High Blood Glucose Does Not Adversely Affect Outcome in Moderately Brain-Injured Rodents

Abstract

In a number of clinical studies researchers have reported that acute hyperglycemia is associated with increased mortality and worsened neurological outcome in patients with traumatic brain injury (TBI). In contrast, it has been demonstrated that intensive insulin therapy to lower blood glucose can lead to an increased frequency of hypoglycemic episodes and poor outcome. Consistent with this, experimental and clinical studies have shown that TBI causes a ''metabolic crisis'' in the injured brain, suggesting that a reduction in glucose availability may exacerbate brain damage. We therefore examined the consequences of hyperglycemia on cognitive and pathological measures. Using a rodent model of TBI, we find that when acute hyperglycemia is induced in animals prior to injury, there is little to no change in motor and cognitive performance, contusion volume, or cerebral edema. To examine the consequences of persistent hyperglycemia (as seen in diabetic patients), animals were treated with streptozotocin (STZ) to induce type 1 diabetes. We find that the presence of persistent STZ-induced hyperglycemia results in a reduction of brain edema. Insulin therapy to reduce blood glucose reverses this beneficial effect of hyperglycemia. Taken together, our results indicate that an acute increase in blood glucose levels may not be harmful, and that intervention with insulin therapy to lower blood glucose levels in TBI patients may increase secondary brain damage.

Stress-induced hyperglycemia is associated with higher mortality in severe traumatic brain injury

“…Moro et al 15 provide support for this hypothesis in a rodent model of controlled cortical impact where exogenous glucose initiated after injury provided significant cellular neuroprotection and improved cerebral metabolism. Likewise, Hill et al 14 examined the effects of persistent hyperglycemia as seen in diabetic patients, on animals that were treated with streptozotocin to induce Type 1 diabetes. In that study, hyperglycemia resulted in a beneficial reduction of brain edema, which was reversed with the administration of insulin to reduce blood glucose.…”

The Neuroprotective Effect of Lactate Is Not Due to Improved Glutamate Uptake after Controlled Cortical Impact in Rats

“…Furthermore, Kinoshita and associates showed that although acute post-traumatic dextrose treatment increased lesion area only slightly, a significant infiltration of neutrophils was seen following fluid percussion injury (FPI; Kinoshita et al, 2002). In contrast, the results of several experimental studies investigating hyperglycemia following TBI did not support adverse effects on brain damage (Gurevich et al, 1997;Hill et al, 2010;Stover et al, 2002). Clinical studies, however, show that hyperglycemia at admission is associated with poor neurological outcomes and mortality following severe TBI, both in pediatric (Melo et al, 2010;Smith, et al, 2012) and adult patients ( Jeremitsky et al, 2005;Pecha et al, 2011).…”

Glucose administration after traumatic brain injury exerts some benefits and no adverse effects on behavioral and histological outcomes

“…When a moderate CCI injury was followed by secondary ischemia (temporary bilateral carotid artery occlusion), pre-injury glucose administration was found to increase contusion volume and to decrease numbers of viable hippocampal neurons (Cherian et al, 1997). Most recently, induction of hyperglycemia 15 min prior to CCI injury in mice was reported to have no effects on balance beam or foot fault tasks in the first week post-CCI, minimal effects (some improved memory of platform location) on MWM performance 2–3 weeks post-injury, and no effect on contusion volume 1 month post-injury (Hill et al, 2010). This pre-injury glucose treatment in mice also had no effect on cerebral edema assessed at 2 days post-CCI.…”

“…This pre-injury glucose treatment in mice also had no effect on cerebral edema assessed at 2 days post-CCI. In contrast, rats with streptozotocin-induced diabetes subjected to CCI injury were found to have significantly reductions in cerebral edema 2 days post-CCI, and if these hyperglycemic rats were given insulin to attenuate blood glucose levels after CCI they had increased cerebral edema at 2 days post-injury (Hill et al, 2010). The latter effect is consistent with reports that post-TBI insulin treatment to lower glucose in humans can lead to detrimental hypoglycemia, increased cerebral metabolic crisis and peri-ischemic cortical depolarizations (Bilotta et al, 2008, Hopwood et al, 2005, Oddo et al, 2008, Vespa et al, 2006, 2012).…”