Effects of Psychological Stress on Insulin Resistance
Abstract
Psychological stress is a significant risk factor for insulin resistance, ergo a risk factor for Type II diabetes mellitus. Understanding how stress plays a role in insulin resistance would be valuable in gaining more insight into diabetes and feasible preventative and therapeutic approaches. This comprehensive literature review aims to explain the multifaceted mechanisms of insulin resistance and how the hypothalamic-pituitary-adrenal axis correlates stress to insulin resistance. Clinical data is examined to recognize stress in the context of insulin resistance and possible preventative measures to reduce insulin resistance by reducing stress. The mechanisms and clinical data were gathered from recent relevant studies and well-known medical journals. Studies involving non-human primates, observational analyses, and interventional trials highlight the impact of stress on insulin sensitivity and the subsequent risk of diabetes. The review then delves into clinical evidence that substantiates cognitive behavioral therapy as a pivotal psychological intervention in mitigating stress-induced insulin resistance in adolescent and adult populations. Reducing psychological stress offers a promising solution to alleviate stress-induced insulin resistance to the existing treatments for diabetes. However, further research in age-dependent mechanisms of insulin resistance and refinement of stress-reducing applications is necessary.
Introduction
Diabetes affects approximately 529 million people globally, and this number is predicted to soar to 1.31 billion by 2050 [1]. Type II diabetes mellitus (T2DM) usually occurs in the later stages of life and is primarily characterized by insulin resistance that precedes its onset by 10 to 15 years [2]. Insulin resistance entails impaired glucose uptake in target tissues from the bloodstream, including skeletal muscle, liver, and adipose tissue. It is exacerbated by long periods of increased blood glucose. Various factors like stress, obesity, sedentary lifestyle, high blood pressure, and family history contribute to it, with psychological stress being a notable, yet often overlooked cause. Psychological stress is defined as the reaction to mental, physical, or environmental pressure caused by stressors that can arise from the various social roles people have [3]. Stress and insulin resistance are closely intertwined via the hypothalamic-pituitary-adrenal (HPA) axis, a neuroendocrine mechanism that links perceived stress to physiological responses by meticulously controlling metabolism [4]. Taking a closer look at the nuanced influences of stress on insulin resistance can be an important step in further understanding preventative measures for T2DM. This review will examine the known mechanisms of insulin resistance, shed light on the factors contributing to it, and specifically discuss how psychological stress influences the risks associated with insulin resistance.
Insulin Resistance: Physiology and Pathophysiology
Extensive research on the pathophysiology of insulin resistance has meticulously characterized its underlying mechanisms. Skeletal muscle, adipose tissue, and liver are the three dominant organs for glucose uptake and circulation [2,5,6]. A well-appreciated mechanism of glucose metabolism involves insulin release by pancreatic β-cells in response to glucose intake, promoting anabolism and uptake of glucose by glucose-consuming tissues [5]. This response is mediated by Insulin Receptor Tyrosine Kinase (IRTK), a type of receptor tyrosine kinase specific to insulin. Initially, insulin binds to the monomeric receptor of IRTK, which initiates downstream cell signaling [5]. The subsequent downstream signaling pathways play varying roles in the distinct target tissues. In skeletal muscle and adipose tissue, insulin signaling increases the translocation of glucose transporter type 4 (GLUT4) to the plasma membrane, facilitating glucose uptake [5]. In the liver, the main role of insulin is to repress gluconeogenesis, a metabolic process that produces glucose from non-glucose precursors, by inhibiting the gene expression of the anabolic enzymes involved [5]. However, this finely tuned system can be disrupted. Insulin resistance compromises these downstream mechanisms, resulting in reduced glucose uptake and elevated blood glucose levels.
Because they are primary sites of glucose metabolism, the three primary sites of insulin resistance are skeletal muscle, adipose tissue, and liver. Insulin resistance is defined as reduced sensitivity to high levels of insulin in insulin-targeting tissues [2,5,6]. In skeletal muscle and adipose tissue, insulin resistance reduces the translocation of GLUT4, thus inhibiting glucose uptake [5,6]. In the liver, insulin resistance causes the derepression of gluconeogenesis. Consequently, further hepatic glucose production exacerbates the increased blood glucose in addition to the lack of uptake by skeletal muscle and adipose tissue [5]. Additionally, in adipose tissue, insulin resistance is associated with the inability to suppress lipolysis, increasing free fatty acid (FFA) circulation in the bloodstream. Increased FFA concentration exacerbates insulin resistance in the liver and skeletal muscle via beta-cell dysfunction that is induced by lipotoxicity [2]. While insulin resistance is potentially linked to defective IRTK kinase activity, there is limited understanding of its causes.
The question revolving around the precise mechanism of insulin resistance is unsettled, with several proposed theories shedding light on different aspects. One such theory involves the lack of IRTK surface content and kinase activity, explaining insulin resistance across the target tissues [7]. Another potential mechanism includes functional IRTKs but defects in the downstream signaling proteins, such as GLUT4, resulting in impaired insulin-stimulated glucose uptake in skeletal muscle and adipose tissue [7]. While the first pathway is primarily seen in obese or diabetic populations, there is still a lack of detailed understanding of how being obese or diabetic leads to IRTK defects [2,5,6,7]. Conversely, the second pathway is explained from a genetic standpoint where genetic mutations lead to loss-of-function of downstream proteins, impairing glucose uptake [7]. In addition to these cellular pathways, it is crucial to acknowledge the role of hormones and the HPA axis in insulin resistance, a factor commonly overlooked. Understanding this mechanism will provide a more comprehensive perspective on the multifaceted nature of insulin resistance.
One metabolic pathway controlled by the HPA axis involves glucocorticoids, a group of catabolic steroid hormones secreted by the adrenal cortex that regulate glucose, protein, and fat metabolism in the body [8]. Glucocorticoids are primarily released in response to stress and play diverse roles that significantly impact the risk of insulin resistance. Prolonged exposure to these hormones can lead to the breakdown of skeletal muscle. Since skeletal muscle is a primary organ responsible for glucose uptake, elevated glucocorticoids lead to a substantial decrease in glucose uptake [8]. Moreover, in adipose tissue, glucocorticoids increase fat metabolism and mobilization. This causes increased FFA and an excess relocation of fat deposits, exacerbating insulin resistance [8]. In addition to these well-known impacts of glucocorticoids, they also indirectly contribute to impaired glucose uptake by binding to their receptors on pancreatic β-cells, inhibiting insulin secretion. Insulin resistance is further escalated by cortisol, a type of glucocorticoid, which enhances hepatic glucose production, impairs glucose uptake in skeletal muscle, and increases free fatty acid levels in the bloodstream by increasing lipolysis in adipose tissue [9]. The intricate interplay between the HPA axis and glucocorticoids, and their effects on metabolism highlights the pivotal role glucocorticoids play in developing insulin resistance. Now, it is imperative to explore the link between these metabolic disruptions and the underlying factor that triggers glucocorticoid release—stress.
Psychological Stress: Pathophysiology
As a complex interaction of psychological and physiological responses, stress has long captivated the attention of researchers. Despite being a pertinent concern, stress lacks a universally accepted definition. For the purpose of this review, stress is considered as an individual's response to challenges that exceed their coping mechanisms [10]. Given this definition of stress, we can investigate how this psychological phenomenon translates into the physiological domain. An individual’s direct physiological response to experiencing stress is the release of cortisol from the adrenal gland, which is regulated by the HPA axis. In healthy individuals who experience normal levels of stress, a negative feedback loop maintains a homeostatic equilibrium of cortisol. Specific receptors in the hypothalamus and anterior pituitary detect and decrease its production if cortisol levels are elevated [11]. However, under conditions of heightened stress, the HPA axis becomes hyperactivated, resulting in the overstimulation of cortisol release and subjecting bodily tissues to increased concentrations of the hormone [11]. This excessive cortisol production has a multitude of consequences in the body, one of which is contributing to the emergence of insulin resistance.
Cortisol directly functions to counteract the physiological effects of insulin, thereby fostering whole-body insulin resistance. There are two primary avenues by which cortisol accomplishes this. First, in skeletal muscle, cortisol enhances muscle protein breakdown. In the liver, it promotes hepatic gluconeogenesis. In both, it reduces glucose utilization, broadly resulting in elevated glucose concentrations [11,12]. Thus, elevated cortisol levels lead to excessively high blood glucose levels, enough to be considered hyperglycemic, or having high blood glucose [12]. Interestingly, in adipose tissue, cortisol stimulates both insulin sensitivity and resistance. On one hand, it amplifies visceral adipogenesis, or the formation of adipose tissue, which also contributes to obesity. On the other hand, it enhances the release of FFAs in the bloodstream, as seen in insulin resistance [12]. This juxtaposing phenomenon seen in adipose tissue has yet to be defined thoroughly, implying the need for further research. However, it can be conclusively stated that elevated levels of cortisol are directly responsible for hyperglycemia, a consequence of insulin resistance. Both cortisol-induced hyperglycemia, as well as elevated cortisol, present significant risks to the onset of insulin resistance by mechanisms that antagonize insulin's intended functions.
Stress and Insulin Resistance: Clinical Data Insights
Stress has emerged as a significant risk factor for insulin resistance, with a growing body of clinical evidence supporting its causal relationship with metabolic health. In a non-human primate model, Silverstein-Metzler et al. introduce macaques to study chronic psychosocial stress and its direct correlation with insulin resistance. In this study, 42 middle-aged female macaques were subject to selective serotonin reuptake inhibitors (SSRIs) to establish a baseline for depressive behaviors [13]. Then, they were randomly stratified into a subordinate and dominant group. For 3 years, they were subjected to a Western-like synthetic diet containing 44% of calories from fat and 0.29 mg/Cal cholesterol [13]. The social subordinates showed greater insulin resistance and higher incidences of clinically impaired carbohydrate metabolism [13]. This finding demonstrates a clear link between social stratification stress, cortisol levels, and increased insulin resistance. Building on this, Wang et al. reveal an independent association with an increased risk of subsequent diabetes development in 224,534 in-patients [14]. Patients with bacteremia, the presence of bacteria in the bloodstream, and nonbacteremia, with stress hyperglycemia had a higher incidence of T2DM independent of age, sex, comorbidity, and other serological markers [14]. These studies establish not only that stress leads to hyperglycemia but it can also directly cause long-term diabetes, in addition to increasing insulin resistance [13,14]. From these studies, a direct correlation between psychological stress and insulin resistance can be seen, where stress has a direct impact on insulin resistance.
The next step to further understanding this complex relationship is to see how manipulating stress impacts insulin resistance. The study by Liu et al. delves into the hormonal mechanisms underlying stress-induced insulin resistance where 34 adult males are allowed to sleep for only 4 hours a night for 4 nights in a row [15]. They were under two randomly assigned conditions: cortisol and testosterone clamp (fixed levels), and no clamp (placebo) [15]. The findings from the placebo group show that sleep restriction alone decreases insulin sensitivity due to a rise in cortisol. The group with the dual clamp showed alleviated development of insulin resistance [15]. This study not only provides a direct link between elevated cortisol levels and insulin resistance but also shows that not increasing cortisol can reduce insulin resistance. Shomaker et al. further explore the relationship between depression and insulin sensitivity in adolescent girls at risk for T2DM. Participants were randomly assigned to a cognitive behavioral group (CB) or a health education group (HE). Baseline and post-intervention depressive symptoms were tested and oral glucose tolerance tests (OGTT) were conducted for insulin sensitivity and beta-cell function [16]. Both CB and HE groups showed significant decreases in depressive symptoms with the CB group having better results [16]. Decreases in depressive symptoms showed lower-than-baseline cortisol levels, but did not display any statistically significant improvement in insulin resistance [16]. These studies underscore the importance of reducing psychosocial stress as a potential preventative measure against T2DM [15,16]. Since cognitive behavioral therapy (CBT) effectively reduces cortisol levels, it may be a valuable approach to preventing or managing insulin resistance, and consequently, T2DM.
In light of CBT as a preventative measure, it is imperative to explore how insulin resistance is influenced when the intervention is implemented earlier versus later in life. The study by Gulley et al. contributes valuable insights into using CBT by demonstrating an indirect link between CBT, depression reduction, and insulin resistance in adolescent females. This research used the same design and data from the study by Shomaker et al. (CB vs. HE groups). The outcomes on changes in BMI, insulin resistance, fasting, and 2-hour insulin from immediately after post-treatment up to 1 year were measured [17]. 1-year fasting insulin decreased significantly by 1 mIU/ml in participants with elevated baseline levels of depression [17]. Examining the adolescent population in more detail, Miri et al. specifically target the effects of CBT on overweight and obese individuals. This study recruited 110 adolescents who were greater than or equal to a BMI of 85th percentile for age and gender [18]. The researchers made sure to factor out any participants who were overweight due to an extrinsic condition such as hypothyroidism, etc. In a 6-month follow-up after CBT, the nutritional status showed significant improvements, alongside BMI, showing statistically significant improvement where the z-score went from 2.18 to 2.09 [18]. These two studies establish a direct correlation between CBT and a significant decrease in BMI, providing compelling evidence for the potential of psychological interventions in reducing obesity-related insulin resistance in a younger demographic [17,18]. While these studies were performed on adolescents, Lores et al. expand the focus to adults and investigated the direct impact of CBT on depression and obesity. 24 adult participants with a mean age of 46 who were positively screened for depression and a BMI greater than or equal to 25 were recruited for a 10-week study that involved 2-hour group therapy sessions each week [19]. The study did not show significant weight reduction, however, it highlighted a substantial improvement in depression symptoms and overall health behaviors [19].
Collectively, there is compelling evidence that CBT is an effective technique to improve depressive symptoms and alleviate stress. The studies provide robust clinical data supporting the notion that psychological stress plays a substantial role in the development of insulin resistance and, consequently, the heightened risk of T2DM [13-18]. The evidence presented highlights the importance of addressing stress as a crucial component of preventive and therapeutic strategies for insulin resistance in adolescents [16-18]. However, this relationship is not universally applicable when considering adults, despite the studies showing small sample sizes. Although CBT demonstrates efficacy in improving depressive symptoms and stress, there is no sign of progress in terms of alleviating insulin resistance or its downstream consequences [19]. Despite the nuanced effects on insulin resistance in adults, CBT has overall positive outcomes in alleviating depressive symptoms in adults and adolescents, alongside its role in mitigating insulin resistance in the younger demographic. This optimistic outlook emphasizes the importance of considering stress not only as a crucial risk factor for insulin resistance and T2DM but also as a viable prophylactic measure for such metabolic syndromes.
Conclusion
Insulin resistance primarily manifests in skeletal muscle, adipose tissue, and the liver, resulting from impaired glucose uptake caused by defective insulin receptors or hindrances in the translocation of GLUT4 transporters. The consequences of insulin resistance encompass elevated blood glucose levels and increased circulating FFA. An often-overlooked contributor to insulin resistance is stress. In response to stress, the HPA axis produces cortisol, further amplifying insulin resistance by increasing glucose production, promoting protein breakdown, and elevating FFA concentration in the bloodstream. Some studies provided conclusive evidence that stress-induced hyperglycemia is a risk factor in insulin resistance and the subsequent development of T2DM and reducing stress via CBT can lead to improvements in insulin resistance in adolescents [13-18]. However, studies performed with adults found no association between lowered stress levels and insulin resistance [19]. With that being said, further research into the mechanisms of stress-induced insulin resistance and age-related differences in stress response is necessary to enhance the understanding of the complex relationship between stress and insulin resistance, potentially leading to more targeted, effective, and less invasive interventions for preventing insulin resistance and its associated health risks.
About the Author: Ishaan Gupta
Ishaan Gupta is a third-year Neurobiology, Physiology, and Behavior undergraduate student at UC Davis with an interest in preventative medicine, specifically involving diseases and disorders that are prevalent in the South-Asian community, such as diabetes. This is the reason he chose to write about diabetes and a niche cause—stress in his UWP 104F class. He wants readers to walk away with a better understanding of how stress and diabetes are connected, pushing for more research and getting healthcare personnel to think about stress management as a preventative measure for diabetes. Being passionate about medicine, Ishaan volunteers at Shifa Community Clinic as a monitor and is a part-time EMT. In his free time, he enjoys working out, playing badminton, watching movies, and sleeping.
Author's Note
This formal scientific literature review was written in response to the culminating assignment of Dr. Sarah Faye’s UWP104F (Writing in the Health Sciences) class. I chose to write about stress-induced diabetes because diabetes is a prevalent and escalating global health concern, and understanding its multifaceted causes is essential for effective prevention and management. Stress, often a pervasive aspect of modern life, has been increasingly recognized as a potential contributor to various health issues, including diabetes. This review highlights the link between stress and diabetes, specifically focusing on stress-induced insulin resistance, and is intended for fellow students, academics, and healthcare professionals who want a detailed take on how stress might affect type 2 diabetes mellitus. I would like to express my sincere gratitude to Professor Faye for granting me the opportunity to write this piece and for her invaluable expertise in guiding me through the approach and structure of my review.
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