Hypoglycemic Neuronal Death
The normal range for blood glucose concentrations is 3.9–7.1 mM (1 mM = ∼18 mg/dL), and hypoglycemia is broadly defined as blood glucose concentrations below this range. Studies using mice and rats indicate that brain injury does not generally occur unless blood glucose concentrations fall below 1 mM and the cortical electroencephalogram (EEG) is isoelectric (silent) for at least 30 min (Auer et al. 1984a, b; Auer et al. 1985a, b; Suh et al. 2003). Case series suggest that a similar degree of hypoglycemia is required to induce brain injury in humans, although this may vary in infants and children, susceptible individuals, with repeated hypoglycemia, and with co-morbid factors (Kalimo and Olsson 1980; Malouf and Brust 1985; Auer et al. 1989; Langan et al. 1991; Ben-Ami et al. 1999; de Courten-Myers et al. 2000; Ennis et al. 2008).
Reduced food intake does not reduce blood glucose levels below 2.8 mM, even with prolonged fasting (Auer 2004); however, reductions below 1 mM can be induced by the administration of insulin, glucagon, and drugs such as sulfonylurea derivatives. Not surprisingly, hypoglycemic brain injury occurs most frequently in diabetic patients attempting tight glucose control (Lincoln et al. 1996; Davis and Jones 1998), and consequently the risk (or fear) of hypoglycemic brain injury is the major factor limiting tight glucose control. While most diabetic patients experience moderate to severe hypoglycemia at times, very few experience hypoglycemia to the degree causing coma or brain injury. This said, the prevalence of diabetes is so high that hypoglycemic brain injury is not rare; in a case series from a single hospital emergency room, there were 125 patients visits for symptomatic hypoglycemia in 1 year. Of these, 23 were comatose, 1 died, and 4 survivors had permanent neurological sequelae (Malouf and Brust 1985).
KeywordsNADPH Oxidase Neuronal Death Blood Glucose Concentration Superoxide Production Mitochondrial Permeability Transition
Supported by the Juvenile Diabetes Research Foundation (JDRF-2-2006-113, S.W.S.), the National Institutes of Health (NS051855, R.A.S.), and the Department of Veterans Affairs.
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