Insulin Restores Metabolic Function in Cultured Cortical Neurons Subjected to Oxidative Stress

Abstract

We previously demonstrated that insulin has a neuroprotective role against oxidative stress, a deleterious condition associated with diabetes, ischemia, and age-related neurodegenerative diseases. In this study, we investigated the effect of insulin on neuronal glucose uptake and metabolism after oxidative stress in rat primary cortical neurons. On oxidative stress, insulin stimulates neuronal glucose uptake and subsequent metabolism into pyruvate, restoring intracellular ATP and phosphocreatine. Insulin also increases intracellular and decreases extracellular adenosine, counteracting the effect of oxidative stress. Insulin effects are apparently mediated by phosphatidylinositol 3-K and extracellular signal-regulated kinase signaling pathways. Extracellular adenosine under oxidative stress is largely inhibited after blockade of ecto-5-nucleotidase, suggesting that extracellular adenosine results preferentially from ATP release and catabolism. Moreover, insulin appears to interfere with the ATP release induced by oxidative stress, regulating extracellular adenosine levels. In conclusion, insulin neuroprotection against oxidative stress-mediated damage involves 1) stimulation of glucose uptake and metabolism, increasing energy levels and intracellular adenosine and, ultimately, uric acid formation and 2) a decrease in extracellular adenosine, which may reduce the facilitatory activity of adenosine receptors.

Erythropoietin: Elucidating new cellular targets that broaden therapeutic strategies

“…Yet, increased EPO secretion during diabetic pregnancies may represent the body's attempt at endogenous protection against the complications of DM (Teramo et al, 2004). Similar to the potential protective role of insulin (Duarte et al, 2006), EPO administration has been shown both in diabetics as well as non-diabetics with severe, resistant congestive heart failure to decrease fatigue, increase left ventricular ejection fraction, and significantly decrease the number of hospitalization days . In vitro studies with vascular cells exposed to elevated glucose also have elucidated a strong cytoprotective effect of EPO.…”

Erythropoietin and Oxidative Stress

“…Yet, increased EPO secretion during diabetic pregnancies may represent the body's attempt at endogenous protection against the complications of DM (Teramo, et al, 2004). Similar to the potential protective role of insulin (Duarte, et al, 2006), EPO administration has been shown both in diabetics as well as non-diabetics with severe, resistant congestive heart failure to decrease fatigue, increase left ventricular ejection fraction, and significantly decrease the number of hospitalization days .Cell culture studies with vascular cells exposed to elevated glucose also have elucidated a strong cytoprotective effect of EPO . Administration of EPO can significantly improve EC survival in a 1.0 ng/ml range .…”

Triple play: Promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

“…Yet, increased EPO secretion during diabetic pregnancies may represent the body's attempt at endogenous protection against the complications of DM [258]. Similar to the potential protective role of insulin [259], EPO administration has been shown both in diabetics as well as non-diabetics with severe, resistant congestive heart failure to decrease fatigue, increase left ventricular ejection fraction, and significantly decrease the number of hospitalization days [205]. In studies that examine the toxic effects of elevated glucose upon vascular cells, EPO is protective and prevents early apoptotic membrane PS exposure and late DNA degradation at concentrations that are clinically relevant [110] to cellular protection in patients with cardiac or renal disease [260,261].…”