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 (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.
Highlights
In an effort to use regular insulin injections to maintain blood glucose levels within a normal range, patients with type 1 diabetes are continuously at risk of encountering episodes of recurrent/moderate hypoglycemia [1,2]
R/M hypoglycemia-induced cortical neuronal death is prevented by pyruvate
We tested whether pyruvate administration prevents microglial activation after R/M hypoglycemia by evaluating microglial staining in parietal and perirhinal cortex at three days after R/M hypoglycemia
Summary
In an effort to use regular insulin injections to maintain blood glucose levels within a normal range, patients with type 1 diabetes are continuously at risk of encountering episodes of recurrent/moderate hypoglycemia [1,2]. It is still possible to induce scattered neuronal death in the cerebral cortex when blood glucose concentrations are sustained just above 1 mM [3,4,5,6]. Moderate hypoglycemia, defined as low blood glucose levels (below 2 mM blood glucose for more than 2 hr) without the presence of iso-EEG, induces scattered neuronal death in the cerebral cortex [12], but not in the hippocampus [13,14].
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