Oxidative Stress, ROS, and Antioxidants with Diabetes Mellitus

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This entry is adapted from the peer-reviewed paper 10.3390/antiox11102003

The Greek physician, Aretaios, coined the term “diabetes” in the 1st Century A.D. “Mellitus” arose from the observation that the urine exhibits a sweetness due to its elevated glucose levels. Diabetes mellitus (DM) accounted for 6.7 million deaths globally in 2021 with expenditures of USD 966 billion. Mortality is predicted to rise nearly 10-fold by 2030. Oxidative stress, an imbalance between the generation and removal of reactive oxygen species (ROS), is implicated in the pathophysiology of diabetes. Whereas ROS are generated in euglycemic, natural insulin-regulated glucose metabolism, levels are regulated by factors that regulate cellular respiration, e.g., the availability of NAD-linked substrates, succinate, and oxygen; and antioxidant enzymes that maintain the cellular redox balance. Only about 1–2% of total oxygen consumption results in the formation of superoxide anion and hydrogen peroxide under normal reduced conditions.

diabetes mellitus oxidative stress ROS antioxidants metabolic syndrome

1. Introduction

Although the Egyptians were aware of the disease nearly 3500 years earlier, it was the Greek physician, Aretaios (1st Century A.D.) who coined the term “diabetes” and was the first to describe the disease as an entity ^[1]^[2]^[3]. The term “mellitus” arose from the observation that the urine exhibits a sweetness resulting from its elevated glucose concentration ^[1]^[2]^[4]. This disease, diabetes mellitus (DM), accounted for 6.7 million deaths globally in 2021 as reported by the IDF Diabetes Atlas, 10th edition ^[5]. In the U.S., 37.3 million people suffer from DM, incurring an annual cost of $379 billion USD ^[6]. This disease results when the body does not synthesize adequate insulin, the hormone that facilitates the transport of blood sugar into cells where it is metabolized and converted to energy or does not respond to insulin sufficiently ^[6]. The Centers for Disease Control (CDC) in the U.S. lists three main types of diabetes ^[6]. Type I diabetes results from autoimmune destruction of beta-cells (pancreatic insulin-producing cells). The American Diabetes Association ^[7] also lists non-autoimmune idiopathic diabetes that has no known etiology and is strongly inherited. This is a Type I diabetes that requires insulin therapy for survival. Type II diabetes (T2DM) is due to insulin secretary defect, “insulin resistance” or insensitivity. T2DM is the major form of diabetes affecting about 90–95% of people with diabetes in the U.S. ^[2]. The CDC lists gestational diabetes as a third type. This type develops in pregnant women who have not been previously diagnosed as diabetic, and although the disorder usually subsides after the baby’s birth, both mother and child are predisposed to T2DM diabetes later in life ^[7].

It was demonstrated, almost 90 years ago, that many diabetic patients were “insulin insensitive”, and it was suggested that patients should be classified as insulin sensitive (later classified as Type 1 DM) and insulin insensitive or non-insulin-dependent diabetes (classified as Type 2 DM) ^[8]. Extensive research has shown that common to insulin resistance, a number of physiologic variables including hyperglycemia, hyperinsulinemia, increased plasma VLDL, higher triglycerides, decreased plasma HDL-cholesterol and high blood pressure increased the risks of T2DM and cardiovascular disease (CVD) ^[9]. This variable cluster of physiologic abnormalities was given the term Syndrome X ^[10]^[11]. Indeed, as it became clear that CVD risks, e.g., insulin resistance/hyperglycemia, obesity, dyslipidemia and hypertension, were not independent of one another and shared underlying and interrelated mechanisms and pathways, they were considered as a “syndrome” and given the term Metabolic Syndrome (MetS) ^[12]. The World Health Organization (WHO) defined the term in 1998 after consultations with experts in DM research ^[13] and required the presence of DM ^[14]. One problem that arose with the WHO definition of MetS was that all risk factors were weighed equally, although the underlying pathophysiology was thought to be related to insulin resistance. Consequently, various groups developed their own version of the definition, and some even questioned whether the clustering of risk factors should be considered a “syndrome” ^[15]. Comparisons of the definitions for MetS from the WHO, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) and the International Diabetes Federation (IDF) show considerable variability in the selection and parameters of risk factors, although all allow the inclusion of diabetic patients ^[15]. Further complication is introduced when some risk factors must be adjusted for specific ethnic populations and country-specific cut-points ^[16]. Overall, MetS is defined as a cluster of metabolic high-risk factors, including T2DM, high blood pressure, dyslipidemia, elevated LDL cholesterol, low HDL, and elevated triglycerides—which are all conditions found in T2DM resulting from insulin resistance. “When diabetes becomes clinically apparent, CVD risk rises sharply” ^[17].

2. Oxidative Stress, ROS, and Antioxidants

Oxidative stress, via the production of Reactive Oxygen Species (ROS) and Reactive Nitrogen Species (RNS), is characterized by an imbalance between the generation and removal of these species. This redox imbalance has been proposed as an etiologic factor involved in insulin resistance, beta-cell dysfunction, and impaired glucose intolerance that ultimately results in T2DM ^[18]. Oxidative stress can arise from excess food intake and a sedentary lifestyle. Indeed, it has been shown that an intake of excessive calories can lead to a 5–10-fold increase in ROS that escape from normal respiratory chain regulation ^[19]. Moreover, evidence has been obtained from T2DM patients that demonstrate increased oxidative stress in response to post-prandial hyperglycemia ^[20].

3. ROS Formation

Super-oxide anion is the primary radical formed by the univalent reduction in molecular oxygen. Subsequent reductions from super oxide anion to hydrogen peroxide and hydroxyl ion are spin-forbidden, and the non-enzymatic reactions proceed very slowly unless catalyzed by a heavy ion such as the metal catalyzed Haber/Weiss cycle ^[21]. These reactions are depicted in Figure 1.

Figure 1. Reductive Pathway of Molecular Oxygen. An important alternate step is shown where an excited state species, singlet oxygen, is produced either via the interaction of molecular oxygen with the excited triplet state of another molecule or an energy exchange reaction upon the absorption of energy from another source, e.g., ultraviolet light ^[22].

ROS are known to damage nucleic acids, proteins and lipids and are implicated in the pathophysiology of diabetes. Whereas ROS are generated in euglycemic, natural insulin-regulated glucose metabolism (Figure 2), levels are regulated by factors that regulate cellular respiration, e.g., the availability of NAD-linked substrates, succinate, and oxygen, and antioxidant enzymes that maintain the cellular redox balance. The latter include super oxide dismutase (SOD), which is a metalloprotein that dismutes superoxide anion to hydrogen peroxide. Other important enzymes are catalase and peroxidases. Catalase and glutathione (GSH) peroxidase reduce hydrogen peroxide to water. Oxidized glutathione (GSSG) is re-reduced to GSH by glutathione reductase in the presence of NADPH ^[21]^[22]. A simplified depiction of these reactions is shown in Figure 3. Under normal reduced conditions, only about 1–2% of the total oxygen consumption results in the formation of superoxide anion and hydrogen peroxide ^[19].

Figure 2. Euglycemic, normal insulin-regulated glucose metabolism. ★ Sites in the respiratory sequence at which low levels of superoxide may be formed through the transfer of electrons via the electron transport chain (ETC). Once glucose moves into the cell, it is retained though phosphorylation by hexokinase and ATP. The product, glucose-6-phosphate, is phosphorylated again to form fructose-1,6-diphosphare prior to splitting into 3-carbon fragments. These 3-carbon fragments are converted to pyruvic acid. All these reactions occur in the cell cytosol. Pyruvic acid enters the mitochondrial matrix and is decarboxylated and oxidized to the 2-carbon, acetyl CoA. This oxidization results in the formation of 2 NADH and the potential formation of low levels of superoxide as the electrons are passed through the ETC. Acetyl CoA enters the Krebs cycle by condensation onto oxaloacetate to form citrate that is decarboxylated and oxidized in the Krebs cycle to form 6 NADH and 2 FADH. These are potential ROS sources as the electrons are passed through the ETC. Flavin mononucleotide (FMN) is a highly oxidative cofactor associated with NADH and FADH dehydrogenases that can accept two electrons to become reduced. The figure depicts GLUT-2, an intestinal glucose transporter that allows effective glucose transport at high glucose concentrations. There are now a wide range of glucose transporters that are tissue specific ^[23].

Figure 3. Schema Depicting Major Antioxidant Enzymes Involved in Maintaining Intracellular Redox Balance ^[22].

However, if the respiratory chain is highly reduced, as under hyperglycemic conditions, or if reduced cofactors accumulate, about 10% of the respiratory oxygen consumed may be lost as ROS ^[19]. This is depicted in Figure 4.

Figure 4. Hyperglycemic, insulin-resistant glucose metabolism. Although ROS are shown being formed at the starred sites of glucose metabolism, the actual formation of ROS occurs as electrons are being transferred from NADH and FADH₂ down the ETC through complexes I, II, III and IV.

4. Electron Transport Chain, ROS Production, and Proton Pump Potential

Superoxide is released only into the matrix of the mitochondria when electrons are transferred through Complexes I and II of the ETC ^[24]. NADH formed in glycolysis and the Krebs cycle are oxidized in Complex I (ubiquinone oxidoreductase) that is composed of NADH dehydrogenase, FMN and iron–sulfur (Fe-S) clusters ^[25]. As electrons are transferred from Fe-S to coenzyme Q, four hydrogen ions pass from the mitochondrial matrix to the intermembrane space, thus increasing the proton motive force (Δp) ^[26]. This occurs in a reasonably tightly coupled phosphorylated-oxidative (P/O) system. Interestingly, superoxide formation is strongly dependent on Δp, and mitochondrial P/O uncoupling has been considered as a cytoprotective strategy in diabetes by reducing mitochondrial superoxide formation ^[26].

Complex II, succinate dehydrogenase, accepts electrons from succinate oxidation in the Krebs cycle and transfers two electrons to FAD. In turn, FADH₂ transfers these electrons to Fe-S and then to coenzyme Q (ubiquinone). This process is similar to Complex I except that no protons are translocated into the intermembrane space.

Complex III, cytochrome c reductase, is composed of cytochrome b, Rieske proteins that contain two Fe-S clusters, and cytochrome c ^[27]. The latter can only accept a single electron at a time, and the process occurs in two steps; the Q cycle that produces superoxide has been comprehensively described ^[24]. The result is that Complex III releases four protons into the intermembrane space, thus contributing to Δp, and it transfers the electrons, one at a time, to Complex IV ^[28].

Complex IV, cytochrome c oxidase, is the final electron carrier in aerobic cellular respiration and catalyzes the transfer of electrons to dioxygen to yield H₂O ^[28].

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