Mechanistic Insight into Oxidative Stress-Triggered Signaling Pathways and Type 2 Diabetes

Abstract

Oxidative stress (OS) is a metabolic dysfunction mediated by the imbalance between the biochemical processes leading to elevated production of reactive oxygen species (ROS) and the antioxidant defense system of the body. It has a ubiquitous role in the development of numerous noncommunicable maladies including cardiovascular diseases, cancers, neurodegenerative diseases, aging and respiratory diseases. Diseases associated with metabolic dysfunction may be influenced by changes in the redox balance. Lately, there has been increasing awareness and evidence that diabetes mellitus (DM), particularly type 2 diabetes, is significantly modulated by oxidative stress. DM is a state of impaired metabolism characterized by hyperglycemia, resulting from defects in insulin secretion or action, or both. ROS such as hydrogen peroxide and the superoxide anion introduce chemical changes virtually in all cellular components, causing deleterious effects on the islets of β-cells, in turn affecting insulin production. Under hyperglycemic conditions, various signaling pathways such as nuclear factor-κβ (NF-κβ) and protein kinase C (PKC) are also activated by ROS. All of these can be linked to a hindrance in insulin signaling pathways, leading to insulin resistance. Hyperglycemia-induced oxidative stress plays a substantial role in complications including diabetic nephropathy. DM patients are more prone to microvascular as well as atherosclerotic macrovascular diseases. This systemic disease affects most countries around the world, owing to population explosion, aging, urbanization, obesity, lifestyle, etc. However, some modulators, with their free radical scavenging properties, can play a prospective role in overcoming the debilitating effects of OS. This review is a modest approach to summarizing the basics and interlinkages of oxidative stress, its modulators and diabetes mellitus. It may add to the understanding of and insight into the pathophysiology of diabetes and the crucial role of antioxidants to weaken the complications and morbidity resulting from this chronic disease.

Keywords: ROS; antioxidants; diabetes mellitus (DM); insulin; mitochondria; oxidative stress (OS).

Figure 1

The symptoms of diabetic conditions and associated complications.

Figure 2

Schematic representation of some sources involved in the production of ROS/RNS, causes of oxidative stress, biomarkers of OS and diseases.

Figure 3

Pathways (glucose metabolism) and products which mediate oxidative stress.

Figure 4

Mechanism of insulin action and factors involved in signaling.

Figure 5

Normal pathway of insulin signaling and inhibitory effect of ROS in insulin signaling.

Figure 6

Pathways and mechanism of biphasic glucose-induced insulin secretion in the cell.