Cortisol and Cardiometabolic Disease: A Target for Advancing Health Equity

INTRODUCTION: Stress and Cardiometabolic Disease

In the past two decades, strides have been made in the improvement of cardiometabolic disease which include the widespread use of statins and the development of Proprotein convertase subtilisin/kexin type 9 serine protease (PCSK-9) inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors [1-3]. However, cardiovascular disease (CVD) remains the leading cause of death in the United States (US) with recent increasing trends in mortality [4,5]. Further, cardiovascular risk factors including obesity, diabetes, hypertension continue to burden large swaths of the US and world population. Obesity rates in children (in children ages 2-19 years) continue to rise over the past two decades [6], CVD and diabetes remains consistently in the top ten causes of mortality in the US [5,7]. Therefore, it is critical to elucidate underlying mechanisms that provide novel targets for therapeutic intervention and/or biomarkers for risk prediction and progression in cardiometabolic disease.

For decades it has been demonstrated that stress, traumatic experiences, and environment impact cardiometabolic disease development and outcomes [8,9]. For example, psychosocial stress in the forms of work and perceived stress have been associated with CVD and diabetes risk in large population cohorts [10]. Early childhood adversity including experiences of abuse and neglect may particularly contribute to higher odds of CVD, obesity, and diabetes in adulthood [11]. Prenatal stress experienced by mothers may increase the risk of metabolic dysregulation with potential risk of diabetes in offspring [10]. Physical stress placed on the body through toxic environments including those with greater pollutants may also increase CVD risk [8]. Not all forms of stress are perceived but may still be internalized, due to daily exposure as in the case of interpersonal, historical and structural racism [12-14]. Structural racism and discrimination may exacerbate inequities through many pathways including neighborhood segregation with both individual and environmental (pollutant and other) exposures that yield greater risk for poor cardiometabolic outcomes [13-15] (Figure 1).

Figure 1. The Multi-factorial, Multi-system Impacts of Racism on the Mechanisms Underpinning Cardiometabolic Disease Risk and Outcomes.

Racism at multiple levels (interpersonal, institutional, structural) may impact cardiometabolic disease risk and outcomes through convergance on stress physiology. Racism contributes to chronic stress, neighborhood inequities, and environmental contirbutors to endocrine disruption that have multi-system impacts (neurobiological and neuroendocrine, epigenetic, and immune. These converging pathways then contribute to dysregulated glycemic control, cholesterol metabolism, and vascular regulation impacting risk for diabetes, obesity, dyslipidemia, hypertension, and cardiovascular disease outcomes.

The underpinnings and clinical significance of the link between stress and cardiometabolic disease are only recently coming into focus [9]. Allostatic load is a biological mechanistic framework, conceptualized as multi-system cumulative “wear and tear’ on the body from chronic stress, that may partially explain the contribution of stress and environmental factors to the onset of cardiometabolic disease [16]. Allostatic load exemplifies how “stress” is more nuanced than acute or chronic, which is relevant to the degree and mechanism of physiological dysregulation [17]. For example, stress may be “positive”, “tolerable”, or “toxic” [13, 14].

While the backbone of the toxic stress (Box 1) and allostatic load models is stress neurophysiology through the hypothalamic-pituitary-adrenal (HPA) and sympathetic-adrenal-medullary axes, downstream effects are driven through adrenal hormones including cortisol [19]. Thus, adrenal hormones as the biological mediators of stress and potential mediators of cardiometabolic disease burden and outcomes warrant further investigation.

Text Box 1. Understanding Toxic Stress.

Stress may be “positive”, “tolerable”, or “toxic” [13, 14]. “Positive stress” is essential for personal development and growth, and is often short-lived, “tolerable stress” may be more intense or prolonged, such as the loss of a loved one, but is able to be overcome with support, and “toxic stress” is most intense and is defined by propagating a chronic deviation from physiological homeostatic baseline, regardless of the duration of exposure [17,18].

CORTISOL

Stress & Cortisol Physiology

Cortisol is a core hormonal mediator of allostatic load and chronic stress [20,21]. When a stressor is experienced, it propagates through the HPA axis commencing with the release of corticotrophin releasing hormone (CRH) at the paraventricular nucleus of the hypothalamus then traveling to the anterior pituitary stimulating the release of adrenocorticotrophic hormone (ACTH) [20]. ACTH is released into the periphery ultimately resulting in increased production of cortisol by the zona fasciculata of the adrenal gland [20]. Cortisol levels rise and follow in a diurnal rhythm with the highest levels 30-45 minutes post awakening and then falling throughout the day, both acute and chronic stress may result in dysregulation of this diurnal rhythm [20], potentially impacting HPA axis negative feedback [20].

“Toxic stress”, (Box 1) specifically, has been consistently associated with dysregulated physiology including diurnal cortisol [17]. Evidence suggests that chronic or toxic stress exposure in childhood has an especially pronounced effect on cortisol patterns throughout life, especially among those with certain HPA-axis gene variants [22]. Toxic stress and associated cortisol dysregulation may originate in childhood after exposure to abuse or challenges in the household environment, like a caregiver who has mental illness or is incarcerated [13, 14]. However, antecedents that propagate a “toxic stress” response can also occur throughout the life course, such as exposure to intergenerational racism and discrimination [23-25], and/or to hazardous environmental chemicals, often as a result of structural racism [26]. Further, internalized racism can directly impact stress neurobiology including the processing centers of the brain (prefrontal cortex, for example), and the stress axis (HPA), as well as the sympathetic control which interacts with cardiovascular regulation (e.g. blood pressure) [27,28] (Figure 1). Additionally, acute experiences of racism, as through an experience of racial exclusion from social engagement, specifically perturbs cortisol release, which is mediated by lower perceived control [29].

The link between toxic stress and cortisol may explain at least part of the mechanisms for disparities in cardiometabolic outcomes. For example, suppressed (lower levels of) morning cortisol has is associated with multiple measures of adiposity including BMI, waist circumference, and leptin [30], and a robust (steep) cortisol awakening response and flatter late decline slope are associated with higher odds of incident diabetes among White, but not Black individuals [31]. Though these findings warrant further research, it is possible they underpin physiological differences in cardiometabolic disease risk manifesting as a result of the impacts of racism on stress physiology. The link between toxic stress and cortisol may also play a role in cardiometabolic comorbidities. For example, chronic stress is a major risk factor for the development of anxiety and depression, which is particularly comorbid with CVD and diabetes [9], linked by dysregulated HPA and cortisol physiology [20].

Cortisol is thought to partially mediate the deleterious effects of stress on health. However, other neuroendocrine factors may contribute to cortisol regulation and warrant consideration in future studies. For example, a relationship between glucocorticoid-associated epigenetic modifications and hormonal regulation of estrogen has been observed, which may be associated with sex-specific expression of glucocorticoid-associated genes [32]. Additionally, there is increasing focus on the importance of cortisol’s 24-hour (diurnal) rhythm rather than its absolute levels throughout the day. The cortisol rhythm is intricately linked with the molecular circadian clock system. In their extensive review of the significance of the circadian glucocorticoid dynamics, Oster et al. summarized accumulating evidence that misalignment between the body’s central and peripheral circadian clock systems has numerous adverse metabolic consequences [33]. Regulatory regions of several molecular clock genes contain glucocorticoid response elements and are phase shifted by cortisol. This is particularly important for populations who experience impaired sleep such as shorter sleep duration, as has been observed in those who identify as Black/African American, or those with a history of childhood experiences of trauma with further disparities (higher frequency of short sleep) in those who also identified as non-White [34,35].

Cortisol & Cardiometabolic Risk

Cortisol plays a critical role in cardiometabolic disease pathophysiology and risk as summarized in Figure 2. In the extreme, this is best exemplified by Cushing’s disease and syndrome, both categorized by hypercortisolism, originating from pituitary tumors (disease), adrenal tumors, or exogenous hypercortisolism (medication). Cushing’s is associated most commonly with features of metabolic syndrome including insulin resistance, abnormal fasting glucose levels, hypertension, obesity and dyslipidemia [36]. Highlighting the contribution of cortisol in cardiometabolic morbidity and mortality, the leading causes of death in Cushing’s disease are cardiovascular (myocardial infarction), uncontrolled diabetes, and associated complications [37]. However, recent work demonstrates an association between milder forms of cortisol dysregulation and diseases such as obesity, diabetes and cardiovascular disease, specifically.

Figure 2. Cortisol Physiology and Cardiometabolic Disease.

Animal and translational research has suggested that cortisol impacts multiple bodily systems that may increase risk for clinical manifestations of cardiometabolic disease. For example, elevated cortisol impacts blood vessel endothelium which may increase risk for hypertension. Over-expression of 11β-hydroxysteroid dehydrogenase type 1 (11B-HSD1), the enzyme that activates cortisone to cortisol, may contribute to a diabetic phenotype increased fat mass, decreased energy expenditure, and dyslipidemia. Specifically in hepatic tissue, it may impair metabolism along with 17-hydrosyprogesterone (17-OHP), which contributes to the conversion of cholesterol to cortisol and potentially induces glucocorticoid receptor activation leading to hyperglycemia, in part through hepatic gluconeogenesis, and insulin resistance.

Cortisol & Adiposity

Dysregulation of cortisol is associated with obesity both in pathophysiological hypercortisolism (Cushing’s disease and syndrome), and also in studies of diurnal cortisol dysregulation in more clinically heterogeneous populations. While it is known that a key clinical feature of Cushing’s is central adiposity [36], milder forms of cortisol diurnal rhythm dysregulation are also associated with obesity. For example, in the Multi-Ethnic Study of Atherosclerosis, both lower morning cortisol and flatter early decline slopes were associated with body mass index (BMI) and waist circumference (WC) [38]. It was similarly observed in the Jackson Heart Study that lower morning serum cortisol was associated with WC and BMI such that a 1-standard deviation higher adiposity metric related to a ~3-4% lower cortisol, respectively [30]. Notably, cortisol was also associated with adipokines including higher leptin and leptin:adiponectin ratio [30]. Longitudinal studies performed in MESA corroborated the previous cross-sectional findings [39]. In evaluating BMI 7 years prior to salivary cortisol diurnal curves, a 1% higher annual BMI change was associated with a 3% lower wake-up and 3% lower total area-under the curve cortisol, while baseline cortisol had no associations with later BMI. Interestingly, among participants with BMI ≥30 kg/m², a more positive late decline slope (flatter) was associated with increasing BMI over 6 years. Taken together, individuals with normal BMI may not see an association of mild-moderate perturbations in cortisol diurnal rhythm with changes in adiposity over time, but animal studies suggest significant flattening of diurnal cortisol can drive fat cell hypertrophy and adipose tissue expansion, as well as hyperinsulinemia [40]. Additionally, the association between cortisol and adiposity in large clinical studies may not be linear as demonstrated in the Whitehall II study. In this study, both those in the highest and lowest categories of BMI had the flattest diurnal slopes [41]. Therefore, longitudinal observational studies and clinical trials, are needed to elucidate the precise mechanisms and time point where adipose and pancreatic tissue is pushed from maintaining balance into pathophysiologic regulation due to allostatic load (cortisol) (Figure 3). Further understanding of the cascading short and long-term mechanistic processes would accelerate the development of therapeutics to ameliorate obesity and disrupt the stress-obesity linkage.

Figure 3. Chronic Stress Dysregulation, Adiposity, and Dysglycemia.

The accumulation of stress may have subclinical detrimental interaction effects with physiologic regulatory systems of adipose tissue and glycemic control that, with time, may manifest in clinical disease risk and outcomes. For example, individuals with normal BMI may not see an association of mild-moderate perturbations in cortisol diurnal rhythm with changes in adiposity over time, but chronic activation of the stress response and dysregulation of the cortisol diurnal curve (e.g., allostasis), or interactions of dysregulated cortisol patterns in obese individuals may induce pathophysiological outcomes such as insulin resistance and potentially ultimately cross the clinical threshold to manifest as diabetes. This is supported by animal studies suggesting significant flattening of diurnal cortisol can drive fat cell hypertrophy and adipose tissue expansion, as well as hyperinsulinemia. Importantly, the interaction between cortisol and dysglycemia may be bidirectional in that hyperinsulinemia, for example, may also drive adiposity.

Cortisol & Diabetes

The association between cortisol dysregulation and diabetes has been demonstrated in population studies while translational animal studies and preliminary clinical trials inform mechanisms of these associations and potential risk for downstream cardiometabolic disease. Multiple aspects of the diurnal cortisol curve have been associated with the development of (incident) diabetes. For example, elevated evening cortisol was associated with incident diabetes over 9-years in the Whitehall II Study [42]. In the CARDIA Study, a concordant observation was shown with a flatter late decline slope being associated with over a 4-fold higher odds of incident diabetes over 10 years (Figure 4) [31]. It was also found that a steeper cortisol awakening response was associated with lower odds of incident diabetes [31].

Figure 4. The Association of Cortisol Curve Features with Incident Diabetes among Whites and African Americans: The CARDIA Study.

Reprinted as permitted by Open Access from Kluwe, et al. Psychoneuroendocrinology 2021 [31]. “A robust CAR and flatter late decline slope are associated with lower and higher odds of incident diabetes, respectively, among younger to middle-aged White, [but not African American], individuals and may provide a future target for diabetes prevention in this population.”

Various mechanisms may explain these associations including: 1) impairment to glucose regulation by glucocorticoid signaling in adipose tissue; 2) disruptions to circadian rhythm reliant physiology; and 3) gene-environment, including epigenetic, modification. The development of diabetes may be due to cortisol’s impact on insulin resistance, specifically. In a Japanese cohort, a Latino cohort, and a cohort in the United Kingdom, higher fasting serum cortisol was associated with greater insulin resistance [43-45]. However, the relationship between cortisol and insulin resistance may be mediated by adiposity, as it has been demonstrated that increases in BMI over time is associated with changes in diurnal cortisol including lower wake-up cortisol and total area under the curve cortisol in MESA [39]. In a cohort of Black participants in the Jackson Heart Study, an association between greater morning cortisol and greater insulin resistance was observed only in the tertile of the population with greatest waist circumference [46]. Similarly, in the Multi-Ethnic Study of Atherosclerosis, increasing waist circumference attenuated the relationship between cortisol and insulin resistance [47].

Mechanistic insights may be garnered from further understanding of the adipocyte-specific cortisol metabolism via 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1), the enzyme that converts cortisol to its active form intracellularly, as discussed below. Another plausible mechanism is disruptions in circadian rhythms. For example, type 2 diabetes may be considered a state of accelerated tissue aging which has been associated with reduced amplitudes of circadian clock proteins including CLOCK/BMAL-1 [48]. Circadian disruption is one potential mechanism explaining the associations between dysregulated morning cortisol and fasting glucose observed in the Jackson Heart Study [46]. In those with type 2 diabetes, concomitantly low CLOCK/BMAL-1 levels and high cortisol exposure may mitigate the “brake” on glucocorticoid-induced morning gluconeogenesis. This may be particularly relevant in minoritized populations given the racial/ethnic disparities in metabolic syndrome and obstructive sleep apnea with higher prevalence in Black populations [49].

After the development of diabetes, cortisol may play a role in glycemic control. Increases in total cortisol exposure throughout the day preceded increases in fasting glucose only among those with diabetes over a 6-year period in MESA [50]. In the Jackson Heart Study, while a doubling of morning serum cortisol was associated with a 2.7 mg/dL higher fasting glucose in participants without diabetes, among those with type 2 diabetes a doubling of morning serum cortisol was associated with a 23.6 mg/dL higher fasting glucose, representing an 8.74-fold greater effect size, as well as a 0.6% higher A1c (Figure 3) [46]. Thus, cortisol has a significant impact on the development and progression of diabetes and remains an underrecognized therapeutic target.

Cortisol & Cardiovascular Disease

Importantly, the association between cortisol and physiologic dysregulation may extend beyond obesity and diabetes to CVD. In a large, longitudinal study of over 100,000 individuals in the UK, receiving high doses of glucocorticoid medications (≥ 7.5mg prednisone daily), were at 2.5 times the risk of CVD over three years [51]. Further, a one standard deviation increase in endogenous morning cortisol was associated with a 28% higher risk of incident CVD in two prospective case control studies and an 18% higher risk in a meta-analysis [52]. The relationship extends to markers of subclinical atherosclerotic CVD such as carotid plaque formation and coronary artery calcification [52,53]. However, these subclinical atherosclerotic CVD relationships may be differential in risk dependent on physiological (lower risk) or exogenous (higher risk) glucocorticoid exposure [54]. Evidence also suggests an association between chronic stress and epigenetic modifications in glucocorticoid-related genes that may have impact on cardiometabolic disease risk. For example, methylation levels are attenuated on the gene of a glucocorticoid receptor chaperone, FKBP5, under chronic environmental exposures in mice and psychosocial stress including child adversity in humans [32,55,56]. As it relates to CVD, the function of FKBP5 has been demonstrated to play a role in endothelial function and in platelet aggregation specifically among individuals with myocardial infarctions [57,58]. Building on this evidence, a study in individuals with diabetes demonstrated that elevated methylation of FKBP5 at two specific loci of the FKBP5 gene was associated with increased biomarkers of CVD risk including hemoglobin A1c, adiposity (waist circumference and BMI), and LDL-cholesterol [59]. While more research is needed to understand the potential underpinnings of FKBP5 involvement in CVD and diabetes, other epigenetic and molecular mechanisms of the HPA axis should be considered in future work. For example, given that CRF modulates cortisol (glucocorticoid) release in a feedback loop, and FKBP5 modulates glucocorticoid receptor signaling [19], it is speculated that CRF and NR3C1 (the glucocorticoid receptor gene) may be subject to epigenetic modification in the setting of HPA axis dysfunction similar to FKBP5 and possibly in the setting of CVD risk (specifically, metabolic syndrome) [60-62]. Future work should consider epigenetics and gene-environment interaction studies to further elucidate targets for intervention.

Understanding mechanistic underpinnings of the association between cortisol and cardiometabolic disease risk is critically important. For example, glucocorticoid receptor (GR) blockade in adipocytes of mice, even when administered exogenous corticosterone, they experienced improved glucose tolerance and insulin sensitivity than mice without GR blockade which was related to increased adiposity, indicating the importance of elucidating adipocyte pathophysiology in future research [63]. Similarly, 11β-Hydroxysteroid dehydrogenase type 1 (11B-HSD1), the enzyme that converts cortisone to cortisol, which then activates the glucocorticoid receptor, overexpression in mice adipose tissue contributes to a diabetic phenotype [64]. Further, inhibition of 11β-HSD1 with an antagonist (Carbenoxone) improved fat mass, energy expenditure, serum lipid profile, serum leptin and insulin and glucose tolerance in these mice [64]. It has also been shown that 11β-HSD1 exacerbates the relationship between existing adiposity and insulin resistance [65]. While 11β-HSD1 is also expressed in hepatic tissue, which may also contribute to metabolic impairment, another hepatic enzyme, 17-hydrosyprogesterone (17-OHP), which contributes to the conversion of cholesterol to cortisol has also been found to be increased in diabetic mice models [66]. It has been shown that 17-OHP in obese mice may also induce GR activation leading to hyperglycemia, in part through hepatic gluconeogenesis, and insulin resistance [66].

These mechanistic understandings may pave the road for novel approaches to modify the stress axis to prevent and treat cardiometabolic disease. For example, recent pharmacological interventions targeting the cortisol to cardiometabolic disease pathway have been explored. In humans with endocrine pathologies associated with metabolic dysfunction, it has been observed that glucocorticoid receptor antagonists, such as mifepristone, improve insulin resistance and moderate glucose levels [67-69]. While mifepristone does appear to increase the dynamicity of the diurnal cortisol curve among individuals with type 2 diabetes [70], it remains to be explored if this might have clinical applications to impact insulin resistance, glycemic control or clinical outcomes in individuals with diabetes but without clinical Cushing’s syndrome or disease. Similarly, more research is needed to investigate 11β-HSD1 inhibitors, as they have been proposed as a therapeutic modality to negate the development of atherosclerosis potentially by inhibiting pro-inflammatory damage to endothelial cell [53].

Non-pharmacological interventions such as mindfulness, meditation, yoga, and tai chi may empower changes that lead to weight loss and improved glycemic control in diabetes, and improved cardiovascular health [71-73]. For example, a mindful eating intervention found reductions in cortisol awakening response and reduced weight among intervention vs. control participants with obesity [74]. In another study, those who completed a mindfulness intervention demonstrated both decreased blood pressure and salivary cortisol levels in response to a presented stressor as compared to controls [75]. However, despite these findings of an impact on cortisol and cardiometabolic outcomes with mindfulness interventions, more work is needed to understand if and how such changes may impact cardiometabolic risk and outcomes. More broadly, evidence and small studies to date suggest larger clinical trials are needed to both assess the impacts of mindfulness on acute stress reactivity, cortisol response and diurnal cortisol profile, dysglycemia and cardiovascular health [73,76,77]. Importantly, such future work must aim to investigate interventions that harness mindfulness, as dispositional or trait mindfulness may itself not be associated with cortisol reactivity [78].

Additionally, to move the field forward through clinical and translational research, such studies must understand cortisol diurnal pattern implications for sample collection. Current studies of associations between cortisol outcomes in metabolic, dysglycemic, and cardiovascular outcomes are heterogenous in assessments of morning cortisol, evening cortisol, overall daytime cortisol, and fasting random cortisol measures [42-46,50]. Our work has shown the importance of a “flattened’’ cortisol profile throughout the day [31], and thus it is critical to have precise collection of cortisol throughout the day. Additionally, cortisol dynamic (also called diurnal) range (CDR), measures the range of cortisol level from peak to nadir in an individual’s diurnal cycle, potentially indicative of their capacity for a versatile biological stress response [79,80]. CDR has been correlated with a biological composite measure for allostatic load, and with childhood adversity [79,80]. Salivary cortisol collection in the community is suitable with in-field guidance and that CDR may be more feasible in community-based studies than time-dependent measures [81]. This novel measure has not yet been widely incorporated into cardiometabolic research. Using such a cortisol measure that specifically captures the overall adaptability of individuals’ stress responses may help identify targets for interventions mitigating the stress to CVD trajectory.

CONCLUDING REMARKS AND FUTURE DIRECTIONS

Opportunities for Novel Intervention

Cortisol is a key regulator of countless processes in the body and may serve as a mechanistic link between stress physiology and cardiometabolic disease. Acknowledging and addressing the contribution of stress physiology and cortisol in interventions to treat cardiometabolic disease at the individual, community and population level are necessary to improve prevention, treatment and control of cardiometabolic disease and advance health equity.

This approach will also begin to address the biological consequences of historical and systemic racism and inequities that have manifested in stress axis pathophysiology [14,81]. Adrenal hormone modulation presents an opportunity for innovative prevention and treatment approaches. Potential applications (Key Figure) include: 1) identifying and addressing the sources of psychological and environmental stress and structural adversities such as adverse childhood experiences, racism & discrimination in environmental exposures, etc.; 2) addressing comorbidities including depression and sleep disturbances; 3) exploring opportunities to modulate the stress pathway including pharmacological (e.g., mifepristone, carbenoxone) and mind-body interventions (e.g., mindfulness); and 4) evaluating further mechanisms and biomarkers (gene x environment interactions, epigenetics, metabolomics/proteomics, etc.) in the stress to adrenal hormones to cardiometabolic disease cascade for future treatment targets.

Key Figure.

Targets for Interventions and Future Directions

Outstanding Questions.

• What environment x biology interactions are most responsible for the mechanisms of cardiometabolic disease?

• How do neuroendocrine factors interact with cortisol physiology to portend cardiometabolic disease risk (e.g., cortisol and estrogen pathways, cortisol and sleep cycles)?

• What HPA-axis-associated epigenetic mechanisms may serve as biomarkers for, or therapeutic targets of, cardiometabolic disease progression and/or prevention?

• Can pharmacomodulation of the glucocorticoid receptor demonstrate clinically meaningful improvements in cardiometabolic risk and disease?

• How can behavioral interventions (e.g., stress reduction, mind-body interventions) be scaled to impact populations at risk for cardiometabolic disease outcomes and disparities?

Highlights.

• Stress in both intrinsic psychosocial and extrinsic physical environmental forms can impact the development of, and outcomes in, cardiovascular disease.

• While experiences of or exposure to stressors may be acute or chronic, its severity and one’s ability to buffer against it is what may be most impactful on the body.

• “Toxic stress” may affect the body through mechanisms involving the hypothalamic-pituitary-adrenal axis (e.g., cortisol).

• Deviations in cortisol diurnal profile have been associated with adiposity, dyslipidemia, incident diabetes, cardiovascular disease such as hypertension.

• Cortisol and its respective receptor, the glucocorticoid receptor, are involved in metabolism within adipocytes that may contribute to dysglycemia and insulin resistance and, therefore, cardiometabolic disease risk.

• Glucocorticoid receptor antagonists and antagonists of the enzymes associated cortisol metabolism, may be promising targets for future research.

• Acknowledging and addressing the contribution of stress physiology and cortisol in interventions to treat cardiometabolic disease at the individual, community and population level are necessary to combat cardiometabolic disease.