Optimal blood glucose levels while using insulin to minimize the size of infarction in focal cerebral ischemia

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Object. Insulin has been shown to ameliorate cerebral necrosis in global and, more recently, in focal cerebral ischemia. The goal of this study was to determine the relationship between this neuroprotective effect and blood sugar levels in a rat model of focal ischemia.

Methods. Thirty-four rats were subjected to 80 minutes of transient middle cerebral artery occlusion at a mean arterial blood pressure of 60 mm Hg and a temperature of 37°C. Insulin (3.5 IU/kg) was administered 1 hour before (12 rats) and 20 minutes after (12 rats) ischemia; 10 animals served as controls. A quantitative histopathological study conducted after 1 week of survival showed that insulin was not beneficial in reducing the size of the infarction or selective neuronal necrosis in the penumbra when administered before or after ischemia. In addition to infarction, six animals from the insulin-treated groups had bilateral selective neuronal necrosis in the hippocampus or the neocortex. A nonlinear regression analysis in which glucose levels were compared with both cortical necrosis and total infarction yielded a U-shaped curve with a nadir for cerebral necrosis that lay in the 6- to 7-mM blood glucose range. The increased brain damage induced by insulin occurred in animals with very low blood sugar values in the range of 2 to 3 mM.

Conclusions. These results in rats indicate that if insulin is used following ischemia, blood glucose levels should be maintained at approximately 6 to 7 mM. From these data one can infer that hypoglycemia of less than 3 mM should be avoided in situations of focal cerebral ischemia in which insulin is used. Additional animal studies and clinical trials in humans are needed to study the effects of insulin on ischemia.

Article Information

Address reprint requests to: Roland N. Auer, M.D., Ph.D., Departments of Pathology and Clinical Neuroscience, University of Calgary, 3330 Hospital Drive N.W, Calgary, Alberta T2N 4N1, Canada. email: rauer@ucalgary.ca.

© AANS, except where prohibited by US copyright law.

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Figures

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    Bar graph demonstrating that the differences in cortical necrosis, striatal necrosis, and the total volume of necrosis and atrophy do not differ significantly (means ± SD) among the three experimental groups, although there is an indication that the damage in Group 2 was most severe. Insulin-pre = insulin given before MCA occlusion; insulin-post = insulin given after MCA occlusion.

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    Bar graph showing that the differences in quantitated selective neuronal necrosis cells (mean ± SD) in the ischemic penumbra of the infarction were not significant in the three groups. Pre-insulin = insulin given before MCA occlusion; post-insulin = insulin given after MCA occlusion.

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    Graph demonstrating that the nonlinear regression analysis between infarction size and mean blood glucose levels in both insulin-treated groups yields a ∪-shaped curve with a nadir for infarction volume at approximately 7 mM.

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