A Review on Cellular and Molecular Mechanisms Linked to the Development of Diabetes Complications

Abstract

: Modern lifestyle, changing eating habits and reduced physical work have been known to culminate into making diabetes a global pandemic. Hyperglycemia during the course of diabetes is an important causative factor for the development of both microvascular (retinopathy, nephropathy and neuropathy) and macrovascular (coronary artery disease, stroke and peripheral artery disease) complications. In this article, we summarize several mechanisms accountable for the development of both microvascular and macrovascular complications of diabetes. Several metabolic and cellular events are linked to the augmentation of oxidative stress like the activation of advanced glycation endproducts (AGE) pathway, polyol pathway, protein kinase C (PKC) pathway, poly-ADP ribose polymerase (PARP) and hexosamine pathway. Oxidative stress also leads to production of reactive oxygen species (ROS) like hydroxyl radical, superoxide anion and peroxides. Enhanced levels of ROS rescind the anti-oxidant defence mechanisms associated with superoxide dismutase, glutathione and ascorbic acid. Moreover, ROS triggers oxidative damages at the level of DNA, protein and lipids which eventually cause cell necrosis or apoptosis. These physiological insults may be related to the microvascular complications of diabetes by negatively impacting the eyes, kidneys and brain. While underlying pathomechanism of the macrovascular complications is quite complex, hyperglycemia associated atherosclerotic abnormalities like changes in the coagulation system, thrombin formation, fibrinolysis, platelet and endothelial function and vascular smooth muscle is well proven. Since hyperglycemia also modulates the vascular inflammation, cytokines, macrophage activation and gene expression of growth factors, elevated blood glucose level may play a central role in the development of macrovascular complications of diabetes. Taken collectively, chronic hyperglycemia and increased production of ROS are the miscreants for the development of microvascular and macrovascular complications of diabetes.

Folic Acid Supplementation Improves Glycemic Control for Diabetes Prevention and Management: A Systematic Review and Dose-Response Meta-Analysis of Randomized Controlled Trials

“…Therefore, since the participants of most included studies had lower folate concentrations than normal or low dietary intakes, folic acid supplementation showed significant improvement in the glycemic profile. From a mechanistic perspective, oxidative stress also leads to the production of reactive oxygen species (ROS) [ 69 ]. It has been shown that oxidative stress has been linked to the development of insulin resistance, β-cell dysfunction, impaired glucose tolerance, and mitochondrial dysfunction [ 70 ].…”

Diabetes and stroke: An important complication

“…Diabetes is associated with a plethora of metabolic changes which may underlie the propensity to development of stroke (Figure 1). 1 Insulin resistance has multiple drivers, is inextricably linked to type 2 diabetes, and is associated with coronary artery 2 and cerebrovascular 3 atherosclerosis. Insulin resistance is mediated by increased levels of bioactive lipids, including ceramides 4 and diacylglycerol, 5 playing a role in cell death in numerous tissues 6 .…”

“…Insulin resistance is mediated by increased levels of bioactive lipids, including ceramides 4 and diacylglycerol, 5 playing a role in cell death in numerous tissues 6 . Hyperglycemia leads to formation of advanced glycation end products and to activation of the polyol pathway, protein kinase C pathway, and the poly‐adenosine diphosphate‐ribose polymerase (PARP) and hexosamine pathways, all increasing oxidative stress, with formation of such reactive oxygen species as the hydroxyl radical, superoxide anion, peroxides, reducing endogenous antioxidants including superoxide dismutase, glutathione, and ascorbic acid and eventuating in oxidative damage of DNA, proteins, and lipids, causing cellular necrosis or apoptosis 1 . Hyperglycemia directly and indirectly increases circulating levels of T cells and macrophages as well as inflammatory and prothrombotic factors, reduces endothelial function, and leads to glycation and oxidation of lipoproteins, increasing their atherogenicity 1 .…”

“…Hyperglycemia leads to formation of advanced glycation end products and to activation of the polyol pathway, protein kinase C pathway, and the poly‐adenosine diphosphate‐ribose polymerase (PARP) and hexosamine pathways, all increasing oxidative stress, with formation of such reactive oxygen species as the hydroxyl radical, superoxide anion, peroxides, reducing endogenous antioxidants including superoxide dismutase, glutathione, and ascorbic acid and eventuating in oxidative damage of DNA, proteins, and lipids, causing cellular necrosis or apoptosis 1 . Hyperglycemia directly and indirectly increases circulating levels of T cells and macrophages as well as inflammatory and prothrombotic factors, reduces endothelial function, and leads to glycation and oxidation of lipoproteins, increasing their atherogenicity 1 . A specific mediator of oxidative stress involves activation of the transient receptor potential melastatin (TRMP) 2 calcium channel by ischemia/reperfusion injury, a pathway upregulated in diabetes and insulin‐resistant states and mediating neuronal cell death in association with oxidative stress 7 .…”

The Role of Epidermal Growth Factor Receptor Family of Receptor Tyrosine Kinases in Mediating Diabetes-Induced Cardiovascular Complications

“…DM results in secondary pathophysiologic alterations in several organ systems that impose an immense burden on both the individual with diabetes and the public health system. Cardiovascular (CV) complications constitute the leading cause of morbidity and mortality in individuals with DM ( Forbes and Cooper, 2013 ; Babel and Dandekar, 2021 ). These include microangiopathy, abnormal vascular reactivity, atherosclerosis, hypertension, cardiomyopathy, ischemic heart disease, and myocardial infarction ( Akhtar and Benter, 2013 ; Babel and Dandekar, 2021 ).…”