BACKGROUND & AIMS: Preventing severe hyperglycemia with insulin reduced the neuropathological alterations in frontal cortex during critical illness. We investigated the impact of increasing glucose load under normoglycemia on neurons and glial cells. METHODS: Hyperinflammatory critically ill rabbits were randomized to fasting or combined parenteral nutrition containing progressively increasing amounts of glucose (low, intermediate, high) within the physiological range but with a similar amount of amino acids and lipids. In all groups, normoglycemia was maintained with insulin. On day 7, we studied the neuropathological alterations in frontal cortex neurons, astrocytes and microglia, and MnSOD as marker of oxidative stress. RESULTS: The percentage of damaged neurons was comparable among all critically ill and healthy rabbits. Critical illness induced an overall 1.8-fold increase in astrocyte density and activation status, largely irrespective of the nutritional intake. The percentage of microglia activation in critically ill rabbits was comparable with that in healthy rabbits, irrespective of glucose load. Likewise, MnSOD expression was comparable in critically ill and healthy rabbits without any clear impact of the nutritional interventions. CONCLUSIONS: During prolonged critical illness, increasing intravenous glucose infusion while strictly maintaining normoglycemia appeared safe for neuronal integrity and did not substantially affect glial cells in frontal cortex.