Ischemic brain injury in diabetes and endoplasmic reticulum stress

Abstract

Diabetes is a widespread disease characterized by high blood glucose levels due to abnormal insulin activity, production, or both. Chronic diabetes causes many secondary complications including cardiovascular disease: a life-threatening complication. Cerebral ischemia-related mortality, morbidity, and the extent of brain injury are high in diabetes. However, the mechanism of increase in ischemic brain injury during diabetes is not well understood. Multiple mechanisms mediate diabetic hyperglycemia and hypoglycemia-induced increase in ischemic brain injury. Endoplasmic reticulum (ER) stress mediates both brain injury as well as brain protection after ischemia-reperfusion injury. The pathways of ER stress are modulated during diabetes. Free radical generation and mitochondrial dysfunction, two of the prominent mechanisms that mediate diabetic increase in ischemic brain injury, are known to stimulate the pathways of ER stress. Increased ischemic brain injury in diabetes is accompanied by a further increase in the activation of ER stress. As there are many metabolic changes associated with diabetes, differential activation of the pathways of ER stress may mediate pronounced ischemic brain injury in subjects suffering from diabetes. We presently discuss the literature on the significance of ER stress in mediating increased ischemia-reperfusion injury in diabetes.

Keywords: Cell death; Cerebral ischemia; Hyperglycemia; Hypoglycemia; Unfolded protein response.

Figure 1:. Schematic representation of the possible ER stress mechanisms that mediate diabetes-induced increase in ischemic cell death:

Diabetic hypoglycemia/ hyperglycemia may activate endoplasmic reticulum (ER) stress via mitochondrial dysfunction-induced free radical generation. The major possible pathways of ER stress that may mediate pronounced ischemic brain injury in diabetes: (1) activating transcription factor-6 (ATF6) translocates from the ER compartment of the cell to the Golgi apparatus where it is activated by site-1 and site-2 proteases via proteolysis. The activated ATF6 then moves to the nucleus and stimulates the production of UPR proteins via ER stress response element dependent changes in gene transcription. This binds to the ER stress response element and activates the transcription of UPR target genes which corrects ER stress. (2) inositol-requiring transmembrane kinase/endoribonuclease 1 (IRE1α) splices X-box protein 1 mRNA resulting in the activation of regulated IRE1-dependent decay (RIDD) and the IRE1α cytosolic domain activates tumor necrosis factor receptor-associated factor (TRAF)-TRAF2–JUN N-terminal kinase (JNK) signaling. (2) PERK causes phosphorylation of eukaryotic translation initiation factor 2 subunit-α (eIF2α) resulting in inhibition of protein synthesis by reducing mRNA translation initiation. Nevertheless, PERK-eIF2α pathway causes increase in the levels of ATF4 and C/EBP homologous protein (CHOP) and associated cell death pathways.

Figure 2:. Representation of the tested ER stress interventions that exerts a protective effect on ischemic damage during diabetes:

Treatment with chemical chaperones like sodium phenylbutyrate and tauroursodeoxycholic acid and modulators of ER stress like DA3-CH (glucagon-like peptide-1/ glucose-dependent insulinotropic polypeptide dual agonist), diallyl trisulfide, and monosialotetrahexosy-1 ganglioside (GM1) decreases diabetic exacerbation of ischemic injury. CHOP: C/EBP homologous protein; ROS: Reactive oxygen species.