Written by Julie Bick, Ph.D.
The role that oxidative stress plays in the development and progression of neurodegenerative diseases is well described and is now being translated into a source of novel therapeutic approaches. However, oxidative stress is also closely linked with the development and progression of many other chronic conditions, including one of the most prevalent, diabetes. The relationship between oxidative stress and diabetes involves complex interactions that contribute to insulin resistance, impaired glucose metabolism, inflammation, as well as many of the other complications associated with diabetes. In this blog, we review some of the most recent data describing the role of oxidative stress in diabetes and novel therapeutics that may help alleviate the burden of diabetes on our healthcare system.
The prevalence of diabetes mellitus is increasing at alarming rates globally, driven by several economic and social factors. There are different forms of the condition, with Type 1 accounting for ~5-10% of cases and Type 2 accounting for between 90-95% depending on region. Whereas Type 1 diabetes is caused by the dysfunction of beta-cells that results in lower insulin release and impacted levels of circulating insulin, Type 2 is principally associated with an inadequate response to insulin and insulin resistance in peripheral tissues. More than 9% of the world’s population are afflicted with Type 2 diabetes; this is across developed and developing countries, and diverse socioeconomic and ethnicities, resulting in 1.5 million deaths per year (World Health Organization Media Centre. WHO Press; 2016. Global report on diabetes). Aside from Type 1 and Type 2 diabetes there are other rarer forms including gestational diabetes, which occurs in pregnant women who experience significant variations in hormone levels throughout the pregnancy. There are also genetic forms of diabetes, autoimmune diabetes and several secondary pathologies that result in disrupted insulin regulation such as pancreatitis. (Reference American Diabetes Association, “Diagnosis and classification of diabetes mellitus,” Diabetes Care, vol. 37, Supplement 1, pp. S81–S90, 2014). Latent autoimmune diabetes (LADA) develops more slowly than classic Type 1 diabetes and is typically not detected before 35 years of age but is associated with the presence of autoantibodies to islet beta cells (Rajkuma and Levine, 2022).
Common among all types of diabetes, is the damaging role of oxidative stress and its responsibility for the pathophysiology of insulin resistance and many of the other complications of diabetes through common molecular mechanisms- lipid peroxidation, DNA damage and mitochondrial dysfunction. Given the strong correlation between diabetes and oxidative stress, it isn’t a surprise that intermittent fasting has been shown to reduce oxidative stress levels and have a positive effect on aging and metabolic homeostasis. In fact a team of students at Tufts University have published a website summarizing this topic as it relates to managing Type 2 diabetes (https://sites.tufts.edu/nurturehealth/ ) and providing a comprehensive summary of the ongoing research in this area.
Oxidative stress arises from an imbalance between the production of reactive oxygen species (ROS) and the body's antioxidant defenses. ROS including superoxide radicals, hydrogen peroxide and hydroxyl radicals are generated both within cells, as well as in our environment, and our cells have intrinsic defenses to manage ROS such as superoxide dismutase (SOD), catalase (CAT), and glutathione (GLT) (A. C. Maritim, et. al. 2003). In addition, other intracellular-generated nitrogen reactive molecules including peroxynitrite, and some metal derivatives including ferric iron and copper, all have unpairs electrons that can oxidize proteins, lipids and nucleic acids and result in oxidative stress. There are several intracellular signaling pathways such as Nuclear Factor Kappa b (Nf-κb), p38 mitogen-activated protein kinase (p38 MAPK), protein kinase C (PKC), stress activated protein kinase/c-Jun NH92)-terminal kinase (JNK/SAPK) that are activated by oxidative stress which can also lead to cell damage (Wulf, 2011).
In the context of diabetes, oxidative stress has been identified as a key contributor to insulin resistance (Asmat et. al. 2016). High levels of ROS can interfere with insulin signaling pathways, disrupting the normal response of cells to insulin. This leads to impaired glucose uptake and utilization in insulin-sensitive tissues such as skeletal muscle, adipose tissue, and liver. Pancreatic beta-cells, responsible for insulin production, are also vulnerable to oxidative stress; the induction of endoplasmic reticulum stress by ROS, particularly in insulin-producing cells, activates signaling pathways that can contribute to insulin resistance and apoptosis of pancreatic beta cells (Porte, 2001). Similarly, chronic exposure to elevated glucose levels and other metabolic factors in diabetes contributes to the production of ROS within beta cells, leading to dysfunction and finally apoptosis of these cells, which results in reduced insulin secretion and exacerbating hyperglycemia. Hyperglycemia enhances the production of ROS through various pathways, including the activation of the polyol pathway and increased mitochondrial ROS production. Chronic oxidative stress can also impair mitochondrial function within beta cells, leading to decreased ATP production and altered cellular energy balance, and resulting in beta-cell failure. Chronic low-grade inflammation is a characteristic feature of diabetes, and the inflammatory pathways activated by oxidative stress can disrupt insulin signaling and contribute to insulin resistance. In turn, insulin resistance can further amplify inflammation (Eizirik, 2009). All of these factors create a detrimental feedback loop that amplifies the burden of oxidative stress on the body and exacerbates the damage it causes. Ultimately, this is why patients with diabetes have an increased risk of stroke, neuropathy, retinopathy and nephropathy (Ceriello, A 2006).
Another mechanism by which oxidative stress contributes to the development and progression of diabetes is by promoting the formation of advanced glycation end products (AGEs) (Halliwell, 2009). These are formed when glucose reacts with proteins and AGEs then accumulate in tissues, leading to the cross-linking of proteins and impaired function. In diabetes, the increased production of AGEs contributes to many of the associated complications such as nephropathy, retinopathy, and cardiovascular diseases.
Oxidative stress is also implicated in the development of microvascular complications associated with diabetes, such as nephropathy and retinopathy. ROS can damage blood vessels and impair endothelial function, contributing to vascular dysfunction and complications (Gray & Jandeleit-Dahm, 2014).
Given this significant association between oxidative stress and diabetes, antioxidant therapies have been explored as potential interventions (Rochette et. al. 2014). However, the effectiveness of antioxidant supplementation in improving outcomes in diabetic patients remains unproven. Lifestyle interventions, including maintaining a healthy diet, regular exercise, and glucose control, along with potential antioxidant-based treatments, represent avenues for addressing oxidative stress in diabetes.
But there are several novel targeted therapies emerging from clinical research into diabetes that aim to modulate oxidative stress that may become useful tools in diabetes management (American Diabetes Association Professional Practice Committee. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022 Jan 01;45(Suppl 1):S125-S143).
Metformin is an oral antidiabetic medication that belongs to the class of drugs known as biguanides and is considered a first-line therapy for many individuals with type 2 diabetes. Metformin helps to lower blood glucose levels by reducing both the production of glucose in the liver (gluconeogenesis) and the absorption of glucose in the digestive tract, as well as increasing the uptake and utilization of glucose by muscle cells by activating AMP-activated protein kinase (AMPK). Biguanides reduce blood sugar levels and therefore have protective effects on kidney function and have also been shown to provide cardiovascular benefits with improvements in lipid profiles. Significantly, Biguanides also reduce oxidative stress by reducing oxidative phosphorylation within mitochondria, complex 1 inhibition and the modulation of key metabolic pathways (Di Magno et. al. 2022).
Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a class of medications used to manage diabetes, particularly type 2 diabetes (Padda et. al. 2023; Jung et. al. 2014). These drugs work by targeting a specific mechanism in the kidneys to reduce blood glucose levels. In the kidneys, glucose is filtered from the blood into the renal tubules. Under normal circumstances, almost all of this filtered glucose is reabsorbed back into the bloodstream through a process that involves specific transporters, one of which is called SGLT-2. It primarily operates in the early segment of the renal tubules, specifically in the proximal convoluted tubule. Inhibition of this transporter helps to prevent the reabsorption of glucose from the renal tubules back into the bloodstream, leading to the excretion of glucose from the body and a reduction of glucose levels in the bloodstream. This provides several benefits to patients taking the drug, including caloric loss leading to weight loss, and the reduction of blood pressure through the mild diuretic effect that SGLT-2 inhibitors have. Some SGLT-2 inhibitors have shown cardiovascular and renal benefits beyond glucose control. These include a reduction in cardiovascular events and improved outcomes for individuals with heart failure or chronic kidney disease (Verma et. al. 2018).
Empagliflozin, dapagliflozin, and canagliflozin are all examples of SGLT-2 inhibitors that were already on the market, but new compounds within this class are currently being evaluated in clinical trials.
By now we have all heard of Glucagon-like peptide-1 (GLP-1) receptor agonists such as Ozempic and their use for weight loss, but these drugs were originally developed for the management of Type 2 diabetes. These drugs mimic the action of the endogenous incretin hormone GLP-1, which is involved in glucose homeostasis. GLP-1 receptor agonists have several mechanisms of action that collectively contribute to their glucose-lowering effects. GLP-1 is an incretin hormone released by the intestine in response to the ingestion of food. Its primary role is to enhance glucose-dependent insulin secretion from pancreatic beta cells. GLP-1 receptor agonists bind to GLP-1 receptors on pancreatic beta cells, leading to an enhanced and glucose-dependent release of insulin (Hinnen, 2017). Importantly, this means that the increase in insulin secretion occurs in response to elevated blood glucose levels, helping to control postprandial hyperglycemia. GLP-1 receptor activation also suppresses the release of glucagon, a hormone that raises blood glucose levels. By inhibiting glucagon secretion from pancreatic alpha cells, GLP-1 receptor agonists contribute to the overall reduction of glucose production by the liver. These drugs also slow down the rate at which the stomach empties its contents into the small intestine, which helps to reduce the postprandial rise in blood glucose by delaying the absorption of nutrients.
GLP-1 receptors are also present in the central nervous system, including the hypothalamus, and activation of these receptors may contribute to the regulation of appetite and food intake, leading to potential weight loss in some individuals (Potts et. al. 2015). Some of the drugs in this class have also been shown to have beneficial effects on pancreatic beta cells, promoting their survival and function over the long term. This can be especially important in the context of Type 2 diabetes, where beta cell dysfunction is a key component of the disease. There have also been studies showing these drugs demonstrate cardiovascular benefits and reno-protective effects that could potentially slow the progression of diabetic kidney disease. Based on all of this, it is not surprising that these drugs have become extremely popular and effective for patients with Type 1 and Type 2 diabetes. Significantly, based on their complementary mechanisms of action, a combination of an GLP-1 receptor agonist and an SGLT-2 inhibitor could represent a highly effective therapeutic strategy to achieve glycemic control in patients with Type 2 diabetes, with a low risk of hypoglycemia (Li et. al. 2022)
Dipeptidyl peptidase-4 (DPP-4) inhibitors, known as gliptins, increase the concentration of active incretin hormones, which stimulate insulin release and inhibit glucagon secretion. As such DDP-4 inhibitors increase the circulating levels of GLP-1 and Glucagon-like Peptide-1 (G1P) which then promotes insulin secretion by the pancreatic beta-cells to support glucose homeostasis (Rosenstock et. al. 2006). Gliptins have been shown to have very good safety profiles, with a very low risk of hypoglycemia or adverse drug interactions, however there are no reported benefits to weight management by these drugs.
Examples of this class of drugs include Teneligliptin, omarigliptin, and gemigliptin. Significantly, these drugs not only help to manage glucose homeostasis, but they have also been shown to provide anti-inflammatory, anti-fibrotic and anti-oxidative stress properties (Kawanami et. al. 2021).
PPAR agonists, such as thiazolidinediones, have also been assessed for their effects on insulin sensitivity. PPARs are ligand-activated nuclear transcription factors that play central roles in lipid and glucose homeostasis. Within clinical trials they have been shown to improve dyslipidemia and insulin resistance, and studies in mouse models for Type 2 diabetes have demonstrated their reno-protective effects through their anti-inflammatory properties and activation of the renin-angiotensin system. This is coupled with their suppressive effects on both oxidative stress and lipid-toxicity (Kume et. al. 2008). Metabolic syndrome is described as a combination of cardiovascular risk factors that includes high blood pressure, visceral obesity, atherogenic dyslipidemia along with hyperglycemia with or without Type 2 diabetes. Inhibitors of the PPAR isoforms (alpha, beta and delta) are being assessed for their ability to manage metabolic syndrome by modulating both glucose and lipid metabolism, without adverse effects (Kim et. al. 2019). Saroglitazar is an example of a dual PPAR agonist that has been studied for its potential in managing diabetic dyslipidemia.
Glucose transporter type 4 (GLUT-4) activators are a potential class of medications that aim to enhance the activity of the GLUT-4 transporter, a key player in insulin-regulated glucose uptake by cells. GLUT-4 is primarily found in insulin-sensitive tissues such as muscle and adipose tissue. The activation GLUT-4 increases the uptake of glucose from the bloodstream into cells, which is particularly relevant for managing diabetes. While there isn't currently an established class of medications specifically referred to as GLUT-4 activators, certain strategies have been shown to indirectly influence GLUT-4 activity. For example, medications that improve insulin sensitivity, such as thiazolidinediones (TZDs), enhance insulin action in peripheral tissues by increasing GLUT-4 expression and translocation to the plasma membrane of insulin-sensitive cells. Similarly, increased GLUT-4 activity is observed in cells exposed to metformin, a compound that activates the enzyme AMP-activated protein kinase (AMPK). AMPK plays a central role in cellular energy balance and its activation increases glucose uptake in cells via the GLUT-4 transporter.
Bile acid sequestrants (BASs)are routinely used to help patients lower their cholesterol levels, however for patients with Type 2 diabetes, they have also been shown to lower blood sugar. Bile acids are made from cholesterol by the liver and stored in the gallbladder and released into the small intestine to facilitate the digestion of fats from our food. The administration of BASs as drugs helps to mop up bile acids in the intestine and enhances their excretion in stool. The body then uses circulating cholesterol to make more bile acid, thereby lowering cholesterol.
The BASs colesevelam (WelCol®) is now FDA approved for the management of the symptoms of Type 2 diabetes. Although not completely understood, the mechanism of action appears to be the reduction of glucose absorption from the digestive tract, and the activation of bile acid receptors, that in turn increases the secretion of insulin, resulting in lower levels of hemoglobin A1c (HbA1c). But BASs also appear to provide anti-oxidative stress and anti-inflammatory benefits (Bays et. al. 2006; Takebayashi et. al. 2010).
Diabetes as a disease is highly complex and highly polymorphic in terms of its’ physiology and underlying pathology. Clinicians classify the type of diabetes based on predetermined criteria but even with these, there are misdiagnoses:
There are certainly forms of diabetes with a strong genetic component, and these are frequently the easiest forms to manage with insulin and sulfonylureas. However, when it comes to Type 2 diabetes, the wide range of drugs available can make effective treatment a hit-or-miss endeavor. This is where pharmacogenomics can really help, not only to prevent adverse drug reactions, but also identify the most potent therapeutics early in the patient’s journey.
Type 2 diabetes is a polygenic disease, driven significantly by environmental factors, and fueled by dysfunction in a variety of pathways. Where pharmacogenomics can really make a difference is by helping clinicians to translate the genetic etiology of the disease to help better address pathophysiology, and therefore identify the specific pathways for therapeutic targeting. This isn’t a simple undertaking but as the field of pharmacogenomics is advancing the way we are developing better genetic handles around the efficacy and safety of different drug classes. An early example of this is the drug Metformin. The pathways for Metformin absorption are mediated by several transporters including those encoded by the genes SLC29A4, SLC22A1/2 and OCT1, and the drug excreted via the MATE transporters encoded by SLC47A2. Pharmacogenomic profiling has identified key variants in these genes that correlate with higher odds of gastrointestinal adverse effects (Dawned et. al. 2019) or increases in HbA1c levels (Al-Eitan et. al. 2019) upon treatment with Metformin. Similar studies have also included genes associated with glycemic responses to Metformin. Now, with so many clinical trials examining the potential for a pharmacogenomics tool kit to address diabetes Type 2, the Metformin Genetics Consortium (https://www.pgrn.org/metgen.html ) was formed to enable more comprehensive and statistically powerful data sets to be combined, which will ultimately improve the clinical validity of pharmacogenomics in this field.
Given the intricate interplay between oxidative stress and diabetes, understanding the nuances of their relationship holds clues to unlocking the processes involved in disease development and progression. From the autoimmune assault on beta cells in Type 1 diabetes to the systemic repercussions of oxidative stress in Type 2 diabetes, the relationships between metabolic pathways provides a roadmap for therapeutic innovations. As research continues to highlight the intricacies of oxidative stress in diabetes, the potential for targeted interventions and pharmacogenomic-driven personalized approaches is now a real option, offering hope towards better symptom management and improved health for so many patients.
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