Role of irisin in physical activity, sarcopenia-associated type 2 diabetes, and cardiovascular complications

Abstract

Irisin is a chief myokine released during physical activity and has garnered attention for its potential therapeutic effects on different metabolic and cardiovascular disorders. This review explores the intricate connections between irisin, physical activity, sarcopenia, type 2 diabetes mellitus (T2DM), and cardiovascular complications. Experimental data suggests that through irisin release, physical activity positively influences muscle health, metabolic regulation, and cardiovascular function. In individuals with sarcopenia, characterized by progressive muscle mass and function loss, irisin plays a pivotal role in maintaining muscle integrity and function. Additionally, irisin’s beneficial effects on insulin sensitivity and glucose metabolism suggest its involvement in the pathophysiology of T2DM. The review will examine how irisin may modulate the development of cardiovascular complications, particularly in the context of diabetes and aging. Additionally, it will explore its potential as a therapeutic target for managing sarcopenia, T2DM, and cardiovascular complications, underscoring the importance of physical activity in mitigating these interconnected health challenges. Further research is needed to elucidate the precise mechanisms by which irisin mediates these effects and assess its clinical applicability in preventing and treating metabolic and cardiovascular disorders.

Key Words: Type 2 diabetes mellitus; Exercise; Myokines; Irisin; Sarcopenia; Vascular complications

Core Tip: Physical inactivity, sarcopenia, and diabetes are interrelated conditions, each exacerbating the others. The impact of these issues is significant, particularly on the cardiovascular system. Irisin, a myokine with autocrine, paracrine, and endocrine functions, may play a key role in metabolic health and could serve as an adjunct to the pharmacological management of prediabetes and diabetes. The exact mechanisms through which irisin exerts its beneficial effects, and the optimal levels for the therapeutic potential, need further investigation. Moreover, assessing irisin levels in response to different exercise types and intensities could be valuable in customizing individualized exercise plans for patients with diabetes and related complications.

INTRODUCTION

Diabetes mellitus is a widespread metabolic disease with a rising incidence that parallels the advancement of age. Although its pathophysiology is complex, type 2 diabetes mellitus (T2DM) and its early-stage precursor, prediabetes, are largely driven by unhealthy lifestyles, including low levels of physical activity and sedentary behavior, which are closely interrelated with insulin resistance (IR), a hallmark of T2DM[1]. Despite extensive research and efforts dedicated to developing individually tailored pharmacotherapy, the management strategies of T2DM remain challenging and often fail to achieve the desired effects, leading to chronic complications that drive unfavorable outcomes[2]. In this vicious cycle, one of the important players is sarcopenia, an age-related condition characterized by a reduction in muscle mass, strength, and function accentuated by physical inactivity and closely linked to physical disability, compromised glycemic control, poor quality of life, and finally, mortality[3]. Unfortunately, sarcopenia is often overlooked, especially in persons with high body mass index, which is often in T2DM. Currently, several diagnostic methods are available for this purpose, ranging from non-invasive, easily accessible, and harmless bio-electrical impedance analysis to less commonly used methods that may involve higher costs, limited accessibility, and potential risks. These include dual-energy X-ray absorptiometry, magnetic resonance imaging, and computed tomography, the latter of which is considered the gold standard for quantifying muscle mass[4].

In patients with T2DM, the incidence of sarcopenia is 2-3 times higher compared to patients without T2DM, and sarcopenia and insufficient physical activity are both independently correlated with the onset of T2DM. On the other hand, a 10% increase in skeletal muscle index decreases the HOMA-IR by 11% and the incidence of prediabetes by 12%[5]. Sarcopenia is extensively found in older adults with T2DM, where it correlates with high HbA1c and macrovascular and microvascular complications of diabetes[6]. Several studies have demonstrated an association between sarcopenia and an increased risk of atherosclerosis, the prevalence of coronary calcification, and major adverse cardiovascular events. Additionally, the presence of microvascular diabetic complications, such as retinopathy, nephropathy, and neuropathy, heightens the risk of developing sarcopenia. The mechanisms linking these factors include IR, chronic inflammation, and advanced glycation end-products, which are exacerbated by reduced mobility, a feature common among patients with comorbid T2DM[7].

PHYSICAL (IN) ACTIVITY, SARCOPENIA, AND DIABETES

Numerous studies and lifestyle intervention programs have shown that engaging in physical activity can provide significant metabolic benefits, often comparable to pharmacological treatments for individuals with prediabetes and early-stage diabetes[8]. Recent molecular research has highlighted that muscle contraction can serve as an underutilized therapy for individuals with metabolic disorders independently or in conjunction with other treatments[9,10]. Indeed, evidence from original studies with decades-long follow-ups, such as Da Quing and the Diabetes Prevention Program, supports lifestyle interventions, including physical activity, in diabetes reversal and prevention[11,12]. This therapeutic effect is mediated through the skeletal muscle either directly, by diminishing peripheral IR and increasing muscular glucose uptake, or indirectly, via its endocrine function, supported by the release of over 600 myokines like myostatin, interleukin-6, interleukin-15, myonectin, etc., with irisin potentially playing a central role in metabolic regulation[13-16].

IRISIN- A LINK LIGHTING FIRE BETWEEN MUSCLE AND METABOLIC HEALTH?

Skeletal muscle is crucial for movement and physical strength and functions as a vital endocrine organ. Recent research has uncovered its role in regulating metabolism and preventing metabolic diseases such as diabetes. When muscles contract, they release various signaling molecules known as myokines. One of the most significant ones for metabolic health is irisin, primarily (more than 72%) secreted by skeletal muscle, and in smaller amounts by heart, adipose tissue, and liver[17]. It is derived from a larger precursor, fibronectin type III domain-containing protein 5, a membrane-spanning protein cleaved to form irisin by an unknown protease[18]. Irisin synthesis and secretion are induced by acute bouts of exercise and peroxisome proliferator-activated receptor-γ coactivator 1-α, but irisin expression appears to be influenced by age, gender, and obesity[19]. Once secreted, irisin can regulate glucose homeostasis in skeletal muscle in an autocrine manner by stimulating glucose uptake via p38 mitogen-activated protein kinase-glucose transporter 4 translocation[20]. In addition, irisin can improve the expression of uncoupling protein 1 and promote the browning of white adipose tissue, increasing mitochondrial density, and potential for aerobic glycolysis with greater energy expenditure[21].

Furthermore, irisin could protect muscles from deterioration and dysfunction, and thus prevent diabetic myopathy. A potential explanation is the reduction of hyperglycemia and inflammation, and consequently diminished IR, and improved insulin sensitivity[22]. In rodent models, irisin's myogenic role was shown through the induction of skeletal muscle hypertrophy and at the same time attenuation of atrophy by activating interleukin (IL)-6, satellite cells, and protein synthesis[23]. Moreover, a study by Park et al[24] showed that irisin may function as a potential promyogenic factor in postmenopausal sarcopenia. Irisin also acts on the adipose tissue, stimulating white adipocyte browning and thermogenesis and reducing visceral fat[25,26]. Moreover, experimental studies showed that irisin has anti-apoptotic actions on pancreatic beta-cells which can stimulate their proliferation, insulin biosynthesis, and secretion[27,28]. Although measurement of irisin concentration is still challenging and faces many discrepancies related to the methodology used (for example tandem mass spectrometry vs ELISA)[29], human studies have consistently shown lower irisin levels in sera of diabetic patients compared to healthy controls[20,30-32].

Besides, studies have shown a link between low circulating irisin levels and muscle weakness and atrophy, suggesting its potential as a biomarker of sarcopenia[33,34], and sarcopenic obesity, a common finding in T2DM patients[35]. A study by Oguz et al[36] showed irisin levels were significantly lower in patients with T2DM with sarcopenia (10.07 ± 6.17 ng/mL) compared to those measured in patients with T2DM and no sarcopenia (13.67 ± 9.07 ng/mL), P = 0.038. In contrast, the lowest irisin levels were detected in patients with T2DM and sarcopenic obesity (7.66 ± 5.27 ng/mL), so the authors suggested an irisin value of < 9.49 ng/mL to be a cut-off for detecting sarcopenic obesity with sensitivity and specificity of 75.8% and 78.1%, respectively[36]. When serum irisin levels were compared between T2DM patients with and without vascular complications, prior had the lowest values, suggesting irisin could be used as a biomarker to further stratify diabetic patients according to their potential risk of developing micro and macrovascular complications[36-39].

CAN IRISIN SLOW DOWN/REVERT THE DIABETIC VASCULAR COMPLICATIONS?

In people with T2DM, sarcopenia increases the risk of developing cardiovascular complications [cardiovascular disease (CVD), hazard ratio (HR) = 1.89, heart failure (HR = 2.59), stroke (HR = 1.90), and myocardial infarction (HR = 1.56)], which might occur 14.5 years earlier than in those without sarcopenia[40]. The risk factor connecting T2DM and CVD is muscle strength, which is lower in the diabetic population, where the prevalence of sarcopenia ranges between 7% and 29.3% and is potentially associated with excess CVD risk[41,42]. The molecular mechanisms responsible for complications are still not fully understood. However, it seems that chronic inflammation and oxidative stress play significant roles in their development through the promotion of atherosclerosis[43]. Studies suggest that irisin can reduce markers of inflammation, such as tumor necrosis factor-alpha and IL-6, which are elevated in diabetes and contribute to CVD. Moreover, irisin could protect the heart by improving endothelial function and exerting anti-inflammatory and antioxidant properties[44]. In a study comparing 350 patients with coronary artery disease with 214 healthy participants, low irisin levels were characteristic of the prior, and inversely correlated with the severity of atherosclerosis expressed using a coronary atherosclerosis index[45]. A similar correlation was also found for carotid artery intima-media thickness. Both findings are mainly speculated to be driven by irisin's regulation of glucose and lipid metabolism, while another explanation lies in the cross-talk between irisin and molecules such as sclerostin and adipocytokines, involved in atherosclerosis[46,47]. Explanations for the direct irisin's effect on the prevention of atherosclerosis originate mainly from animal studies and are still controversial. They include the regulation of endothelial function, through suppression of inflammation and oxidation, activation of eNOS signaling, reduction of oxidative stress, inhibition of the generation of reactive oxygen species, and the nuclear translocation of NF-kB. In addition, irisin might also act on macrophages, slowing down plaque formation[19].

Although research is still in the early stages, there is evidence that irisin might prevent or reduce the severity of diabetic microvascular complications- nephropathy and retinopathy by promoting cellular repair and reducing inflammation[44,48]. Preliminary studies show irisin might also exert neuroprotective mechanisms, and promote nerve regeneration[48]. The production of irisin is largely triggered by muscle contraction during exercise. Regular physical activity that strengthens the muscles is expected to improve their function as an endocrine organ. Consequently, muscle-derived irisin could serve as a promising therapeutic target. However until the evidence is gathered from the large-scale prospective cohort studies validating the causal relationship between irisin levels and diabetic complications, irisin's true potential to prevent or treat vascular complications is speculative. Understanding the effects of different types of exercise on an individual level is crucial for optimizing and enhancing metabolic health.

IRISIN LEVELS IN AEROBIC, RESISTANCE, AND HIGH-INTENSITY TRAINING: IS IT TIME TO OPTIMIZE AND INDIVIDUALIZE EXERCISE TREATMENT FOR DIABETIC PATIENTS?

Studies exploring the effects of physical exercise on irisin levels have yielded varying results suggesting exercise type, intensity, and duration, besides an individual's age, sex, and fitness level, might be important factors influencing irisin levels[49]. Aerobic exercise increases FNDC5 expression, which leads to the irisin release. Long-term moderate-intensity aerobic training increases irisin levels, which might be an explanation for the way it influences body composition and insulin sensitivity[50]. In addition, endurance training leads to a significant increase in irisin serum levels in middle-aged/older individuals, which inversely correlates with the reduction of visceral fat[51].

Resistance training and skeletal muscle contraction can activate PGC-1α and consequently increase irisin production[52,53]. Evidence suggests that a single bout of resistance exercise causes significantly greater elevations in plasma irisin compared to those after endurance exercise alone or after the same duration of combined resistance and endurance exercises[53]. A recent meta-analysis involving only data available from randomized control trials with a control group and including 921 participants (64% in the intervention group) suggests that physical exercise significantly increases circulating irisin and at the same time decreases insulin, glucose, and IR. For patients with prediabetes and T2DM, the best results can be achieved with resistance and combined training[54]. Although there is limited research on the effects of high-intensity training on irisin production and release, it seems it may increase irisin levels in T2DM patients, regardless of the interval or continuous modality of training[55]. Utilizing findings on physiological irisin levels in the human population is crucial for assessing exercise-based therapies, considering variations in ethnicity, age, weight, sex, and metabolic status. A key challenge is separating the metabolic benefits of exercise-induced irisin from the energy expenditure it brings. Achieving therapeutic irisin levels may require more than exercise alone. Current alternatives include antidiabetic agents like metformin and GLP-1RA, which boost FNDC5 expression, and inorganic nitrate, as shown in studies with beetroot juice[56,57]. Future research should clarify how irisin is released and cleared during different types of exercise. This, together with better defining basal irisin levels, is a prerequisite for its potential therapeutic use[58-60] (Figure 1).

Figure 1 Exercise as a promotor of irisin, a potential key mediator of the beneficial effects of exercise on glucose metabolism, insulin sensitivity, and energy metabolism. CV: Cardiovascular; T2DM: Type 2 diabetes mellitus.

CONCLUSION

Irisin is emerging as a promising molecule in the context of sarcopenia and diabetes. Experimental evidence of effects on insulin sensitivity, fat browning, inflammation, and diabetic complications suggest that it could offer a novel approach to managing and mitigating the long-term effects of diabetes, Despite promising results from animal models, clinical studies in humans are still limited and give conflictive results. The exact mechanisms through which irisin exerts its beneficial effects and the optimal levels for the therapeutic potential need further investigation. Moreover, future research is required to determine whether strategies to increase irisin levels—such as physical exercise, pharmacological agents, or supplementation—could serve as an effective adjunct to conventional diabetes treatment.