Type 2 diabetes is the most prevalent metabolic disease currently known to man. Its hallmarks are pancreatic beta-cell dysfunction and insulin resistance. The Reactive Oxygen Species (ROS) is a little-understood factor as far as the progression of Type 2 diabetes is concerned. Therefore, in this article, I will shed some light on what it is and the effect it has on this chronic disease.
ROS is a type of unstable molecule that contains oxygen and that easily reacts with other molecules in a cell. A buildup of reactive oxygen species in cells may cause damage to DNA, RNA, and proteins, and may cause cell death. Reactive oxygen species are free radicals, also called oxygen radicals.
Traditionally, ROS has been thought of as useless by-products of respiratory metabolism in mitochondria and believed to be generally harmful to biological systems. However, growing evidence shows that, in many instances, ROS generation is not a useless or harmful process but, rather, an essential element for certain biological responses.
Although ROS, such as H2O2, have been demonstrated to be critical factors in normal cellular signal transduction and have the potential to regulate glucose-stimulated insulin secretion (GSIS) in β-cells, excessive and/or sustained ROS production can directly or indirectly disturb the integrity and physiological function of cellular macromolecules, such as DNA, protein, or lipids.
As discussed above, ROS action is generally beneficial. However, under diabetic conditions, chronic hyperglycemia and consequent augmentation of reactive oxygen species (ROS) deteriorate beta-cell function and escalate insulin resistance. This leads to an aggravation of type 2 diabetes. Additionally, chronic hyperglycemia and ROS are also involved in the development of atherosclerosis which is often observed under diabetic conditions.
Such disturbances contribute to the pathogenesis of various diseases, including diabetes. To counteract these insults, most cells, including β-cells, have intricate mechanisms of defense against ROS toxicity. Among these, the transcription factor NF-E2–related factor 2 (Nrf2) is a pivotal component for protecting cells from oxidative damage.
In response to oxidative stress, activation of Nrf2 dramatically increases intracellular antioxidant potential by directly increasing the transcription of many so-called antioxidant enzymes. Thus, the Nrf2-mediated induction of antioxidant enzymes is critically important for proper oxidation/reduction (redox) homeostasis to protect cells from irreversible oxidative damage.
However, a possible consequence of this augmented cellular ROS-scavenging ability is the potential to blunt normal ROS signals. Despite intensive research focused on oxidative stress and diabetes, the role of cellular adaptive responses to increased oxidative stress in β-cell dysfunction remains incompletely understood.
Diabetes mellitus (DM) is an independent risk factor for heart failure. The Framingham Heart Study reported that the frequency of heart failure is 2-fold higher in male diabetics and 5-fold higher in female diabetics than in age-matched control subjects. An increase in reactive oxygen species (ROS) has been regarded as a dominant mechanism of cardiac dysfunction in patients with DM. ROS are important intracellular signaling molecules and mediate various cellular functions, including activation of transcriptional factors, protein kinases, and ion channels; however, high levels of ROS are detrimental to cardiomyocytes.
It can, therefore, be said that Reactive oxygen species (ROS) are the main facilitators of cardiovascular complications in diabetes mellitus (DM). Emerging evidence shows that mitochondria and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase are dominant mechanisms of ROS production in the diabetic heart. Hyperpolarization of the mitochondrial inner membrane potentials and impaired mitochondrial function promote ROS production in the mitochondria of the diabetic heart.
In physiological conditions, ROS levels are appropriately controlled by endogenous antioxidant systems to minimize oxidative cellular damage. Oxidative stress occurs when ROS production overwhelms antioxidant capacity in pathological conditions. It is apparent that ROS production and oxidative stress are increased in the diabetic heart, and oxidative stress induces various cardiovascular complications, including cardiac dysfunction, which is facilitated by inflammation, apoptosis, and fibrosis
The rise in the ROS level in the diabetic heart is brought about by multiple mechanisms. Among these, NADPH oxidase and mitochondria play a pivotal role and mutually stimulate to enhance ROS production. UCPs regulate ROS production in mitochondria by dissipating the mitochondrial inner membrane potential. PKC, angiotensin II, AGEs/RAGE, and CaMKII facilitate ROS production in NADPH oxidase. The mechanisms of ROS increase in DM are complex because the multiple factors interact and enhance each other
ROS are induced under diabetic conditions, which are possibly involved in the progression of pancreatic -cell dysfunction and insulin resistance found in type 2 diabetes. Suppression of ROS in obese type 2 diabetic mice restores -cell function and insulin sensitivity, leading to amelioration of glucose intolerance. In addition, ROS is involved in the progression of atherosclerosis which is often observed as a macroangiopathy under diabetic conditions.
Taken together, it is likely that ROS is closely associated with the development of type 2 diabetes and atherosclerosis. Although at present several clinical trials with antioxidants show only a little effect, if any, on the progression of type 2 diabetes. Future therapy might look into the suppression of ROS and, infusion of stronger and more appropriate antioxidants as a way of exerting some beneficial effects against the development of type 2 diabetes and atherosclerosis.