Hyperglycemia and Oxidative Stress: An Integral, Updated and Critical Overview of Their Metabolic Interconnections

Abstract

This review focuses on the multiple and reciprocal relationships that exist between oxidative stress, hyperglycemia and diabetes and related metabolic disorders. Human metabolism uses most of the consumed glucose under aerobic conditions. Oxygen is needed in the mitochondria to obtain energy, as well as for the action of microsomal oxidases and cytosolic pro-oxidant enzymes. This relentlessly generates a certain amount of reactive oxygen species (ROS). Although ROS are intracellular signals necessary for some physiological processes, their accumulation leads to oxidative stress, hyperglycemia, and progressive resistance to insulin. A cellular pro-oxidant versus an antioxidant equilibrium would regulate ROS levels, but oxidative stress, hyperglycemia, and pro-inflammatory conditions feed back to each other and the relevance of the interconnections tends to increase those conditions. Hyperglycemia promotes collateral glucose metabolism through protein kinase C, polyols and hexosamine routes. In addition, it also facilitates spontaneous glucose auto-oxidation and the formation of advanced glycation end products (AGEs), which in turn interact with their receptors (RAGE). The mentioned processes undermine cellular structures, finally giving place to a progressively greater degree of oxidative stress with further hyperglycemia, metabolic alterations, and diabetes complications. NFκB is the major transcription factor involved in the expression of most of the pro-oxidant mediators, while Nrf2 is the major transcription factor regulating the antioxidant response. FoxO is also involved in the equilibrium, but its role is controversial. This review summarizes the key factors linking the diverse glucose metabolic routes enhanced in hyperglycemia with ROS formation and vice versa, emphasizing the role of the major transcription factors involved in the desirable balance between pro-oxidant and antioxidant proteins.

Keywords: AGE & RAGE; NFκB; Nrf2; ROS; diabetes type II; hyperglycemia; insulin resistance; oxidative stress; pro-oxidant and antioxidant enzymes; protein glycation.

Scheme 1

(a) Monoelectronic reductions from atmospheric dioxygen into water; the 3 central species are considered ROS, although trace amounts of singlet oxygen are also formed in the Haber–Weiss reaction and should also be considered; (b) SOD-catalyzed and spontaneous Haber–Weiss and Fenton reactions for ROS interconversions.

Figure 1

Metabolic fate of glucose and the multiple pathways leading to ROS generation. Polyols (upper left), mitochondrial ETC and collateral routes including spontaneous reactions are involved in ROS generation (salmon-colored, on the right) and possible harmful tissular effects. See text for details.

Figure 2

Cellular processes and main molecules involved in hyperglycemia-induced ROS production and ROS-induced hyperglycemia. Hyperglycemia increases aerobic glycolysis, and mitochondrial ETC gives place to superoxide generation and mitochondrial dysfunction. In turn, the greater availability of glucose diverts this nutrient to other pathways. The polyol pathway competes with glutathione reductase for NADPH, leading to a lower level of reduced glutathione (GSH) and a lower cellular antioxidant response. In addition, high NADH obstructs sirtuin action. Diacylglycerol (DAG) stimulates the PKC pathway and advanced glycation end product (AGE) formation. The hexosamine pathway increases the formation of O-linked-N-acetylglucosaminylated proteins, creating endoplasmic reticulum (ER) stress and insulin resistance. Furthermore, hyperglycemia facilitates the spontaneous addition of glucose to serum proteins (protein glycation) or glucose fragmentation to yield ketoaldehydes and subsequent AGEs for AGE receptor (RAGE) binding. Altogether, these pathways contribute to causing tissue-specific oxidative stress and low-grade inflammation through a variety of molecular mediators. Most of these are proteins whose expression is modulated by the nuclear transcription factor kappa B (NFκB), which promotes the appearance of kinases, cytokines, cellular adhesion molecules, fibrogenic factors and pro-oxidant enzymes. As hyperglycemia and oxidative stress feed back to each other, the overall effect accounts for pathological alterations due to diabetes. Nuclear factor erythroid 2-like 2 (Nrf2) is the major transcription factor able to induce the antioxidant response to neutralize NFκB action. Taking nutritional supplements that scavenge ROS, induce Nrf2 and induce sirtuins is a suitable approach to decreasing the prevalence of the reciprocal stimulation of hyperglycemia–oxidative stress.

Figure 3

AGE-RAGE pathway highlighting the role of NFκB in a mesangial or endothelial cell. Briefly, the binding of extracellular AGEs to RAGEs or intracellular AGEs resulting from oxidative stress routes activates transduction signals that stimulate NFκB action. This transcription factor is a master regulator of the expression of a variety of genes encoding proteins involved in the reinforcement of pro-oxidant signals, and either pro-oxidant enzymes or proteins able to alter cellular and tissular patterns and function, such as TGFβ and others.