title: Pyruvate administration reduces recurrent/moderate hypoglycemia-induced cortical neuron death in diabetic rats.
abstract: Recurrent/moderate (R/M) hypoglycemia is common in type 1 diabetes patients. Moderate hypoglycemia is not life-threatening, but if experienced recurrently it may present several clinical complications. Activated PARP-1 consumes cytosolic NAD, and because NAD is required for glycolysis, hypoglycemia-induced PARP-1 activation may render cells unable to use glucose even when glucose availability is restored. Pyruvate, however, can be metabolized in the absence of cytosolic NAD. We therefore hypothesized that pyruvate may be able to improve the outcome in diabetic rats subjected to insulin-induced R/M hypoglycemia by terminating hypoglycemia with glucose plus pyruvate, as compared with delivering just glucose alone. In an effort to mimic juvenile type 1 diabetes the experiments were conducted in one-month-old young rats that were rendered diabetic by streptozotocin (STZ, 50mg/kg, i.p.) injection. One week after STZ injection, rats were subjected to moderate hypoglycemia by insulin injection (10 U/kg, i.p.) without anesthesia for five consecutive days. Pyruvate (500 mg/kg) was given by intraperitoneal injection after each R/M hypoglycemia. Three hours after last R/M hypoglycemia, zinc accumulation was evaluated. Three days after R/M hypoglycemia, neuronal death, oxidative stress, microglial activation and GSH concentrations in the cerebral cortex were analyzed. Sparse neuronal death was observed in the cortex. Zinc accumulation, oxidative injury, microglial activation and GSH loss in the cortex after R/M hypoglycemia were all reduced by pyruvate injection. These findings suggest that when delivered alongside glucose, pyruvate may significantly improve the outcome after R/M hypoglycemia by circumventing a sustained impairment in neuronal glucose utilization resulting from PARP-1 activation.
authors.affiliation: Department of Physiology, Hallym University, College of Medicine, Chuncheon, Korea.
authors.forename: Bo Young
authors.initials: BY
authors.lastname: Choi
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Kim
authors.forename: Hyun Jung
authors.initials: HJ
authors.lastname: Kim
authors.forename: Jin Hyuk
authors.initials: JH
authors.lastname: Yoo
authors.forename: Hong Ki
authors.initials: HK
authors.lastname: Song
authors.forename: Min
authors.initials: M
authors.lastname: Sohn
authors.forename: Seok Joon
authors.initials: SJ
authors.lastname: Won
authors.forename: Sang Won
authors.initials: SW
authors.lastname: Suh
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002540:Cerebral Cortex / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism* / Q000473:pathology; D003922:Diabetes Mellitus, Type 1; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D007003:Hypoglycemia / Q000378:metabolism* / Q000473:pathology; D008297:Male; D017628:Microglia / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology; D018384:Oxidative Stress; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D019289:Pyruvic Acid / Q000494:pharmacology*; D051381:Rats; D015032:Zinc / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; D019289:Pyruvic Acid; D011065:Poly(ADP-ribose) Polymerases; D005978:Glutathione; D015032:Zinc