Diabetes and the brain: oxidative stress, inflammation, and autophagy

María Muriach, Miguel Flores-Bellver, Francisco J Romero, Jorge M Barcia, María Muriach, Miguel Flores-Bellver, Francisco J Romero, Jorge M Barcia

Abstract

Diabetes mellitus is a common metabolic disorder associated with chronic complications including a state of mild to moderate cognitive impairment, in particular psychomotor slowing and reduced mental flexibility, not attributable to other causes, and shares many symptoms that are best described as accelerated brain ageing. A common theory for aging and for the pathogenesis of this cerebral dysfunctioning in diabetes relates cell death to oxidative stress in strong association to inflammation, and in fact nuclear factor κB (NFκB), a master regulator of inflammation and also a sensor of oxidative stress, has a strategic position at the crossroad between oxidative stress and inflammation. Moreover, metabolic inflammation is, in turn, related to the induction of various intracellular stresses such as mitochondrial oxidative stress, endoplasmic reticulum (ER) stress, and autophagy defect. In parallel, blockade of autophagy can relate to proinflammatory signaling via oxidative stress pathway and NFκB-mediated inflammation.

Figures

Figure 1
Figure 1
Scheme summarizing the involvement of oxidative stress (mitochondrial dysfunction and ER stress), inflammation, and autophagy in the diabetic brain. GSH: reduced glutathione; GSSG: glutathione disulfide; SOD: superoxide dismutase; NADP+: nicotinamide adenine dinucleotide phosphate oxidized; NADPH: nicotinamide adenine dinucleotide phosphate reduced; NAD+: nicotinamide adenine dinucleotide oxidized; NADH: nicotinamide adenine dinucleotide reduced; CAT: catalase; IκBa: nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor, alpha; NFκB: nuclear factor kappa-light-chain-enhancer of activated B cells; ER: endoplasmic reticulum; GLU: glucose; INS: insulin; P: phosphate; MDA: malondialdehyde; ATP: adenosine triphosphate; ETC: electron transport chain; ROS: reactive oxygen species; MnSOD: manganese superoxide dismutase; GSR: glutathione reductase; CHOP: C/EBP Homology Protein; TNFα: tumor necrosis factor alpha; NOS: nitric oxide synthases.

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