Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats: role of glutamate

Abstract

Abu Fanne R, Nassar T, Heyman SN, Hijazi N, Higazi AA. Insulin and glucagon share the same mechanism of neuroprotection in diabetic rats: role of glutamate. Am J Physiol Regul Integr Comp Physiol 301: R668 -R673, 2011. First published June 15, 2011 doi:10.1152/ajpregu.00058.2011In patients with acute ischemic stroke, diabetes and hyperglycemia are associated with increased infarct size, more profound neurologic deficits and higher mortality. Notwithstanding extensive clinical and experimental data, treatment of stroke-associated hyperglycemia with insulin is controversial. In addition to hyperglycemia, diabetes and even early prediabetic insulin resistance are associated with increased levels of amino acids, including the neurotoxic glutamate, in the circulation. The pleiotropic metabolic effects of insulin include a reduction in the concentration of amino acids in the circulation. In this article, we show that in diabetic rats exposed to transient middle cerebral artery occlusion, a decrease of plasma glutamate by insulin or glucagon reduces CSF glutamate, improves brain histology, and preserves neurologic function. The neuroprotective effect of insulin and glucagon was similar, notwithstanding their opposite effects on blood glucose. The therapeutic window of both hormones overlapped with the short duration (ϳ30 min) of elevated brain glutamate following brain trauma in rodents. Similar neuroprotective effects were found after administration of the glutamate scavenger oxaloacetate, which does not affect glucose metabolism. These data indicate that insulin and glucagon exert a neuroprotective effect within a very brief therapeutic window that correlates with their capacity to reduce glutamate, rather than by modifying glucose levels. stroke; brain damage; glutamate IN ϳ30 -40% OF PATIENTS WITH acute ischemic stroke, diabetes is found at presentation (5, 24), ϳ70% have elevated blood glucose levels (27), and about 25% develop persistent hyperglycemia (21). Hyperglycemia is associated with increased infarct size (5,9,12,21,36,44), as well as with a ϳ3-fold higher risk of death (15), and survivors have more profound neurologic deficits and disability (26). Hyperglycemia is also associated with aggravated postischemic brain damage in animal models. In cats, acute hyperglycemia is associated with a ϳ3-fold increase in the volume of hemispheric infarcts induced by cerebrovascular occlusion (19), and in dogs, even moderate hyperglycemia has been shown to increase brain damage and mortality induced by ischemia (33). Consistent with these findings, treatment of hyperglycemia with insulin in these models, improves the outcome (10, 29, 45). Notwithstanding extensive clinical and experimental data indicating that hyperglycemia exacerbates poststroke brain damage and evidence from animal models that reversal of hyperglycemia with insulin attenuates injury (10, 29, 45), in clinical practice, this approach is controversial (8,23,25,31,35,37). This disconcerting lack of clinical success is not entirely surprising, since insu...

Role of Hypoxia Inducible Factor 1 in Hyperglycemia-Exacerbated Blood-Brain Barrier Disruption in Ischemic Stroke

“…Another group of STZ mice were treated with a low dose of insulin which was not able to correct the mice blood glucose level. Mice were injected with insulin at the onset of reperfusion at 2 U/kg (about 0.04-0.05 U/mouse) (Fanne et al, 2011; Rizk et al, 2006). The level of blood glucose in each group before and after ischemia was summarized in Table 1.…”

Endogenous plasminogen activators mediate progressive intracerebral hemorrhage after traumatic brain injury in mice

“…uPA and tPA were detected using western blot analysis 23 ; expression of b-actin was used as loading control. The CSF combined from 4 to 6 mice per sample 28,29 was taken from sham or injured mice at the indicated time points after CHI, and tPA and uPA were measured by enzyme-linked immunosorbent assay. 34,35 In other experiments, CSF fibrinolytic activity was measured using plasma-derived blood clots.…”

Neurotrophic and neuroprotective effects of oxyntomodulin in neuronal cells and a rat model of stroke

“…The neuroprotective effects of glucagon have been reported in the literature. The mechanism of glucagon's neuroprotection is suggested mediated through stimulation of the cAMP/PKA pathway and reduction of neurotoxic glutamate (Fanne et al, 2011 and Armstead et al, 2011). It is also possible that OXM may stimulate a specific yet to be discovered receptor that explains these differences.…”