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What are the mechanisms of insulin resistance? ​

Abstract ​

Insulin resistance is a critical pathological condition characterized by the diminished responsiveness of target tissues to insulin, playing a vital role in regulating glucose homeostasis. This phenomenon is a precursor to various metabolic disorders, particularly type 2 diabetes mellitus (T2DM) and cardiovascular diseases. As the prevalence of these conditions continues to rise globally, understanding the underlying mechanisms of insulin resistance has become increasingly important for developing effective therapeutic strategies. The significance of insulin resistance extends beyond its direct impact on glucose metabolism; it is intricately linked to a spectrum of health issues, including obesity, hypertension, dyslipidemia, and even neurodegenerative diseases like Alzheimer's disease. Research has revealed a complex interplay of genetic, environmental, and cellular factors contributing to insulin resistance. Genetic predispositions, such as mutations in insulin receptor substrates, play a foundational role, while environmental influences, including diet and physical activity, significantly affect insulin sensitivity. Cellular mechanisms, particularly those involving lipid metabolism, inflammation, and mitochondrial dysfunction, have emerged as crucial contributors. For instance, ectopic lipid accumulation in skeletal muscle and liver, coupled with endoplasmic reticulum stress and chronic low-grade inflammation, can lead to impaired insulin signaling. Obesity, a major risk factor, is associated with significant alterations in adipose tissue function, resulting in increased secretion of pro-inflammatory cytokines that exacerbate insulin signaling defects. Additionally, lifestyle choices such as physical activity and dietary habits play a pivotal role in modulating insulin sensitivity. Regular exercise enhances insulin action and improves glucose uptake, while diets high in saturated fats and sugars promote insulin resistance. This review synthesizes current research findings to enhance understanding of the multifactorial mechanisms underlying insulin resistance, paving the way for improved management and prevention of related metabolic disorders. The complexity of insulin resistance necessitates a multidisciplinary approach, integrating insights from genetics, physiology, and lifestyle interventions to develop effective therapeutic strategies.

Outline ​

This report will discuss the following questions.

  • 1 Introduction
  • 2 Definition and Importance of Insulin Resistance
    • 2.1 Definition of Insulin Resistance
    • 2.2 Epidemiology and Public Health Impact
  • 3 Mechanisms of Insulin Resistance
    • 3.1 Genetic Factors
    • 3.2 Environmental Influences
    • 3.3 Cellular Mechanisms and Signaling Pathways
  • 4 Role of Obesity and Inflammation
    • 4.1 Adipose Tissue Dysfunction
    • 4.2 Chronic Inflammation and Insulin Resistance
  • 5 Impact of Lifestyle Factors
    • 5.1 Physical Activity and Insulin Sensitivity
    • 5.2 Dietary Habits and Their Effects
  • 6 Therapeutic Approaches and Future Directions
    • 6.1 Current Treatments for Insulin Resistance
    • 6.2 Emerging Research and Potential Therapies
  • 7 Summary

1 Introduction ​

Insulin resistance is a critical pathological condition characterized by the diminished responsiveness of target tissues to insulin, which plays a vital role in regulating glucose homeostasis. This phenomenon is a precursor to various metabolic disorders, particularly type 2 diabetes mellitus (T2DM) and cardiovascular diseases. As the prevalence of these conditions continues to rise globally, understanding the underlying mechanisms of insulin resistance has become increasingly important for developing effective therapeutic strategies[1][2].

The significance of insulin resistance extends beyond its direct impact on glucose metabolism; it is intricately linked to a spectrum of health issues, including obesity, hypertension, dyslipidemia, and even neurodegenerative diseases like Alzheimer's disease[2][3]. This multifaceted nature underscores the need for a comprehensive exploration of the mechanisms contributing to insulin resistance, which can be broadly categorized into genetic, environmental, and cellular factors[4].

Research into the mechanisms of insulin resistance has revealed a complex interplay of various factors. Genetic predispositions, such as mutations in insulin receptor substrates, play a foundational role[5]. Environmental influences, including diet and physical activity, significantly affect insulin sensitivity[6][7]. Moreover, cellular mechanisms, particularly those involving lipid metabolism, inflammation, and mitochondrial dysfunction, have emerged as crucial contributors to the development of insulin resistance[8][9]. For instance, the accumulation of ectopic lipids in skeletal muscle and liver, coupled with endoplasmic reticulum stress and chronic low-grade inflammation, can lead to impaired insulin signaling[1][8].

Obesity, often considered a major risk factor for insulin resistance, is associated with significant alterations in adipose tissue function, leading to increased secretion of pro-inflammatory cytokines and free fatty acids that further exacerbate insulin signaling defects[7][10]. This inflammatory milieu not only disrupts insulin action but also contributes to the development of associated comorbidities, such as cardiovascular diseases[11][12].

In addition to these factors, lifestyle choices such as physical activity and dietary habits play a pivotal role in modulating insulin sensitivity. Regular exercise has been shown to enhance insulin action and improve glucose uptake in peripheral tissues, while a diet high in saturated fats and sugars can promote insulin resistance[3][13]. The impact of lifestyle modifications on insulin sensitivity highlights the potential for preventive strategies in at-risk populations.

This review will be organized into several key sections to provide a comprehensive overview of insulin resistance mechanisms. Following this introduction, we will define insulin resistance and discuss its epidemiological significance and public health implications. Subsequently, we will explore the genetic and environmental factors contributing to insulin resistance, alongside the cellular mechanisms and signaling pathways involved. The role of obesity and inflammation will be examined in detail, focusing on adipose tissue dysfunction and chronic inflammation. Additionally, we will assess the impact of lifestyle factors, including physical activity and dietary habits, on insulin sensitivity. Finally, we will review current therapeutic approaches and emerging research aimed at addressing insulin resistance, culminating in a summary that highlights potential areas for future investigation and intervention.

Through this synthesis of current research findings, we aim to enhance understanding of the multifactorial mechanisms underlying insulin resistance, thereby paving the way for improved management and prevention of related metabolic disorders. The complexity of insulin resistance necessitates a multidisciplinary approach, integrating insights from genetics, physiology, and lifestyle interventions to develop effective therapeutic strategies[2][10].

2 Definition and Importance of Insulin Resistance ​

2.1 Definition of Insulin Resistance ​

Insulin resistance is defined as a state in which insulin-targeting tissues exhibit reduced responsiveness to physiological levels of insulin. This condition is a pivotal pathogenic component of many metabolic diseases, particularly type 2 diabetes mellitus (T2DM) [1]. The mechanisms underlying insulin resistance are complex and multifaceted, involving various physiological and molecular factors.

One of the primary mechanisms of insulin resistance is ectopic lipid accumulation in tissues such as the liver and skeletal muscle. This accumulation disrupts normal insulin signaling pathways, leading to impaired glucose metabolism [1]. Additionally, endoplasmic reticulum (ER) stress plays a significant role in the development of insulin resistance, as it can induce inflammatory responses that further exacerbate insulin signaling defects [7].

Inflammation is another critical factor contributing to insulin resistance. Low-grade chronic inflammation is often associated with obesity and metabolic syndrome, leading to the release of inflammatory cytokines that interfere with insulin signaling [14]. These cytokines can impair the function of insulin receptor substrates (IRS) and disrupt downstream signaling pathways, resulting in decreased glucose uptake in insulin-sensitive tissues [6].

Oxidative stress, which arises from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses, is also implicated in insulin resistance. Increased oxidative stress can damage insulin signaling components and impair insulin action [8]. Mitochondrial dysfunction is another contributing factor, as it affects cellular energy metabolism and can lead to increased lipotoxicity [15].

The genetic predisposition of individuals can influence the development of insulin resistance. Genetic variations in insulin signaling pathways and the presence of specific polymorphisms have been associated with an increased risk of insulin resistance [5]. Moreover, lifestyle factors such as physical inactivity, poor diet, and excessive salt intake can exacerbate insulin resistance [16].

In summary, insulin resistance is characterized by a reduced response of insulin-targeting tissues to insulin, primarily due to mechanisms such as ectopic lipid accumulation, ER stress, inflammation, oxidative stress, and genetic predispositions. Understanding these mechanisms is crucial for developing effective therapeutic strategies to combat insulin resistance and its associated metabolic disorders [2][9][17].

2.2 Epidemiology and Public Health Impact ​

Insulin resistance is defined as a state of reduced responsiveness of insulin-targeting tissues to physiological levels of insulin, which plays a pivotal role in various metabolic diseases, including type 2 diabetes mellitus (T2DM) [1]. It is characterized by a decreased ability of insulin to induce glucose uptake by target tissues such as fat and skeletal muscle cells [18]. This condition is crucial to understand as it is often associated with obesity, cardiovascular disease, and other metabolic disorders, highlighting its significance in public health [19].

The mechanisms underlying insulin resistance are complex and multifactorial. Several credible theories have been proposed, which can be categorized into various pathways:

  1. Ectopic Lipid Accumulation: One of the primary mechanisms involves the accumulation of lipids in non-adipose tissues, such as the liver and skeletal muscle. This ectopic fat can disrupt normal cellular functions and insulin signaling pathways [1].

  2. Endoplasmic Reticulum Stress: Increased lipid accumulation can lead to stress in the endoplasmic reticulum, which is responsible for protein folding and processing. This stress can impair insulin signaling, contributing to insulin resistance [2].

  3. Inflammation: Chronic low-grade inflammation is a significant factor in the development of insulin resistance. This state is characterized by the activation of immune cells, which release pro-inflammatory cytokines that can interfere with insulin signaling [19].

  4. Mitochondrial Dysfunction: Obesity-related inflammation can lead to mitochondrial dysfunction, resulting in oxidative stress. This stress may further diminish insulin sensitivity by affecting cellular energy metabolism [2].

  5. Altered Hormonal Environment: Hormones such as catecholamines, glucocorticoids, and sex steroids can antagonize insulin action. Dysregulation of these hormones may lead to impaired glucose uptake and insulin resistance [20].

  6. Genetic Factors: Genetic predisposition also plays a role in insulin resistance. Variants in genes related to insulin signaling and metabolism can contribute to an individual's susceptibility to this condition [21].

  7. Environmental Influences: External factors such as diet, physical inactivity, and exposure to environmental toxins (e.g., heavy metals) have been implicated in the development of insulin resistance [22].

The epidemiology of insulin resistance is alarming, particularly given the rising prevalence of obesity and related comorbidities. In the United States and globally, obesity rates have increased significantly over the past few decades, contributing to a corresponding rise in insulin resistance and T2DM [19]. Insulin resistance is not only a precursor to T2DM but is also linked to cardiovascular disease, which has a profound impact on public health [6].

In conclusion, understanding the mechanisms of insulin resistance is essential for developing effective therapeutic strategies and public health interventions aimed at combating the growing epidemic of metabolic diseases. The interplay of genetic, environmental, and lifestyle factors underscores the complexity of insulin resistance and its far-reaching implications for health outcomes.

3 Mechanisms of Insulin Resistance ​

3.1 Genetic Factors ​

Insulin resistance is a complex metabolic condition characterized by a decreased ability of insulin to exert its biological effects, which is primarily linked to various genetic and environmental factors. The etiology of insulin resistance is multifaceted, involving both genetic predispositions and environmental influences that interact to affect insulin signaling pathways and glucose metabolism.

Genetic factors play a significant role in the development of insulin resistance. Numerous studies have indicated that genetic variations can influence insulin sensitivity, often leading to a predisposition to metabolic disorders such as type 2 diabetes and cardiovascular diseases. For instance, the genetic basis for common forms of insulin resistance is likely to be polygenic and heterogeneous, with moderate genetic influences observed in epidemiological and family studies [21]. Specific gene variants, including those associated with insulin action and lipid metabolism, have been identified as contributing factors to insulin resistance [23].

Research has also shown that insulin resistance can arise from genetic defects in insulin signaling pathways. These defects may manifest as mutations in genes encoding key components of the insulin signaling cascade, such as the insulin receptor and insulin receptor substrate proteins [24]. For example, a reduction in tyrosine phosphorylation of the insulin receptor and its substrates has been observed in insulin-resistant states, indicating impaired signaling capacity [25]. Furthermore, specific alleles related to insulin sensitivity have been identified, which can affect glucose disposal and contribute to the overall metabolic profile of individuals [26].

In addition to these direct genetic influences, there is evidence suggesting that genetic variations may also have pleiotropic effects, impacting multiple traits associated with insulin resistance, including obesity, dyslipidemia, and hypertension [27]. This interconnectedness underscores the complexity of insulin resistance as a syndrome that encompasses various metabolic abnormalities.

Moreover, the interaction between genetic factors and environmental triggers, such as diet and physical activity, is crucial in the manifestation of insulin resistance. Nutrient overload, particularly excess glucose and fat, has been implicated in the development of insulin resistance, further complicating the genetic landscape [28]. Genetic susceptibility may modulate individual responses to dietary composition, influencing the likelihood of developing insulin resistance [29].

In summary, the mechanisms of insulin resistance are deeply rooted in genetic factors that affect insulin signaling and metabolic pathways. These genetic predispositions interact with environmental factors, creating a complex web of influences that determine an individual's risk for developing insulin resistance and related metabolic disorders. Understanding these mechanisms is vital for developing targeted therapeutic strategies to combat insulin resistance and its associated health consequences.

3.2 Environmental Influences ​

Insulin resistance is a complex metabolic disorder characterized by a diminished response of target tissues to insulin, which is pivotal for glucose homeostasis. Various environmental influences contribute significantly to the development of insulin resistance, as highlighted in several studies.

One major environmental factor is the exposure to heavy metals. Research indicates that sustained, low-dose exposure to heavy metals can lead to hepatic insulin resistance. The human liver, being a primary site for heavy metal accumulation, may suffer long-term health impacts due to these exposures, which are not yet fully understood. Heavy metals can induce cellular dysfunction through altered signaling pathways, increased oxidative stress, and bioenergetic imbalances, all of which are known to exacerbate insulin resistance (Kumar et al., 2025) [22].

Another environmental contributor is dietary factors. Specific diets, particularly those high in unhealthy fats and sugars, can promote insulin resistance. The interplay between dietary habits and genetic predispositions is critical, as certain gene variants may influence how individuals respond to dietary intake, thereby affecting insulin sensitivity (López-Miranda et al., 2007) [29]. Additionally, the role of the gut microbiome, which can be influenced by diet and environmental exposures, is emerging as a significant factor in metabolic health, including insulin sensitivity (Johnson & Olefsky, 2013) [30].

Furthermore, pollutants in the environment, such as pesticides and industrial chemicals, have been increasingly recognized for their potential role in disrupting glucose metabolism. These pollutants can interfere with normal metabolic processes, leading to a decline in insulin sensitivity and contributing to conditions like type 2 diabetes and non-alcoholic fatty liver disease (Młynarska et al., 2025) [31].

Inflammation, often triggered by environmental stressors such as obesity and exposure to toxins, is another crucial mechanism linking environmental factors to insulin resistance. Chronic low-grade inflammation can impair insulin signaling pathways, thereby exacerbating insulin resistance (Thorsø Larsen et al., 2025) [10].

In summary, the mechanisms of insulin resistance are multifaceted and involve a complex interplay of environmental influences, including exposure to heavy metals, dietary habits, pollutants, and inflammation. Understanding these mechanisms is vital for developing effective prevention and treatment strategies for insulin resistance and its associated metabolic disorders.

3.3 Cellular Mechanisms and Signaling Pathways ​

Insulin resistance (IR) is a complex condition characterized by a reduced biological response to insulin, leading to impaired glucose uptake and metabolism. Various cellular mechanisms and signaling pathways contribute to the development of insulin resistance, particularly in the context of type 2 diabetes and metabolic disorders.

A primary mechanism involves the disruption of insulin signaling pathways. Insulin binds to its receptor, initiating a cascade of phosphorylation events mediated by key proteins such as insulin receptor substrates (IRS) and phosphatidylinositol 3-kinase (PI3K). However, in insulin-resistant states, these pathways can become impaired due to post-translational modifications, such as serine phosphorylation of IRS proteins, which inhibit their signaling capabilities [32].

Oxidative stress and inflammation are also significant contributors to insulin resistance. Increased production of reactive oxygen species (ROS) can lead to cellular stress, which impairs insulin signaling by affecting mitochondrial function and promoting inflammation. Inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), can activate pathways that further disrupt insulin receptor signaling [14][33]. For instance, cytokines can promote serine phosphorylation of IRS-1, thus diminishing its ability to mediate insulin signaling [33].

Additionally, lipotoxicity and glucotoxicity are critical factors in the development of insulin resistance. The accumulation of excess lipids in tissues such as muscle and liver can lead to the activation of inflammatory pathways and disrupt insulin signaling. Similarly, high levels of glucose can exert toxic effects on pancreatic beta cells, contributing to the decline in insulin secretion and exacerbating insulin resistance [6][34].

The interplay between genetic predispositions and environmental factors, such as high-salt diets, has also been shown to influence insulin resistance. Genetic variations in insulin signaling pathways may interact with dietary components to exacerbate insulin resistance, as observed in studies using Dahl rats [5].

Furthermore, recent research has highlighted the role of nuclear mechanisms in insulin resistance. Transcription factors involved in insulin action can be dysregulated, leading to altered gene expression that impacts insulin sensitivity. For example, the GSK3β-FBXW7-ERRα signaling axis has been implicated in the transcriptional regulation of insulin sensitivity [35].

In summary, insulin resistance is a multifaceted condition arising from disruptions in insulin signaling pathways, oxidative stress, inflammation, lipotoxicity, and genetic factors. Understanding these mechanisms is crucial for developing effective therapeutic strategies to combat insulin resistance and its associated metabolic disorders.

4 Role of Obesity and Inflammation ​

4.1 Adipose Tissue Dysfunction ​

Insulin resistance is a complex pathophysiological state characterized by a decreased response of insulin-targeting tissues to insulin, leading to metabolic dysregulation and an increased risk of conditions such as type 2 diabetes and cardiovascular diseases. A significant contributor to insulin resistance is obesity, particularly through the dysfunction of adipose tissue, which is associated with chronic low-grade inflammation.

Obesity leads to an expansion of adipose tissue, which in turn becomes dysfunctional. This dysfunction is marked by changes in adipocyte size and number, leading to an altered secretion profile of adipokines and cytokines. As adipocytes enlarge, they become hypoxic and stressed, which promotes the infiltration of macrophages into adipose tissue. These macrophages, along with other immune cells, secrete pro-inflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6, which have been shown to interfere with insulin signaling pathways. The increased expression of these pro-inflammatory cytokines is closely linked to systemic inflammation and insulin resistance[36][37].

Moreover, the accumulation of free fatty acids (FFAs) and reactive oxygen species (ROS) released from dysfunctional adipose tissue can lead to lipotoxicity, which further disrupts cellular function in non-adipose tissues such as the liver and skeletal muscle. This ectopic fat deposition can cause insulin resistance in these tissues by disrupting normal insulin signaling and glucose homeostasis[37][38].

Chronic inflammation resulting from obesity has been implicated as a key mechanism driving insulin resistance. Studies have shown that the inflammatory response can lead to anomalies in glucose and lipid metabolism, contributing to β-cell dysfunction in diabetes. This chronic inflammatory state alters endocrine variables and interferes with insulin signaling pathways, ultimately impairing glucose tolerance[38][39].

In addition to inflammation, the dysregulation of bioactive lipids within adipose tissue also plays a critical role in the development of insulin resistance. The accumulation of specific lipid species, such as ceramides and diacylglycerols, has been associated with the disruption of insulin signaling and the induction of insulin resistance. These lipids can interfere with insulin receptor signaling and promote inflammatory pathways, creating a vicious cycle that exacerbates metabolic dysfunction[40][41].

The interplay between obesity, inflammation, and insulin resistance highlights the importance of adipose tissue as both a source and a target of inflammatory mediators. The recognition of chronic inflammation in adipose tissue as a central mechanism underlying insulin resistance underscores the potential for therapeutic strategies aimed at reducing inflammation to improve insulin sensitivity and metabolic health[42][43].

4.2 Chronic Inflammation and Insulin Resistance ​

Insulin resistance is a critical pathophysiological state associated with obesity and is recognized as a major factor in the development of type 2 diabetes mellitus (T2DM) and other metabolic disorders. A significant body of research has elucidated the mechanisms by which obesity-induced chronic inflammation contributes to insulin resistance.

Obesity is characterized by excessive accumulation of adipose tissue, which triggers a state of chronic low-grade inflammation. This inflammation is primarily mediated by immune responses within adipose tissue, leading to the activation of pro-inflammatory pathways. Specifically, the recruitment and activation of macrophages in adipose tissue are pivotal in this process. These macrophages secrete various pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1, and IL-6, which have been shown to impair insulin signaling in target tissues, including muscle and liver [36][44].

The mechanisms through which inflammation induces insulin resistance involve several key pathways. Chronic inflammation in adipose tissue leads to the secretion of inflammatory mediators that disrupt insulin signaling pathways. For instance, pro-inflammatory cytokines can inhibit the phosphorylation of insulin receptor substrates, thereby reducing insulin's effectiveness in promoting glucose uptake [44][45]. Furthermore, inflammatory mediators can activate signaling cascades that promote endoplasmic reticulum (ER) stress and oxidative stress, both of which are known to impair insulin signaling [1][43].

Additionally, the accumulation of ceramides, a type of sphingolipid, has been identified as a significant factor linking inflammation and insulin resistance. Ceramides can disrupt insulin signaling by inhibiting the activation of Akt, a crucial protein in the insulin signaling pathway, thereby leading to decreased glucose uptake in insulin-sensitive tissues [41].

The relationship between obesity, inflammation, and insulin resistance is further complicated by the presence of ectopic fat deposition in non-adipose tissues such as liver and muscle. This ectopic fat accumulation can exacerbate the inflammatory response and contribute to insulin resistance [10]. In particular, the liver plays a central role in metabolic regulation, and hepatic insulin resistance is often associated with increased inflammatory signaling [22].

Overall, the interplay between chronic inflammation and insulin resistance underscores the importance of addressing inflammatory pathways in the treatment and prevention of obesity-related metabolic disorders. Therapeutic strategies targeting inflammation, such as anti-inflammatory agents, may provide new avenues for improving insulin sensitivity and managing metabolic diseases [39][42]. Understanding these mechanisms is crucial for developing effective interventions aimed at mitigating the adverse effects of obesity on insulin sensitivity and overall metabolic health.

5 Impact of Lifestyle Factors ​

5.1 Physical Activity and Insulin Sensitivity ​

Insulin resistance is a complex metabolic disorder characterized by a diminished ability of insulin to elicit its biological effects, primarily resulting in impaired glucose uptake in insulin-sensitive tissues such as skeletal muscle, adipose tissue, and liver. The mechanisms underlying insulin resistance are multifactorial, encompassing both genetic and environmental influences, with lifestyle factors, particularly physical activity, playing a crucial role.

Physical inactivity has been shown to significantly contribute to the development of insulin resistance. Sedentary behavior interferes with metabolic homeostasis, increasing the risk of various metabolic disorders, including type 2 diabetes mellitus (T2DM) (Yaribeygi et al. 2021). Regular physical activity enhances insulin sensitivity through several mechanisms. For instance, exercise promotes the translocation of glucose transporter type 4 (GLUT4) to the plasma membrane of muscle cells, facilitating glucose uptake independent of insulin signaling (Hawley & Houmard 2004). Furthermore, physical activity can induce beneficial changes in body composition, such as reductions in total and abdominal fat, which are associated with improved insulin sensitivity (Ryan 2000).

Moreover, different intensities of physical activity have varying impacts on insulin levels. High-intensity physical activity has been associated with significant reductions in insulin levels across different lipid indices and serum uric acid levels, suggesting that exercise intensity plays a critical role in modulating insulin sensitivity (Lin et al. 2022). In contrast, lower levels of physical activity may not provide the same benefits, highlighting the importance of engaging in regular, vigorous exercise to combat insulin resistance.

In addition to the direct effects of physical activity on insulin signaling pathways, lifestyle modifications, including dietary changes, are also vital in managing insulin resistance. Diets high in refined carbohydrates and saturated fats have been linked to increased insulin resistance, while diets rich in fiber may enhance insulin action (Bessesen 2001). The combination of exercise and a balanced diet can synergistically improve insulin sensitivity and overall metabolic health.

The pathophysiological mechanisms contributing to insulin resistance include alterations in insulin signaling pathways, increased free fatty acid levels, and changes in the expression of key metabolic enzymes. For example, the accumulation of biologically active lipids, such as diacylglycerols and ceramides, has been implicated in the disruption of insulin signaling (Imierska et al. 2020). Additionally, environmental factors, including exposure to pollutants and heavy metals, may further exacerbate insulin resistance by inducing oxidative stress and inflammation, which can impair insulin action (Młynarska et al. 2025; Kumar et al. 2025).

In summary, the mechanisms of insulin resistance are intricate and involve a combination of genetic predispositions, lifestyle factors, and environmental influences. Physical activity emerges as a pivotal modifiable factor that enhances insulin sensitivity through various biological pathways, while dietary interventions also play a significant role in managing this condition. Addressing both physical inactivity and dietary habits is essential for preventing and treating insulin resistance and its associated metabolic disorders.

5.2 Dietary Habits and Their Effects ​

Insulin resistance is a condition characterized by the diminished responsiveness of insulin-targeting tissues to physiological levels of insulin, which is a pivotal factor in the development of various metabolic diseases, including type 2 diabetes mellitus (T2DM) and cardiovascular diseases. The mechanisms underlying insulin resistance are multifaceted and involve a combination of genetic, environmental, and lifestyle factors, particularly dietary habits.

A significant contributor to insulin resistance is ectopic lipid accumulation in the liver and skeletal muscle. This accumulation leads to lipotoxicity, which can impair insulin signaling pathways, resulting in decreased glucose uptake and utilization in these tissues (Lee et al. 2022) [1]. Furthermore, endoplasmic reticulum (ER) stress, which can be exacerbated by unhealthy dietary habits, plays a crucial role in the pathogenesis of insulin resistance. Diets high in saturated fats and refined carbohydrates have been shown to increase insulin resistance, likely due to their effects on lipid metabolism and inflammation (Rupp 1992) [46].

Inflammation is another critical mechanism that contributes to insulin resistance. Chronic low-grade inflammation, often associated with obesity and unhealthy diets, can lead to the release of pro-inflammatory cytokines that interfere with insulin signaling (Kang et al. 2016) [7]. This inflammatory response can result in oxidative stress, further impairing insulin action by disrupting cellular signaling pathways.

The role of dietary habits in influencing insulin sensitivity is substantial. For instance, diets rich in trans fats and sugars can promote the development of insulin resistance through various biochemical pathways. Conversely, dietary interventions, such as the inclusion of weak organic acids, have been suggested to improve insulin sensitivity by altering the pH of interstitial fluids, thereby enhancing insulin receptor affinity (Marunaka 2023) [2].

Physical inactivity is also a lifestyle factor that significantly impacts insulin resistance. Sedentary behavior has been linked to increased insulin resistance, and regular physical activity is known to enhance insulin sensitivity by improving glucose uptake in muscle tissues (Hawley & Houmard 2004) [47].

In summary, the mechanisms of insulin resistance are complex and influenced by dietary habits, physical activity, and inflammatory processes. The interplay of these factors highlights the importance of lifestyle modifications, such as adopting a balanced diet and engaging in regular exercise, in preventing and managing insulin resistance and its associated metabolic disorders.

6 Therapeutic Approaches and Future Directions ​

6.1 Current Treatments for Insulin Resistance ​

Insulin resistance is a complex pathological condition characterized by the diminished responsiveness of insulin-targeting tissues to physiological levels of insulin, leading to impaired glucose metabolism and increased blood glucose levels. The mechanisms underlying insulin resistance are multifactorial and include several biological processes and pathways.

One significant mechanism is ectopic lipid accumulation in insulin-sensitive tissues, such as the liver and skeletal muscle, which disrupts insulin signaling pathways. This accumulation can lead to lipotoxicity, glucotoxicity, oxidative stress, and low-grade inflammation, all of which contribute to the development of insulin resistance (Mastrototaro & Roden, 2021) [48]. Inflammation plays a critical role, with inflammatory cytokines and reactive oxygen species being involved in the impairment of insulin signaling (Dali-Youcef et al., 2013) [14].

Moreover, chronic kidney disease (CKD) has been shown to induce insulin resistance through mechanisms such as increased inflammation, oxidative stress, and alterations in hormone levels, including elevated aldosterone and angiotensin II. These factors can degrade insulin receptor substrates, impairing insulin signaling and glucose metabolism (Dave et al., 2018) [17].

At the molecular level, insulin resistance is associated with defects in the insulin signaling pathway, particularly in insulin receptor signaling and post-receptor signaling events. The AGE-RAGE-NF-κB axis has been implicated as a critical pathway involved in insulin resistance, linking inflammation and oxidative stress to the dysfunction of pancreatic β-cells (Khalid et al., 2021) [6].

Therapeutic approaches to manage insulin resistance have evolved significantly, with a variety of strategies being employed. Lifestyle modifications, including dietary changes and increased physical activity, are fundamental in improving insulin sensitivity. Bariatric surgery has also been shown to reduce fat mass and enhance insulin sensitivity (Mastrototaro & Roden, 2021) [48].

Pharmacological interventions include older antihyperglycemic agents such as metformin and thiazolidinediones, which have been found to improve insulin sensitivity. Novel agents, including sodium-glucose cotransporter-2 (SGLT2) inhibitors and incretin mimetics, are also being explored for their potential to reduce insulin resistance (Lin et al., 2023) [9].

Looking towards the future, new therapeutic concepts are emerging, such as dual amylin and calcitonin receptor agonists (DACRAs), which may provide weight-independent insulin-sensitizing effects, thus addressing insulin resistance through multiple pathways (Larsen et al., 2025) [10].

In summary, the mechanisms of insulin resistance are complex and involve a combination of metabolic, inflammatory, and hormonal factors. Current treatments focus on lifestyle changes and pharmacological interventions, while future strategies may leverage novel drug candidates targeting the underlying mechanisms of insulin resistance.

6.2 Emerging Research and Potential Therapies ​

Insulin resistance (IR) is characterized by a diminished response of insulin-sensitive tissues to insulin, leading to impaired glucose uptake and a range of metabolic disorders, including type 2 diabetes mellitus. The mechanisms underlying insulin resistance are multifaceted and involve various biological pathways and environmental factors.

One of the primary mechanisms contributing to insulin resistance is ectopic lipid accumulation, particularly in the liver and skeletal muscle. This accumulation disrupts normal insulin signaling, leading to a state of lipotoxicity, which adversely affects insulin action (Lee et al., 2022) [1]. Additionally, endoplasmic reticulum (ER) stress plays a significant role in the pathogenesis of IR. When cells are overwhelmed by excessive nutrient intake, the ER becomes stressed, resulting in impaired insulin signaling and increased inflammatory responses (Mastrototaro & Roden, 2021) [48].

Chronic low-grade inflammation is another critical contributor to insulin resistance. Inflammatory cytokines and reactive oxygen species (ROS) produced during inflammation can interfere with insulin signaling pathways, exacerbating the condition (Dali-Youcef et al., 2013) [14]. Furthermore, factors such as oxidative stress, hypoxia, and alterations in gut microbiota also contribute to the inflammatory milieu that promotes insulin resistance (Zhao et al., 2023) [49].

At the molecular level, defects in the insulin signaling pathway, particularly involving insulin receptor substrate (IRS) proteins and the downstream AKT pathway, are pivotal in the development of insulin resistance. Insulin resistance has been associated with the dysregulation of these signaling proteins, which can be affected by various factors, including adipokines released from dysfunctional adipose tissue (James et al., 2021) [4].

In the context of chronic kidney disease (CKD), additional mechanisms of insulin resistance have been identified, including inflammation, oxidative stress, and metabolic acidosis. These factors can lead to the degradation of IRS proteins, further impairing insulin signaling (Dave et al., 2018) [17].

Emerging therapeutic approaches aim to target these underlying mechanisms of insulin resistance. Lifestyle modifications, including exercise and dietary changes, remain foundational in managing insulin sensitivity. Pharmacological interventions have also evolved, with several agents showing promise in improving insulin action. For instance, dual amylin and calcitonin receptor agonists (DACRAs) are being investigated for their ability to enhance insulin sensitivity through both weight-dependent and weight-independent mechanisms (Larsen et al., 2025) [10].

Moreover, traditional antihyperglycemic medications, such as metformin and thiazolidinediones, have been shown to exert insulin-sensitizing effects, addressing the multifactorial nature of insulin resistance (Khalid et al., 2021) [6]. Novel agents targeting specific pathways involved in insulin signaling are also under investigation, aiming to provide more effective treatment options for individuals with insulin resistance.

In conclusion, the mechanisms of insulin resistance are complex and involve interactions between metabolic, inflammatory, and genetic factors. Understanding these pathways is crucial for developing targeted therapeutic strategies that can effectively address insulin resistance and its associated complications. The ongoing research in this area continues to unveil new potential therapies that may enhance insulin sensitivity and improve metabolic health.

7 Conclusion ​

The exploration of insulin resistance has unveiled a multifaceted condition characterized by a reduced response of insulin-targeting tissues to insulin, which is pivotal in the development of metabolic disorders such as type 2 diabetes mellitus and cardiovascular diseases. Key findings highlight the significant role of genetic predispositions, environmental factors, and lifestyle choices in modulating insulin sensitivity. The mechanisms contributing to insulin resistance include ectopic lipid accumulation, chronic inflammation, oxidative stress, and mitochondrial dysfunction, each playing a critical role in disrupting insulin signaling pathways. Furthermore, the interplay between obesity and inflammation underscores the importance of addressing these factors in therapeutic strategies. Current interventions primarily focus on lifestyle modifications and pharmacological treatments aimed at enhancing insulin sensitivity. Looking forward, future research should emphasize the development of novel therapeutic approaches that target the underlying mechanisms of insulin resistance, as well as preventive strategies that incorporate lifestyle changes to mitigate the rising prevalence of related metabolic disorders. A comprehensive understanding of these mechanisms is essential for devising effective management strategies and improving public health outcomes in the context of insulin resistance and its associated conditions.

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