Pyruvate Administration Reduces Recurrent-Moderate Hypoglycemia-Induced Cortical Neuron Death in Diabetic RatsReport as inadecuate

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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 10U-kg, i.p. without anesthesia for five consecutive days. Pyruvate 500mg-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.

Author: Bo Young Choi, Jin Hee Kim, Hyun Jung Kim, Jin Hyuk Yoo, Hong Ki Song, Min Sohn, Seok Joon Won, Sang Won Suh



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