Incretin-Based Therapies: A Promising Approach for Modulating Oxidative Stress and Insulin Resistance in Sarcopenia

Article information

J Bone Metab. 2024;31(4):251-263

Publication date (electronic) : 2024 November 4

doi : https://doi.org/10.11005/jbm.24.739

Raniah I. Alnaser ¹^,²

, Fawaz A. Alassaf ²

, Mohammed N. Abed^,³

¹Nineveh Health Directorate, Mosul, Iraq

²Department of Pharmacology and Toxicology, College of Pharmacy, University of Mosul, Mosul, Iraq

³Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, Iraq

Corresponding author Mohammed N. Abed Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, University Street, Mosul 41002, Iraq Tel: +964-7518354126 Fax: +964-7518354126 E-mail: m.n.abed@uomosul.edu.iq

Received 2024 March 27; Revised 2024 May 30; Accepted 2024 July 7.

Abstract

Background

Recent studies have linked sarcopenia development to the hallmarks of diabetes, oxidative stress, and insulin resistance. The anti-oxidant and insulin sensitivityenhancing effects of incretin-based therapies may provide a promising option for the treatment of sarcopenia. This review aimed to unveil the role of oxidative stress and insulin resistance in the pathogenesis of sarcopenia and explore the potential benefits of incretin-based therapies in individuals with sarcopenia.

Methods

PubMed, the Cochrane Library, and Google Scholar databases were searched by applying keywords relevant to the main topic, to identify articles that met our selection criteria.

Results

Incretin-based therapies manifested anti-oxidant effects by increasing the anti-oxidant defense system and decreasing free radical generation or by indirectly minimizing glucotoxicity, which was mainly achieved by improving insulin signaling and glucose homeostasis. Likewise, these drugs exhibit insulin-sensitizing activities by increasing insulin secretion, transduction, and β-cell function or by reducing inflammation and lipotoxicity.

Conclusions

Incretin-based therapies, as modulators of oxidation and insulin resistance, may target the main pathophysiological factors of sarcopenia, thus providing a promising strategy for the treatment of this disease.

Keywords: Incretins; Insulin resistance; Oxidative stress; Sarcopenia

GRAPHICAL ABSTRACT

INTRODUCTION

Sarcopenia is mainly characterized by loss of skeletal muscle mass and function. [1] Despite its association with advanced age, the loss in muscle mass could develop earlier.[2] Hence, sarcopenia has a major impact on the quality of life, disability, and increasing mortality rates.[3] Sarcopenia can arise from hormonal differences (endocrine-related disease), biological changes in the structure of muscles, drugs, and external stimuli like deficiency in energy intake.[4] Additionally, people with chronic diseases, such as diabetes mellitus (DM), are at increased risk of developing sarcopenia.[5]

DM is a chronic condition characterized by an elevation in blood glucose, as a result of several factors including defects in insulin secretion, insulin resistance, and oxidative stress.[6] The causative factors of DM are thought to further predispose to sarcopenia in susceptible patients. Accordingly, treatment of DM should also focus on minimizing the likelihood of the occurrence of sarcopenia by interfering with factors that aggravate it. Several classes of antidiabetics have been used to treat diabetes, but incretin-based therapies provided an attractive area of research for minimizing diabetes-related complications.[7]

Diabetic complications can be divided into two categories macrovascular and microvascular complications. Macrovascular complications include cerebrovascular disease, coronary artery diseases such as atherosclerosis, and peripheral artery diseases.[8] Microvascular complications include retinopathy, neuropathy, and nephropathy.[9]

Incretin-based agents include glucagon-like peptide 1 (GLP-1) agonists and dipeptidyl peptidase-4 inhibitors (DPP-4i). Medications that are related to this class show a range of effects on the human body, characterized mainly by reducing high blood sugar levels after meals while providing a minimal risk of causing hypoglycemia. This happens due to their ability to act only when glucose levels are high.[10] The drugs that belong to DPP-4i are used to treat diabetes by inhibiting the breakdown of GLP-1, a hormone that promotes insulin secretion and slows down digestion, thereby increasing its availability in the body.[11] Furthermore, incretin-based therapies are an excitable topic for targeting several diseases due to their multiple beneficial actions beyond glycemic control.[12,13] Accordingly, based on their evidenced anti-oxidants and insulin sensitivity enhancement effects in the peripheral tissues including liver, adipose tissue, and muscles,[14-16] a potential beneficial impact of incretin-based drugs in sarcopenic patients could be applicable.

This review aims to investigate the pathophysiological association between oxidative stress, insulin resistance, and sarcopenia. In addition, the potential benefits of incretin-based therapies on minimizing the risk of development of sarcopenia in susceptible individuals through combating oxidative stress and insulin resistance will also be explored.

OXIDATIVE STRESS AND SARCOPENIA

The imbalance between free radicals and antioxidants results in oxidative stress.[17] The inappropriate overproductions of reactive species will impact protein homeostasis in muscles, leading to loss of both muscle mass and strength.[18,19] Protein synthesis in the muscle is regulated by several signals, including the insulin-like growth factor-1/phosphoinositide 3-kinase/protein kinase B (IGF-1/ PI3K/PKB) pathway. A key regulator of skeletal muscle tropism is PKB (or activation of protein kinase [AKT]), which acts to activate anabolic targets like the mammalian target of rapamycin (mTOR) and inhibit catabolic targets like forkhead box O transcription factors (FoxOs).[20]

Attractively, the IGF-1/AKT/mTOR pathway in myocytes is activated by reactive species resulting in the synthesis of protein and cellular tropism.[21] However, FoxOs are directly activated by reactive species and mediate protein catabolism. Thus, reactive species use IGF-1 to mediate the balance between protein anabolism and catabolism. Unfortunately, with age, the skeletal muscle becomes resistant to IGF-1 signals.[22] Additionally, the increased incidence of inflammation in aged skeletal muscle is thought to be connected to oxidative stress, with subsequent activation of tumor necrosis factor (TNF) and nuclear factor-κB (NF-κB). Similar to FoxOs, NF-κB is linked to catabolism and loss of skeletal muscle mass. It’s worth noting that by overexpressing the endogenous antioxidant enzyme catalase (CAT), inhibition of FoxOs and NF-κB will take place, leading to the prevention of skeletal muscle atrophy.[23]

As one of the primary prooxidant agents during muscle wasting is myostatin, myostatin may also participate in protein degradation through the TNF/NF-κB pathway and reactive species. It has been shown that NF-κB is activated constitutively in the skeletal muscle of both aged and superoxide dismutase-deficient mice (a mitochondrial antioxidant enzyme), leading to an increase in proinflammatory cytokine production and an excess of mitochondrial hydrogen peroxide, proposing a possible role for this mechanism in the pathophysiology of sarcopenia.[24] Likewise, the dysfunctional mitochondria may result in loss of energy and overproduction of reactive species, which participate in the activation of the oxidative stress pathway and subsequently loss of muscle mass and function. Thus, sarcopenia could be prevented by the preservation of mitochondrial function.[25]

The oxidative metabolism and mitochondrial homeostasis could be controlled by peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α; a transcriptional factor stimulated by muscle contraction and considered as a master regulator of mitochondrial homeostasis). The overexpression of PGC-1α on the skeletal muscle aids in the prevention of mitochondrial degradation.[26] Again, with age the expression of PGC-1α is compromised, leading to the overproduction of reactive species.[27] However, overproduction of reactive species promotes the transcription of PGC-1α through adenosine monophosphate-activated protein kinase (AMPK) and promotes mitochondrial respiration.[28] Additionally, PGC-1α induces the expression of uncoupled protein which has antioxidant activity.[29] When considered collectively, these data point to the potential significance of PGC-1α as a therapeutic target to avoid age-associated sarcopenia, with potentially positive effects on protein homeostasis and metabolism. This could also have positive effects on how the body maintains protein levels and metabolism. Further research, both in vitro and in vivo or human studies, could help for a better understanding of these potential benefits.

INSULIN RESISTANCE AND SARCOPENIA

Insulin resistance is another contributor to the pathogenicity of sarcopenia. It refers to the reduction of the responsiveness to insulin in peripheral tissues (including the skeletal muscles), with impaired metabolism of glucose inside these cells.[30] Different mechanisms that are attributed to insulin resistance may contribute to the development of sarcopenia. These mechanisms mainly share common features of defects in the protein homeostasis in the skeletal muscles (reduce protein synthesis and promote protein catabolism), autophagy in skeletal muscle cells, and overexpression of the FoxOs family.[31]

In general, insufficient amino acid intake and decreased insulin sensitivity can lead to muscle weakness and damage. Insulin and amino acid signal transduction pathways may work together to increase skeletal muscle protein. This process is governed by two key factors, which include AKT and mTOR.[32,33]

The two classifications of insulin receptor substrate (IRS) are present; IRS-1 and IRS-2. These receptors have important roles in the development and growth of skeletal muscles. It has been reported that blocking IRS-1 in the skeletal muscle of mice led to a reduction in the mass of skeletal muscle with insulin sensitivity, but blocking IRS-2 did not reflect similar results. While concurrent blockade of both IRS-1 with IRS-2 resulted in severe attenuation of muscle mass and decreased the insulin signaling pathway activation, indicating a duplicated effect in skeletal muscle.[34] Following activation of IRS-1 by insulin, continued activation of the downstream PI3K will take place. PI3K helps in catalyzing phosphatidylinositol 4,5-bisphosphate (PIP2) to produce phosphatidylinositol 3,4,5-triphosphate (PIP3). PIP3 then recruits proteins with pleckstrin homology domains to the lipid membrane and facilitates the localization of downstream signaling factors such as phosphoinositide-dependent protein kinase-1 and AKT.[35] Additionally, the accumulation of PIP3 can transfer and intensify the downstream insulin signaling.

AKT mediates the activation of mTOR and reduces the gene expression of FoxOs, thus promoting protein synthesis in the muscle.[36] Furthermore, activation of mTOR promotes protein synthesis by phosphorylation of different substrates that are involved in mTOR downstream, these substrates can stimulate the expression level of initiation factor of the two messenger RNAs, thus, promoting protein synthesis.[37] Accordingly, any defect in the activation of mTOR causes a reduction in protein synthesis and insulin resistance.[38]

Overexpression of the FoxOs family causes direct attenuation of skeletal muscle or inducing protein degradation. Insulin can directly inhibit the activity of FoxOs through the action of AKT.[36] Preclinical studies indicate a direct relationship between the FoxOs family and sarcopenia.[39- 41] Moreover, overactivation of the autophagy process can lead to various impacts on insulin resistance and muscle attenuation. Autophagy is the process of degradation and damage of cytosolic proteins and organelles by lysosomes, and muscle is one of the active organs in the autophagy process.[42]

A deficiency in nutrient supply and growth factors (such as insulin and IGF-1) are the two main causes of autophagy in the cells. The activation of mTOR results in inhibitory impact on the autophagy, while the activation of FoxOs family causes activation of autophagy. Therefore, insulin, by its activator potential on mTOR and inhibitory action on FoxOs family, may provide a role in the inhibition of autophagy. However, despite the controversial results about the association between insulin resistance and autophagy, both higher and lower levels of autophagy could lead to insulin resistance.[31]

The PI3K/AKT/mTOR pathway is a crucial mechanism that leads to insulin resistance, it links skeletal muscle with insulin and regulates several pathways like FoxOs and autophagy.[43]

OXIDATIVE STRESS AND INSULIN RESISTANCE AS DRIVERS FOR SARCOPENIA

Several studies have related the state of oxidative stress in the body to the promotion of insulin resistance and thus, diabetes. Such an association could predispose to serious compilations including sarcopenia as shown in Figure 1. However, the detailed relationship have not yet been fully illustrated.[44]

Fig. 1.

Schematic graph illustrating oxidative stress and insulin resistance as drivers for sarcopenia. AMPK, adenosine monophosphate-activated protein kinase; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator-1α; TNF, tumor necrosis factor; NF-κB, nuclear factor-κB; Fox-Os, forkhead box O transcription factors; IGF-1, insulin-like growth factor-1; PI3K, phosphoinositide 3-kinase; AKT, activation of protein kinase; mTOR, mammalian target of rapamycin; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-triphosphate.

Generally, oxidative stress plays a critical role in the development of many diabetes-related complications and insulin resistance. Many cellular pathways have been showed to be activated by reactive species, and this can block the cellular signaling pathways.[45] The activated pathways include IκB kinase, JNK, p38, and extracellular receptor kinase, this activation resulting in the cellular reduction to the insulin responsiveness, which decreases the insulin capacity to promote glucose uptake and stimulate protein, and glycogen synthesis. Additionally, the phosphorylation of IRS-1 will reduce its stimulation by insulin and PIP kinase transfer between cytosol and microsome, IRS degradation decreases protein kinase phosphorylation, and thus, diminishes the translocation of glucose transporter type 4 to the plasma membrane. The abovementioned pathways are the main complex mechanisms that underlying the oxidative stress in the cell.[46] Therefore, it has been recognized that oxidative stress is the main contributing factor in developing insulin resistance in peripheral tissue including muscle, and it is crucial to restore the balance between free radicals and antioxidative elements in favor of physiological stats, this balance can help to manage different serious health diseases including diabetes and sarcopenia. [47,48]

In 2011, Khamseh with his colleagues [49] discussed the pathophysiological pathways of sarcopenia in relation to oxidative stress and insulin resistance status; they concluded that subclinical inflammation, oxidative damage, and insulin resistance are important milestones in the development of sarcopenia and diabetes. Mesinovic with his colleagues [50] in 2019 exposed the bidirectional link between DM and sarcopenia; many factors can impact muscle health including; oxidative stress, insulin resistance, advanced end-product accumulation, and inflammation. In 2022, Purnamasari with her colleagues [51] built the relationship between the pathophysiological factors of sarcopenia and DM and explained how sarcopenia could be a chronic complication of DM through insulin resistance and oxidative stress. In 2023, Tack with his colleague [52] explored how the pathophysiological interactions between sarcopenia and DM could be a two-way street affecting the diagnosis and treatment strategies. All of the studies and contributing factors between DM and sarcopenia suggest using anti-diabetic agents that target the main pathophysiological pathways in these diseases.

THE ACTION OF INCRETIN-BASED THERAPIES ON OXIDATIVE STRESS AND INSULIN SENSITIVITY

The incretin-based therapy can improve oxidative stress through several direct and indirect mechanisms.[53] The direct anti-oxidant effect is achieved through increasing the anti-oxidant defense system and decreasing free radical generation. The anti-oxidant defense system is a protective system of the body that is composed of both enzymatic and nonenzymatic components such as glutathione peroxidase superoxide dismutase, glutathione reductase, and CAT. These elements are highly effective in scavenging free radicals, and thus their concentration and activity play a significant role in determining the redox state of biological cells. Therefore, any agent that can enhance this protective system will help alleviate different oxidative stresses and minimize oxidative damage.[54] Interestingly, there is developing evidence signifying that incretin-based therapies induce the activation of such defense system at least partly via sirtuin (Sirt) signaling and NF-erythroid 2-related factor (Nrf2) pathways.[55-57] The second direct effect is by several pathways to reduce free radical generation, including suppressing pro-oxidant enzymes and promoting the function of mitochondria.[8,58]

The indirect anti-oxidant effect of incretin-based therapies is mediated by decreasing glucotoxicity, mainly by improving insulin signaling and glucose homeostasis. Such activity may result in reduced levels of harmful byproducts like advanced glycated end products,[59] malondialdehyde,[60] and inflammation-dependent oxidative stress (which is reflected by decreasing TNF and other inflammatory cytokines).[61] Similar to their antioxidant effects, incretin-based therapies can improve insulin sensitivity in insulin-dependent peripheral tissue through direct and indirect mechanisms.[62] These mechanisms work to increase insulin secretion,[63] decrease oxidative stress,[63] decrease inflammatory response,[64] increase expression and localization of GLUT-4 in insulin-sensitive tissue,[65] improve the plasma lipid profile; which regulates lipid metabolism,[66] enhance the function of pancreatic β-cells by inducing neogenesis and inhibiting apoptosis,[67] amplify the transduction signal of insulin at different ways; such as AKT and IRS-1 phosphorylation,[68] and decrease endoplasmic reticulum stress via mTOR signaling.[69]

Recent researches indicate that GLP-1 receptor stimulation by incretin-based therapies can lead to enhanced antioxidative outcomes. In 2011, Tomas et al. [70] explored a nano peptide derived from GLP-1, this peptide has the potential to decrease oxidative stress through a mitochondria-dependent mechanism. Puddu et al. [71] suggested that GLP-1 could reduce oxidative stress by inhibiting the interaction between advanced glycated end products and receptor-advanced glycated end products in diabetic settings. In 2013, Patel and colleagues [72] demonstrated that GLP-1 can improve the sensitivity to insulin in diabetic mice by reducing oxidative stress. In 2014, Okada et al. [73] and 2015, Rizzo et al. [74] supported clinical evidence that liraglutide can decrease oxidative stress in patients with type 2 diabetes. Fernández-Millán et al. [75] reported an increase in Nrf2 signals after GLP-1 administration, leading to resolved oxidative stress in the β-cells of the pancreas. In 2017, Oh and Jun [76] proposed a GLP-1 anti-oxidative potential, either through an effect on glucose or by activation of Nrf2 signals and enhancement of the anti-oxidant defense system. The induction of Nrf2 signals can improve the sensitivity to insulin in diabetic patients. In 2018, Deng and coworkers [58] revealed that GLP-1 can stimulate Nrf2 signals, leading to an increase in the expression of anti-oxidant elements in neuronic cells. Based on the supported evidence, it seems likely that GLP-1 can improve the sensitivity to insulin by reducing oxidative stress.

Accordingly, incretin-based therapies could attenuate oxidative stress through several direct and indirect molecular pathways and subsequently lead to direct and indirect attenuation of insulin resistance. The proposed pathways for incretin-based therapies action are illustrated in Figure 2.

Fig. 2.

The impacts of incretin-based therapies on sarcopenia. Incretin-based therapies may attenuate oxidative stress and insulin resistance through several direct and indirect molecular pathways and subsequently lead to reduction of the risk of sarcopenia. GLUT4, glucose transporter type 4.

RATIONAL USE OF INCRETIN-BASED THERAPIES TO AMELIORATE AND REDUCE THE RISK OF SARCOPENIA

The involvement of oxidative stress and insulin resistance in the pathogenesis of sarcopenia urges a focus on targeting them for better management outcomes, especially in diabetic patients. Recently, the promising data obtained from research on incretin-based therapies encouraged their use in the treatment of several diseases beyond their glycemic control. These include decreasing the risk of cardiovascular diseases through lowering blood pressure, improving endothelial function and lipid profile, increasing myocardial contractility, and enhancing weight loss in obese patients.[77] Additionally, incretin-based therapies have the ability to prevent and treat neurodegenerative disorders through their neuroprotective actions.[78] Furthermore, they have a promising action on bone health and preservation of the musculoskeletal system.[79] These actions could be attributed to their beneficial insulin-sensitizing effect, in addition to their anti-oxidant and anti-inflammatory potential.[80,81] Through the continuous exploration of the signaling pathways targets of each protein, new sites for identifying novel treatment candidates for oxidative stress, insulin resistance, and sarcopenia can be determined.

In recent years, an increasing number of downstream factors have been discovered in this field, which will be an exciting area of future research. Therefore, exploring the impact of incretin-based therapies on sarcopenia gives the hope to consider them as treatment strategies for diabetic patients with sarcopenia or those with a risk of developing sarcopenia.

BALANCING THE RISKS AND BENEFITS OF USING INCRETIN-BASED THERAPIES IN SARCOPENIA

Skeletal muscle is a major site for glucose disposal and energy metabolism, it plays a crucial role in glucose homeostasis. However, muscle wasting results from different causes that can impede the quality of life and physical activity.[82]

Several factors have been suggested as contributors to muscle wasting including diabetes, decreased physical activity, inflammation, oxidative stress, insulin resistance, mitochondrial dysfunction, age, and obesity.[83-85] Certain antidiabetics including incretin mimetics could positively impact muscle mass as shown in vitro and in vivo studies through different mechanisms. Exenatide-4 and liraglutide are GLP-1 agonists were shown to increase the glucose uptake by the muscle of diabetic rats through the activation of AMPK pathway.[86] Another glucose-independent effect was observed with exenatide-4 which modulated the oxidative stress and significantly enlarged the myocytes of Zucker rats.[87] Moreover, exenatide-4 has contributed to enhanced mitochondrial function and exercise capacity in mice models.[88]

In clinical trials, liraglutide has been observed to increase the mass of skeletal muscle in type 2 diabetic patients who were overweight or obese.[89] Also, in type 2 diabetic patients, exenatide-4 has increased the irisin, a myokine, which is usually induced by exercise.[90] Despite the abovementioned studies on the beneficial impact of GLP-1 agonists on muscle mass, a study in Japan showed a decrease in muscle mass in diabetic patients undergoing hemodialysis, after six months of using GLP-1 agonist, dulaglutide.[91] Importantly, the impact of GLP-1 agonists on weight loss has gained the attention of healthcare providers for using these agents in different clinical conditions including obesity-associated diseases. However, the rapid loss of body mass could be associated with the loss of muscle mass and negatively linked to sarcopenia. For that reason, it is crucial to balance the risks and benefits of using GLP-1 agonists. Accordingly, to address this challenge, it is important to outline the mechanism of GLP-1 agonists on weight loss and its effect on body composition, particularly skeletal muscles. Generally, the actions of GLP-1 agonists on weight loss are mediated through a reduction in appetite and hunger, improvement of eating control, and slowing gastric emptying.[92] These mechanisms are linked to the central and peripheral nervous system, mainly through the activation of neuronal pathways of the hypothalamus, hindbrain, and vagus nerve.[93,94] Notably, when body weight decreases, a reduction of lean body mass could occur, which is comprised mainly of skeletal muscle. Consequently, lower muscle mass and function raise the risk of sarcopenia, falls, physical frailty, and hospitalization, since they are associated with impaired muscular strength and endurance, especially in the elderly.[95,96] Meanwhile, the incidences of lower muscle mass with the GLP-1 agonists are rarely severe and could be avoided by several strategies, they would therefore not be assumed to cause a barrier for using them in preventing sarcopenia. These strategies include resistance exercise; incorporating strength exercise training into the daily routine to reverse the consequence of rapid weight loss and stimulate muscle building.[97] Besides, maintaining balanced diets rich in protein and essential nutrients to support muscle growth and repair is advised.[98] As well, proper hydration may provide a beneficial impact on muscle health, while dehydration inversely affects muscle health and function.[99] Furthermore, regular monitoring of body composition is important to track any reduction in muscle mass.[100]

CONCLUSIONS

Despite the lack of sarcopenia treatment options that significantly enhance the quality of life and physical function, controlling the main pathophysiological contributing factors in sarcopenia is an attractive area of research. Additionally, the vital roles of incretin-based therapies in several health conditions highlight their use in sarcopenia. This could be attributed to their beneficial effects on preserving muscle mass, contractility, and functions. Incretin-based therapies appear to provide a promising treatment option for patients with sarcopenia, probably by their direct and indirect antioxidant and insulin-sensitizing action in the skeletal muscles. However, further researches are needed to address the molecular mechanisms for their impact on muscle health and to provide a valuable insights into how these agents could improve sarcopenia. Moreover, clinical trials are essential to evaluate the effectiveness of incretin-based therapy in sarcopenia via targeting different populations; such as the elderly with or without diabetes, taking the treatment duration, dosages, and combinational therapies into consideration to maximize benefits.

Acknowledgements

The authors acknowledge the assistance provided by Nineveh Health Directorate, the University of Mosul and the College of Pharmacy.

Notes

Ethics approval and consent to participate

Not applicable.

Conflict of interest

No potential conflict of interest relevant to this article was reported.

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