May 3, 2005 A natural, non-toxic byproduct of glucose may prevent brain cell death and cognitive impairment in diabetics following an episode of severely low blood sugar, according to researchers at the San Francisco VA Medical Center (SFVAMC).
In research studies with rats, senior investigator Raymond A. Swanson, MD, and lead author Sang Won Suh, PhD, demonstrated the effectiveness of pyruvate, a naturally-occurring byproduct of glucose, when administered along with glucose after 30 minutes of diabetic coma. The therapy prevented brain damage and subsequent memory and learning impairment far better than treatment with glucose alone.
The study findings, appearing in the May 1, 2005 issue of Diabetes, have direct implications for the treatment of diabetic patients in hypoglycemic coma, according to the researchers.
Glucose is a form of sugar that serves as the body's primary fuel. People with diabetes lack the ability to make insulin, the primary enzyme that metabolizes glucose and regulates its levels in the blood, and must inject insulin to make up for this lack. Abnormally low blood glucose is called hypoglycemia; severe hypoglycemia can cause coma.
"It's estimated that between 2 and 15 percent of people with diabetes will have at least one episode of diabetic coma resulting from severe hypoglycemia," says Swanson, chief of the Neurology and Rehabilitation Service at SFVAMC and professor of neurology at UCSF.
"Anybody who's worked at a busy emergency room has seen a patient like this," he adds. A patient admitted with severe hypoglycemia is immediately given glucose as a standard treatment. This restores consciousness right away, but may not always prevent the subsequent death of neurons and possible cognitive impairment, he says.
In an earlier paper, Swanson and Suh, an assistant adjunct professor of neurology at UCSF, demonstrated the cause of this brain cell death: hypoglycemia triggers the activation of an enzyme called PARP-1, which in turn prevents neurons from metabolizing glucose into pyruvate, which is used to power cells. Deprived of pyruvate, the neurons starve and die.
In the current study, Swanson and Suh discovered they could circumvent the action of PARP-1 and keep neurons alive by administering pyruvate directly.
The key to neuron survival is the amount of the dose: 100 times the normal blood level. Pyruvate usually circulates throughout the brain and body at low concentrations, but ordinarily cannot penetrate the blood-brain barrier. However, "when we increase the levels to 100-fold normal, it gets into the brain well enough to preserve the neurons," says Swanson. The paper concludes that "pyruvate may be an effective intervention for patients with severe hypoglycemia."
In the research study, male rats experienced hypoglycemia and subsequent coma after insulin administration. After 30 minutes of diabetic coma?determined by monitoring the animals' brainwaves using EEG (electro-encephalogram)?one group of rats was restored to consciousness with the administration of glucose plus pyruvate. Another group received glucose only, which is the current standard treatment for hypoglycemic coma. A control "sham hypoglycemia" group was administered insulin and then immediately given glucose to prevent coma.
Six weeks later, the rats were tested for memory and learning using a standard test involving a maze. Rats that had received only glucose showed significant impairment of learning and memory compared to the control group. By contrast, rats that had received pyruvate along with glucose did not show any significant cognitive deficit compared to the control group.
Followup necropsy of brain tissue evaluated four areas of the hippocampus most vulnerable to damage from hypoglycemia: CA1, dentate granule cell, subiculum, and perirhinal cortex. The rats receiving glucose plus pyruvate had 70 to 90 percent less neuronal death than the rats given glucose only, indicating that pyruvate prevented neuronal death.
In a separate group of rats, the investigators also studied the protective effects of delayed administration of pyruvate. Hypoglycemic coma was induced using insulin and ended 30 minutes later with glucose only. The rats were then given pyruvate 1, 3, or 6 hours later. In the rats given pyruvate 1 hour after hypoglycemia was induced, all four regions of the brain were protected. A 3-hour delay achieved significant protection only in the dentate granule cell and the cortical areas. Pyruvate had no protective effect after 6 hours.
The current study findings have set the stage for two lines of future research, according to Swanson. One will involve the study of animals under circumstances less severe, and more realistic, than a 30-minute coma: "At this point, we need to also examine the effect of pyruvate after more moderate hypoglycemia, as more commonly experienced by diabetic patients." At the same time, Swanson believes that research on pyruvate therapy is ready to advance to the clinical level. "Pyruvate is a natural metabolite, present in our blood. There's no reason to think that it would have any long-term adverse effects."
Additional authors of the study are Koji Aoyama, PhD, of SFVAMC and the UCSF Department of Neurology, and Yasuhiko Matsumori, PhD, and Jialing Liu, PhD, of SFVAMC and the UCSF Department of Neurosurgery.
The research was funded by the Juvenile Diabetes Research Foundation, the Department of Veterans Affairs, and by a grant from the National Institutes of Health that was administered by the Northern California Institute for Research and Education (NCIRE).
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