated vasodilation were measured.. After 2 h of hypoglycemia, flow mediated vasodilation significantly decreased, while sICAM-1, 8-iso-PGF2a, nitrotyrosine and IL-6 significantly increased. While recovering with normoglycemia was accompanied by a significant improvement of endothelial dysfunction, oxidative stress and inflammation, a period of hyperglycemia after hypoglycemia worsens all these parameters. These effects were counterbalanced by GLP-1 and better by vitamin C, while the simultaneous infusion of both almost completely abolished the effect of hyperglycemia post hypoglycemia.. This study shows that GLP-1 infusion, during induced hyperglycemia post hypoglycemia, reduces the generation of oxidative stress and inflammation, improving the endothelial dysfunction, in type 1 diabetes. Furthermore, the data support that vitamin C and GLP-1 may have an additive protective effect in such condition.

Topics: Adult; Antioxidants; Ascorbic Acid; Biomarkers; Blood Glucose; Diabetes Mellitus, Type 1; Dinoprost; Female; Glucagon-Like Peptide 1; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Inflammation; Inflammation Mediators; Infusions, Parenteral; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Oxidative Stress; Reperfusion Injury; Time Factors; Treatment Outcome; Tyrosine; Vasodilation; Young Adult

Insulin-induced hypoglycemia causes the death of neurons in particular brain regions including the cerebral cortex, the striatum and the hippocampus, while the cerebellum and the brain stem are more resistant. The mechanisms underlying this selective vulnerability to hypoglycemic damage are unknown. In the present study we have analyzed the presence of lipoperoxidation products and nitrosilated protein residues in different rat brain regions during and after the induction of hypoglycemia. Insulin-injected hypoglycemic rats were sacrificed before the onset of the isoelectric period or infused with glucose to end hypoglycemia, and then sacrificed at different times. Increased lipoperoxidation levels were observed before the onset of the isoelectric period, while 3-nitrotyrosine (NT) residues in proteins and NT-positive cells were only observed after glucose reperfusion. These changes were found only in vulnerable brain regions, while none of them was evident in the cerebellum, suggesting a correlation between oxidative damage and vulnerability to hypoglycemic neuronal death in selective brain regions. Results suggest that a pro-oxidant state is promoted in certain brain regions during hypoglycemia and after the glucose reperfusion phase, which might result from the activation of several oxidative stress pathways and may be related to subsequent cell death.

Topics: Animals; Biomarkers; Brain; Cerebellum; Cerebral Cortex; Corpus Striatum; Electroencephalography; Hippocampus; Hypoglycemia; Hypoglycemic Agents; Immunohistochemistry; Insulin; Lipid Peroxidation; Male; Oxidative Stress; Rats; Rats, Wistar; Time Factors; Tyrosine

Severe hypoglycemia causes neuronal death and cognitive impairment. Evidence suggests that hypoglycemic neuronal death involves excitotoxicity and DNA damage. Poly(ADP-ribose) polymerase-1 (PARP-1) normally functions in DNA repair, but promotes cell death when extensively activated by DNA damage. Cortical neuron cultures were subjected to glucose deprivation to assess the role of PARP-1 in hypoglycemic neuronal death. PARP-1-/- neurons and wild-type, PARP-1+/+ neurons treated with the PARP inhibitor 3,4-dihydro-5-[4-(1-piperidinyl)butoxy]-1(2H)-isoquinolinone both showed increased resistance to glucose deprivation. A rat model of insulin-induced hypoglycemia was used to assess the therapeutic potential of PARP inhibitors after hypoglycemia. Rats subjected to severe hypoglycemia (30 min EEG isoelectricity) accumulated both nitrotyrosine and the PARP-1 product, poly(ADP-ribose), in vulnerable neurons. Treatment with PARP inhibitors immediately after hypoglycemia blocked production of poly(ADP-ribose) and reduced neuronal death by >80% in most brain regions examined. Increased neuronal survival was also achieved when PARP inhibitors were administered up to 2 hr after blood glucose correction. Behavioral and histological assessments performed 6 weeks after hypoglycemia confirmed a sustained salutary effect of PARP inhibition. These results suggest that PARP-1 activation is a major factor mediating hypoglycemic neuronal death and that PARP-1 inhibitors can rescue neurons that would otherwise die after severe hypoglycemia.

Topics: Animals; Astrocytes; Behavior, Animal; Benzamides; Benzopyrans; Cell Death; Cells, Cultured; Cognition Disorders; Disease Models, Animal; Drug Administration Schedule; Enzyme Inhibitors; Hypoglycemia; Isoquinolines; Male; Maze Learning; Mice; Mice, Knockout; Neurons; Poly(ADP-ribose) Polymerase Inhibitors; Rats; Rats, Sprague-Dawley; Receptors, Glutamate; Time Factors; Treatment Outcome; Tyrosine