Abstract
Context
Increased activity of the hypothalamic-pituitary-adrenal (HPA) axis may underlie the metabolic syndrome but whether circulating cortisol levels predict cardiovascular end points is less clear. People with type 2 diabetes are at increased cardiovascular disease risk and thus are suitable to study associations of plasma cortisol with cardiovascular risk.
Objective
We aimed to assess whether altered HPA axis activity was associated with features of the metabolic syndrome and ischaemic heart disease in people with type 2 diabetes.
Design
Cross-sectional cohort study including 919 men and women aged 67.9 (4.2) years with type 2 diabetes, the Edinburgh Type 2 Diabetes Study
Setting
General community
Intervention
Measurement of fasting morning plasma cortisol
Main outcome measurement
Associations between cortisol levels, features of the metabolic syndrome, obesity and ischaemic heart disease
Results
Elevated plasma cortisol levels were associated with raised fasting glucose and total cholesterol levels (p<0.001). These findings remained significant after adjustment for potential confounding factors (p<0.001). Elevated cortisol levels were associated with prevalent ischaemic heart disease (>800 vs. <600nmol/l, OR 1.58, p=0.02). This association remained significant after adjustment for duration and control of diabetes and other cardiovascular risk factors (p=0.03).
Conclusions
The previously described associations between HPA axis activation and features of the metabolic syndrome are present among people with type 2 diabetes. Elevated plasma cortisol is also associated with a greater prevalence of ischaemic heart disease, independent of conventional risk factors. Understanding the role of cortisol in the pathogenesis of ischaemic heart disease merits further exploration.
Keywords: cortisol, type 2 diabetes, metabolic syndrome, ischaemic heart disease
Introduction
In Cushing’s syndrome, glucocorticoid excess causes central obesity, insulin resistance, type 2 diabetes, hypertension and other cardiovascular risk factors. Recent studies have suggested that a subtle increase in plasma cortisol might underlie the cluster of cardiovascular risk factors comprising the ‘metabolic syndrome’. Elevated plasma cortisol, measured in the morning, has been described in individuals with glucose intolerance, hypertension and dyslipidaemia (1-6). This has been associated with alterations in central regulation of the hypothalamic-pituitary-adrenal (HPA) axis (5;7-9). In people with diabetes, early studies of HPA axis regulation showed inconsistencies. This was partly caused by inclusion of individuals with type 1 and type 2 diabetes (10), or a failure to control for other factors influencing cortisol levels such as obesity and gender (11). In studies that included subjects with type 2 diabetes alone, elevated basal plasma cortisol levels (12-14) and late night salivary cortisol levels (15) have been reported. Elevated ACTH levels (16;17), increased cortisol levels following overnight dexamethasone suppression (10;18) and impaired habituation of cortisol levels to repeated stress (19) are consistent with a ‘central’ dysregulation of the HPA axis in type 2 diabetes.
Glucocorticoid excess also promotes atherogenesis and cardiovascular disease (6). Whether circulating plasma cortisol can also predict cardiovascular end-points is less clear. For example, in a large prospective study a higher morning cortisol:testosterone ratio was associated with ischaemic heart disease in men, although cortisol levels alone were not predictive of future cardiac events (20). Likewise, no significant associations were observed between basal cortisol levels and coronary artery disease demonstrated by angiography (21). However, in a different study, cortisol levels in blood obtained on the morning prior to coronary angiography correlated positively with severity of coronary artery disease, independently of other cardiovascular risk factors (22).
Since plasma cortisol and the prevalence of cardiovascular disease and its risk factors are all higher in people with type 2 diabetes, we hypothesized that, if elevated plasma cortisol does increase cardiovascular risk, this should be apparent in a cohort of individuals with type 2 diabetes. Such an association may also help explain the increased risk of cardiovascular disease in people with type 2 diabetes.
Methods
Participants
The Edinburgh Type 2 Diabetes Study (ET2DS) is a prospective study investigating mechanisms and risk factors for diabetes-related cognitive decline and for the development and progression of micro- and macro-vascular disease in diabetes (23). Participants aged 60 to 75 years were recruited at random from a comprehensive database of people with type 2 diabetes living in the Lothian area of central Scotland. The recruitment and study protocol have been described in detail previously (23). Briefly, subjects attended a local research clinic for physical examination and completion of questionnaires containing validated questions on demographic characteristics, recall of a doctor diagnosis of MI and angina, the WHO chest pain questionnaire and standard cardiovascular risk factors. The Hospital Anxiety and Depression Scale (HADS) was used to evaluate current anxiety and depressive symptoms. This scale performs well in screening for the separate dimensions of anxiety and depression and allows identification of cases of anxiety disorders and depression in patients from non-psychiatric hospital clinics. Data were also collected from the Information Services Division of NHS Health Services Scotland on all medical and surgical discharges from Scottish hospitals since 1981 (SMR01 scheme). Any ICD10 or ICD9 codes for cardiovascular or cerebrovascular disease were extracted. The study complied with the Declaration of Helsinki and ethical approval and written informed consent were obtained.
Assessment of cardiovascular risk factors and disease
After an overnight fast, venous blood samples were collected between 0800h and 0830h and sera and plasma stored at −80C. Height, weight, hip circumference, % body fat, brachial blood pressure, and systolic ankle pressures were measured as described previously (23). The ankle brachial index (ABI), a measure of subclinical atherosclerosis, was calculated by dividing the lowest of the ankle pressures (right and left posterior tibial and dorsalis pedis) by the higher of the right and left arm pressures. A resting 12-lead electrocardiogram (ECG) was recorded and coded using the Minnesota code (http://www.epi.umn.edu/ecg/).
Assays
Plasma glucose, HbA1c, and total and high density lipoprotein (HDL) cholesterol were measured as described previously (23). Plasma cortisol was measured by radio-immunoassay (MP Biomedicals, UK) with an intra-assay coefficient of variation (CV) 5.1-7.0%, and inter-assay CV 6.0-7.9%.
Definitions of ischaemic heart disease
Criteria used to define myocardial infarction (MI) included: (1) self report of doctor-diagnosed heart attack, (2) myocardial infarction indicated by WHO Chest Pain Questionnaire (24), (3) ECG evidence of ischaemia, or (4) a prior hospital discharge code for MI (ICD10 codes I21-I23, I252). MI was recorded if two out of the first three of these criteria were met, or if both the first and last criteria were met. Equivalent criteria for angina included: (1) self report of doctor-diagnosed angina or being on regular medication for angina, (2) angina indicated on Chest Pain Questionnaire, (3) ischaemic ECG code, or (4) a prior hospital discharge code for ischaemic heart disease (ICD10 codes I20-25). Angina was recorded if two out of the first three of these criteria were met, or if both the first and last criteria were met. Ischaemic heart disease was defined as including those subjects who satisfied the criteria both for MI and angina.
Statistical analysis
Data were analysed using SPSS 15.0 with p-value ≤0.05 considered statistically significant. Subjects taking glucocorticoid therapy by any route within the 3 months prior to examination were excluded from the analysis. All continuous variables were normally distributed. Correlations between fasting plasma cortisol levels and cardiovascular risk factors and ischaemic heart disease outcomes, measures of obesity, and duration of diabetes were examined using Pearson or Spearman correlation coefficients as appropriate. Multiple linear regression was performed to assess the relationship between cortisol and metabolic syndrome variables (plasma glucose, HbA1c, total cholesterol, HDL-cholesterol, systolic and diastolic blood pressures), with additional covariates (age, gender, BMI, duration of diabetes mellitus, treatment with oral hypoglycaemic agents or insulin, antihypertensive treatment or lipid-lowering treatment) subsequently entered into a multivariate model. When adjusting for covariates, interactions between variables (e.g: BMI by gender) were also examined leaving only statistically significant interactions in the final models. Multiple logistic regression was used to determine the association between cortisol and odds of ischaemic heart disease. Plasma cortisol levels, categorized into near tertiles as <600 nmol/L, 600-800 nmol/L and >800 nmol/L, were included in the analysis as an independent variable with cortisol <600 nmol/L as the reference group. Sociodemographic variables, metabolic syndrome variables, obesity, other cardiovascular risk factors, and depression were included in the analyses as independent variables in a second step.
Results
Subject characteristics and potential confounding factors
From a total of 5454 invitations sent to potential study participants, 1066 subjects were recruited into the ET2DS. Characteristics of subjects participating in the study were similar to those of the non-responders in terms of age, social class, duration of diabetes, HbA1c levels, percentage using insulin, total cholesterol and systolic blood pressure (data not shown). Characteristics of the study population used for the current analysis (n=919, excluding those on exogenous glucocorticoids) are shown in Table 1. Men had a greater waist circumference, but lower BMI than women (both p<0.001). Men and women had similar glycaemic control, but men had significantly higher diastolic blood pressure, and significantly lower total and HDL-cholesterol levels (all p<0.001). Men also had a greater prevalence of ischaemic heart disease (p<0.001). Cortisol levels increased with age (r=0.07, p=0.046) but did not significantly differ according to gender, smoking, alcohol consumption, marital status or highest educational level attained. In men, cortisol levels were significantly lower in those with a higher waist circumference (r=−0.166, p<0.001), and higher BMI (r=−0.159, p<0.001) but did not differ significantly according to % body fat (−0.078, p=0.089). Cortisol levels were not significantly associated with obesity measurements in women (waist circumference, r = −0.001, p=0.979; BMI, r = −0.037, p= 0.442; % body fat, r = 0.024, p=0.625).
Table 1. Sociodemographic and metabolic characteristics of study participants.
| All N= 919 | Males N= 483 | Females N= 436 | P-value | |
|---|---|---|---|---|
| Socio-demographic and life-style variables | ||||
| Age at assessment (years) | 67.9 ± 4.2 | 68.0 ± 4.1 | 67.7 ± 4.3 | 0.433 |
| Marital Status | <0.001 | |||
| Married | 649 (70.8) | 394 (81.9) | 255 (58.5) | |
| Living with long-term partner | 49 (5.3) | 24 (5.0) | 25 (5.7) | |
| Single | 131 (14.3) | 26 (5.4) | 105 (24.1) | |
| Widowed | 88 (9.6) | 37 (7.7) | 51 (11.7) | |
| Education (highest level attained) | 0.077 | |||
| University/College | 148 (16.1) | 87 (18.0) | 61 (14.0) | |
| Other professional qualification | 265 (28.8) | 143 (29.6) | 122 (28.0) | |
| Secondary School | 500 (54.4) | 248 (51.3) | 252 (57.8) | |
| Primary School | 6 (0.7) | 5 (1.0) | 1 (0.2) | |
| Employment status | <0.001 | |||
| Worker | 134 (14.6) | 94 (19.5) | 40 (9.2) | |
| Retired | 740 (80.5) | 367 (76.0) | 373 (85.6) | |
| Other: housewife, unemployed | 45 (4.9) | 22 (4.6) | 23 (5.3) | |
| Ethnic group | 0.091 | |||
| Caucasian | 876 (95.3) | 455 (94.2) | 421 (96.6) | |
| Other | 43 (4.7) | 28 (5.8) | 15 (3.4) | |
| Current smoking | 120 (13.1) | 73 (15.1) | 47 (10.8) | |
| Alcohol consumption (frequency) | <0.001 | |||
| Never | 187 (20.5) | 59 (12.3) | 128 (29.6) | |
| 1-4 times/month | 402 (44.0) | 185 (38.5) | 217 (50.1) | |
| 2-5 times/week | 229 (25.1) | 162 (33.7) | 67 (15.5) | |
| 6 or more times/week | 96 (10.5) | 75 (15.1) | 21 (4.8) | |
| Depressive symptoms | ||||
| HADS- Depression score | 3.8 ± 2.8 | 3.5 ± 2.7 | 4.0 ± 3.0 | 0.015 |
| Depression (HADS-D≥8) | 100 (10.9) | 45 (9.3) | 55 (12.6) | 0.111 |
| Obesity measures | ||||
| Weight (kg) | 86.2 ± 15.9 | 90.0 ± 15.2 | 82.1 ± 15.7 | <0.001 |
| BMI (kg/m2) | 31.3 ± 5.6 | 30.2 ± 4.8 | 32.4 ± 6.2 | <0.001 |
| Waist (cm) | 106.4 ± 12.6 | 107.7 ± 11.9 | 105.0 ± 13.2 | 0.001 |
| Plasma measurements | ||||
| Glucose (mmol/l) | 7.6 ± 2.1 | 7.6 ± 2.1 | 7.5 ± 2.1 | 0.275 |
| HbAlc (%) | 7.4 ± 1.1 | 7.4 ± 1.1 | 7.4 ± 1.0 | 0.591 |
| Total Cholesterol (mmol/L) | 4.3 ± 0.9 | 4.1 ± 0.8 | 4.5 ± 0.9 | <0.001 |
| HDL-Cholesterol (mmol/L) | 1.3 ± 0.4 | 1.2 ± 0.3 | 1.4 ± 0.3 | <0.001 |
| Cortisol (nmol/L) | 731 ±190.4 | 731 ±181.8 | 732 ±199.9 | 0.917 |
| Diabetes and cardiovascular variables | ||||
| Duration of DM (years) | 9.1 ± 6.5 | 9.5 ± 6.8 | 8.7 ± 6.3 | 0.057 |
| Systolic blood pressure (mmHg) | 133.2 ± 16.3 | 133.4 ± 15.5 | 132.8 (17.2) | 0.917 |
| Diastolic blood pressure (mmHg) | 69.1 ± 9.1 | 70.6 ± 8.8 | 67.4 ± 9.2 | <0.001 |
| Ischaemic heart disease (angina or MI) | 278 (30.3) | 175 (36.2) | 103 (23.6) | <0.001 |
| Ankle Brachial Index | 0.98 ± 0.21 | 1.01 ± 0.24 | 0.96 ± 0.16 | <0.001 |
| Treatments | ||||
| Treatment of DM | 0.920 | |||
| Diet alone | 171 (18.6) | 88 (18.2) | 83 (19.0) | |
| Oral hypoglycaemic agents | 590 (64.2) | 313 (64.8) | 277 (63.5) | |
| Insulin ± Oral hypoglycaemic agents | 158 (17.2) | 82 (17.0) | 76 (17.4) | |
| Lipid-lowering drugs | 777 (84.5) | 402 (83.2) | 375 (86.0) | 0.244 |
| Anti-hypertensive treatment | 725 (78.9) | 380 (78.7) | 345 (79.1) | 0.866 |
| Antidepressant(s) | 108 (11.8) | 43 (8.9) | 65 (14.9) | 0.005 |
Values are mean ± SD or n(%)
HADS – Hospital anxiety and depression Scale; HADS-D ≥8 = score indicating high risk of depression
Cortisol and metabolic syndrome variables
Elevated plasma cortisol was significantly associated with higher fasting glucose (Table 2), but not with HbA1c or diabetes duration. A significant positive association was observed between cortisol and total cholesterol, but no significant association was noted with HDL cholesterol (Table 2). These findings remained significant after adjustment for age, gender, BMI and treatment with glucose-lowering (oral anti-diabetic agents and/or insulin) therapy, lipid-lowering, or anti-hypertensive medication (Table 3). There were no significant associations of cortisol with systolic or diastolic blood pressure (Table 2 and 3).
Table 2. Differences in metabolic characteristics of participants according to cortisol levels.
| Cortisol levels | Group 1 <600 nmol/L n=249 |
Group 2 600-800 nmol/L n=371 |
Group 3 >800 nmol/L n=300 |
P value* |
|---|---|---|---|---|
| Glucose (mmol/L) | 7.1 (1.9) | 7.5 (1.8) | 8.0 (2.4) | <0.001abc |
| HbA1c (%) | 7.4 (1.1) | 7.3 (1.0) | 7.4 (1.1) | 0.629 |
| Total cholesterol (mmol/L) | 4.2 (0.9) | 4.2 (0.8) | 4.5 (1.0) | <0.001bc |
| HDL cholesterol (mmol/L) | 1.3 (0.3) | 1.3 (0.4) | 1.3 (0.4) | 0.891 |
| Systolic blood pressure (mmHg) | 131.2 (15.1) | 133.9 (16.5) | 133.8 (17.1) | 0.103 |
| Diastolic blood pressure (mmHg) | 68.6 (9.2) | 69.5 (8.6) | 69.0 (9.6) | 0.458 |
| Body mass index (kg/m2) | 32.0 (5.6) | 31.3 (5.7) | 30.7 (5.4) | 0.021b |
| Waist (cm) | 108.0 (12.6) | 106.3 (13.0) | 105.4 (12.1) | 0.060 |
p-value for post hoc comparisons between the three cortisol groups by ANOVA (using a Bonferroni adjustment.
Significant comparisons are highlighted:
Group 1 vs Group 2
Group 1 vs Group 3
Group 2 vs Group 3
Table 3. Association between metabolic syndrome variables and plasma cortisol levels multiple linear regression*.
| Unadjusted model | Multi-adjusted model1 | |||||||
|---|---|---|---|---|---|---|---|---|
| Metabolic variables | ß | SE | 95% CI | P-value | ß | SE | 95% CI | P-value |
| Glucose (mmol/L) | 17.8 | 3.0 | 11.9 to 23.7 | <0.001 | 19.3 | 3.1 | 13.3 to 25.3 | <0.001 |
| HbA1c (%) | 6.2 | 6.1 | −5.8 to 18.0 | 0.313 | 11.9 | 6.7 | −1.3 to 25.1 | 0.077 |
| Total cholesterol (mmol/L) | 32.9 | 7.0 | 19.2 to 46.6 | <0.001 | 37.7 | 7.4 | 23.1 to 52.2 | <0.001 |
| HDL-cholesterol (mmol/L) | 8.7 | 18.2 | −27.1 to 44.5 | 0.634 | −4.7 | 19.3 | −43.6 to 33.1 | 0.806 |
| Systolic blood pressure (mmHg) | 0.6 | 0.4 | −0.2 to 1.3 | 0.144 | 0.5 | 0.4 | −0.2 to 1.3 | 0.183 |
| Diastolic blood pressure (mmHg) | 0.03 | 0.7 | −1.3 to 1.4 | 0.964 | 0.5 | 0.7 | −0.9 to 1.9 | 0.485 |
Abbreviations: ß= Unstandardized beta coefficient; SE= Standard error; CI= Confidence interval
change in plasma cortisol for a one unit (1mmol/l or 1%) increase in metabolic syndrome variable
Covariates were age, gender, BMI, duration of diabetes mellitus, treatment of diabetes mellitus (diet, hypoglycaemic oral agent or insulin), antihypertensive treatment, lipid-lowering treatment, interaction of BMI by gender
Cortisol and ischaemic heart disease
In univariate analysis, high cortisol levels (>800 nmol/L) were related to increased odds of ischaemic heart disease (Table 4). This finding remained significant on multivariate analysis adjusting for age, gender, education, marital status, depression, hypertension, dyslipidaemia, smoking, alcohol consumption, duration of diabetes, HbA1c and treatment modality for diabetes (Table 4). Cortisol levels were not independently related to ABI in univariate or multivariate regression analysis (data not shown).
Table 4. Plasma cortisol levels and ischaemic heart disease (logistic regression).
| Unadjusted model) | OR | 95% CI | P-value |
|---|---|---|---|
| Cortisol level (nmol/l) | |||
| <600 | 1.00 | ||
| 600-800 | 1.33 | 0.92 to 1.94 | 0.134 |
| >800 | 1.58 | 1.07 to 2.33 | 0.021 |
|
| |||
| Adjusted model | OR | 95% CI | P-value |
|
| |||
| Cortisol level (nmol/l) | |||
| <600 | 1.00 | ||
| 600–800 | 1.33 | 0.89 to 1.99 | 0.166 |
| >800 | 1.58 | 1.04 to 2.39 | 0.031 |
| Gender | |||
| Male | 1.00 | ||
| Female | 0.43 | 0.30 to 0.61 | <0.001 |
| Age | 1.04 | 1.00 to 1.08 | 0.042 |
| Education | |||
| University | 1.00 | ||
| Technical/other | 2.06 | 1.21 to 3.51 | 0.008 |
| Primary/secondary | 2.37 | 1.44 to 3.90 | 0.001 |
| Depression | |||
| No | 1.00 | ||
| Yes | 2.35 | 1.46 to 3.76 | <0.001 |
| Dyslipidaemia | |||
| No | 1.00 | ||
| Yes | 3.29 | 1.81 to 6.00 | <0.001 |
OR, odds ratio; CI, confidence interval
Adjusted for age, gender, education level, marital status, depression (HADS-Depression score≥ 8), hypertension (blood pressure>130/85 or treatment with antihypertensive drugs), dyslipidaemia (HDL-Cholesterol <1.0 mmol/L or lipid-lowering treatment), current smoking, frequency of alcohol consumption, duration of diabetes mellitus (years), HbA1c and treatment of diabetes mellitus (diet, tablets or insulin).
Only statistically significant covariates are shown in the table.
Discussion
A series of studies have described alterations in cortisol action in individuals with cardiovascular risk factors comprising the metabolic syndrome. In case-control and cross-sectional studies, elevated fasting plasma cortisol was associated with higher glucose, blood pressure and dyslipidaemia (1;3-5;9;25;26). Here we report similar associations of high fasting cortisol measurements with higher glucose and total cholesterol in subjects with type 2 diabetes. In addition, we found that those with the highest fasting cortisol levels had an increased prevalence of ischaemic heart disease.
The present results support the findings of two recent small studies where alterations in cortisol measured in blood or saliva have been linked to aspects of metabolic control including measures of glycaemia and blood pressure in individuals with type 2 diabetes (27;28). We found significant associations of cortisol with fasting glucose, but not with HbA1c. In this cohort of patients, HbA1c has been targeted by aggressive therapy and metabolic control is generally good, so that a relationship between chronic elevation of plasma cortisol and glycaemic control might have been obscured. Alternatively, it may be that elevated plasma cortisol in these subjects reflects acute activation of the HPA axis only at the time of stress, as discussed further below, which is then associated with direct effects to increase hepatic gluconeogenesis and fasting glucose (29). We found no significant associations between cortisol and clinic blood pressure, but a high proportion (78%) of our subjects were treated with antihypertensive drugs.
Type 2 diabetes is known to be associated with high cardiovascular risk (30) and indeed, in our population 14% had a history of myocardial infarction and 28% had angina. We found that high cortisol levels were independently associated with established cardiovascular disease. Results from studies examining the relationship between cortisol levels and symptomatic cardiovascular disease have been inconsistent and to our knowledge no prior large studies have been performed in people with diabetes. Differences in outcome may reflect differences in sampling conditions. Studies where cortisol has been collected under basal, ‘unstressed’ conditions have not detected a relationship between circulating levels and cardiovascular disease (20;21). In contrast, a recent small study where cortisol was collected on the morning prior to coronary angiography, conditions described by the authors as ‘high anticipatory stress’, found the highest cortisol levels in those with the most severe coronary heart disease (22). The blood samples in the present study were collected in a hospital setting under carefully timed conditions in the morning with all subjects in the fasting state. Thus, these cortisol concentrations might reflect a ‘stress’ response related to a combination of fasting, venesection and the novel clinic setting in which the samples were obtained. Interestingly, an association between work stress and a greater cortisol awakening response in association with coronary heart disease has been reported (30). These findings suggest that responsiveness of the HPA axis may be more predictive of cardiovascular disease than basal activity of the HPA axis.
It is possible that people with type 2 diabetes may be more susceptible to the effects of stress on plasma cortisol. The fasting cortisol levels in our subjects were high (mean 733 nmol/L), and were much higher than levels that we have reported previously in people without diabetes (3). Interestingly even higher fasting cortisol levels were reported by Bruehl et al (27) who found fasting levels of 1873 nmol/L in 30 men and women with type 2 diabetes. The mechanisms underlying the elevated cortisol levels in diabetes are not known. Corticosteroid binding globulin levels are not elevated in diabetes. Our own studies of impaired habituation of cortisol responses to venepuncture (19) would be consistent with activation of the HPA axis from ‘higher’ centres in type 2 diabetes. Whether subjects with type 2 diabetes have impaired central negative feedback sensitivity of the HPA axis that contributes to high cortisol levels is not clear, with previous reports of both impaired (10;18) and enhanced (31) feedback responses. Further detailed studies, including examining both the glucocorticoid and mineralocorticoid receptor components of central negative feedback sensitivity as has been described recently in obesity (7), are required.
The main limitation of our study is the cross-sectional design and therefore we cannot determine the direction of the associations between cortisol and metabolic or ischaemic heart disease variables. Our study was representative of elderly Caucasian people with type 2 diabetes in the general population. Subjects varied from those treated with diet alone, with few complications of diabetes, to those treated with insulin with established complications. The findings of lower fasting cortisol levels with greater adiposity were as expected and consistent with other studies (26;32). We found no significant differences in cortisol levels with use of medication for treating diabetes. Circulating cortisol levels are not affected by use of rosiglitazone (33) and we are not aware of reports indicating that other oral antidiabetic agents or insulin therapy influence cortisol levels. Many of the subjects were also taking medication for primary or secondary prevention against cardiovascular disease including statins, although data suggest that cortisol levels are not altered by statin use (34) and there are no data indicating that other commonly prescribed cardiovascular drugs alter HPA axis activity.
In summary, the previously described associations between HPA axis activation and the metabolic syndrome are evident in people with type 2 diabetes. Elevated plasma cortisol levels are also associated with greater prevalence of ischaemic heart disease in people with type 2 diabetes. Further studies investigating the role of cortisol in the pathogenesis are needed. If proved causal, strategies targeted at lowering cortisol action (6) may be useful to improve the metabolic and cardiovascular phenotype in subjects with type 2 diabetes.
Acknowledgements
This study was supported by a grant from the Medical Research Council. We thank our co-investigators and collaborators on the ET2DS (IJ Deary, K Swa, GDO Lowe), all study participants and staff, and researchers at the Wellcome Trust Clinical Research Facility in Edinburgh where the study was performed.
Footnotes
Conflict of Interests
None declared
Disclosure summary: All authors have no conflicts of interest
Reference List
- 1.Filipovsky J, Ducimetiere P, Eschwege E, Richard JL, Rosselin G, Claude JR. The relationship of blood pressure with glucose, insulin, heart rate, free fatty acids and plasma cortisol levels according to degree of obesity in middle-aged men. J Hypertens. 1996;14:229–235. doi: 10.1097/00004872-199602000-00012. [DOI] [PubMed] [Google Scholar]
- 2.Fraser R, Ingram MC, Anderson NH, Morrison C, Davies E, Connell JMC. Cortisol effects on body mass, blood pressure, and cholesterol in the general population. Hypertension. 1999;33:1364–1368. doi: 10.1161/01.hyp.33.6.1364. [DOI] [PubMed] [Google Scholar]
- 3.Phillips DIW, Barker DJP, Fall CHD, Whorwood CB, Seckl JR, Wood PJ, Walker BR. Elevated plasma cortisol concentrations: an explanation for the relationship between low birthweight and adult cardiovascular risk factors. J Clin Endocrinol Metab. 1998;83:757–760. doi: 10.1210/jcem.83.3.4634. [DOI] [PubMed] [Google Scholar]
- 4.Phillips DIW, Walker BR, Reynolds RM, Flanagan DEH, Wood PJ, Osmond C, Barker DJP, Whorwood CB. Low birthweight and elevated plasma cortisol concentrations in adults from three populations. Hypertension. 2000;35:1301–1306. doi: 10.1161/01.hyp.35.6.1301. [DOI] [PubMed] [Google Scholar]
- 5.Reynolds RM, Walker BR, Phillips DIW, Sydall HE, Andrew R, Wood PJ, Whorwood CB. Altered control of cortisol secretion in adult men with low birthweight and cardiovascular risk factors. J Clin Endocrinol Metab. 2001;86:245–250. doi: 10.1210/jcem.86.1.7145. [DOI] [PubMed] [Google Scholar]
- 6.Walker BR. Glucocorticoids and cardiovascular disease. Eur J Endocrinol. 2007;157:545–559. doi: 10.1530/EJE-07-0455. [DOI] [PubMed] [Google Scholar]
- 7.Mattsson C, Reynolds RM, Simonyte K, Olsson T, Walker BR. Combined Receptor Antagonist Stimulation of the HPA axis test identifies impaired negative feedback sensitivity to cortisol in obese men. J Clin Endocrinol Metab. 2009;94:1347–1352. doi: 10.1210/jc.2008-2054. [DOI] [PubMed] [Google Scholar]
- 8.Solano MP, Kumar M, Fernandez B, Jones L, Goldberg RB. The pituitary response to ovine corticotropin-releasing hormone is enhanced in obese men and correlates with insulin resistance. Horm Metab Res. 2001;33:39–43. doi: 10.1055/s-2001-12625. [DOI] [PubMed] [Google Scholar]
- 9.Stolk RP, Lamberts SWJ, de Jong FH, Pols HAP, Grobbee DE. Gender differences in the associations between cortisol and insulin sensitivity in healthy subjects. J Endocrinol. 1996;149:313–318. doi: 10.1677/joe.0.1490313. [DOI] [PubMed] [Google Scholar]
- 10.Cameron OG, Kronfol Z, Greden JF, Carroll BJ. Hypothalamic-pituitary-adrenocortical activity in patients with diabetes mellitus. Archives of General Psychiatry. 1984;41:1090–1095. doi: 10.1001/archpsyc.1983.01790220080013. [DOI] [PubMed] [Google Scholar]
- 11.Andrew R, Phillips DIW, Walker BR. Obesity and gender influence cortisol secretion and metabolism in man. J Clin Endocrinol Metab. 1998;83:1806–1809. doi: 10.1210/jcem.83.5.4951. [DOI] [PubMed] [Google Scholar]
- 12.Lee ZS, Chan JC, Yeung VT, Chow CC, Lau MS, Ko GT, Li JK, Cockram CS, Critchley JA. Plasma insulin, growth hormone, cortisol, and central obesity among young Chinese type 2 diabetic patients. Diabetes Care. 1999;22:1450–1457. doi: 10.2337/diacare.22.9.1450. [DOI] [PubMed] [Google Scholar]
- 13.Lentle BC, Thomas JP. Adrenal function and the complications of diabetes mellitus. Lancet. 1964:545–549. doi: 10.1016/s0140-6736(64)90616-6. [DOI] [PubMed] [Google Scholar]
- 14.Roy M, Collier B, Roy A. Hypothalamic-pituitary-adrenal axis dysregulation among diabetic outpatients. Psychiatry Res. 1990;31:31–37. doi: 10.1016/0165-1781(90)90106-f. [DOI] [PubMed] [Google Scholar]
- 15.Liu H, Bravata DM, Cabaccan J, Raff H, Ryzen E. Elevated late-night salivary cortisol levels in elderly male type 2 diabetic veterans. Clin Endocrinol (Oxf) 2005;63:642–649. doi: 10.1111/j.1365-2265.2005.02395.x. [DOI] [PubMed] [Google Scholar]
- 16.Cameron OG, Thomas B, Tiongco D, Hariharan M, Greden JF. Hypercortisolism in diabetes mellitus. Diabetes Care. 1987;10:663. doi: 10.2337/diacare.10.5.662. [DOI] [PubMed] [Google Scholar]
- 17.Vermes I, Steinmetz E, Schoorl J, van d V, Tilders FJ. Increased plasma levels of immunoreactive beta-endorphin and corticotropin in non-insulin-dependent diabetes. Lancet. 1985;2:725–726. doi: 10.1016/s0140-6736(85)92964-2. [DOI] [PubMed] [Google Scholar]
- 18.Hudson JI, Hudson MS, Rothschild AJ, Vignati L, Scatzberg AF, Melby JC. Abnormal results of dexamethasone suppression tests in nondepressed patients with diabetes mellitus. Archives of General Psychiatry. 1984;41:1087–1089. doi: 10.1001/archpsyc.1983.01790220076012. [DOI] [PubMed] [Google Scholar]
- 19.Reynolds RM, Sydall HE, Wood PJ, Phillips DIW, Walker BR. Elevated plasma cortisol in glucose intolerant men: different responses to glucose and habituation to venepuncture. J Clin Endocrinol Metab. 2001;86:1149–1153. doi: 10.1210/jcem.86.3.7300. [DOI] [PubMed] [Google Scholar]
- 20.Davey Smith G, Ben-Shlomo Y, Beswick A, Yarnell J, Lightman SL, Elwood P. Cortisol, testosterone and coronary heart disease. Prospective evidence from the Caerphilly study. Circulation. 2005;112:332–340. doi: 10.1161/CIRCULATIONAHA.104.489088. [DOI] [PubMed] [Google Scholar]
- 21.Reynolds RM, Ilyas B, Price JF, Fowkes FG, Newby DE, Webb DJ, Walker BR. Circulating plasma cortisol concentrations are not associated with coronary artery disease or peripheral vascular disease. QJM. 2009 doi: 10.1093/qjmed/hcp057. [DOI] [PubMed] [Google Scholar]
- 22.Alevizaki M, Cimponeriu A, Lekakis J, Papamichael C, Chrousos GP. High anticipatory stress plasma cortisol levels and sensitivity to glucocorticoids predict severity of coronary artery disease in subjects undergoing coronary angiography. Metabolism. 2007;56:222–226. doi: 10.1016/j.metabol.2006.09.017. [DOI] [PubMed] [Google Scholar]
- 23.Price JF, Reynolds RM, Mitchell RJ, Williamson RM, Fowkes FG, Deary IJ, Lee AJ, Frier BM, Hayes PC, Strachan MW. The Edinburgh Type 2 Diabetes Study: study protocol. BMC Endocr Disord. 2008;8:18. doi: 10.1186/1472-6823-8-18. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Rose GA. The diagnosis of ischaemic heart pain and intermittent claudication in field surveys. Bull World Health Organ. 1962;27:645–658. [PMC free article] [PubMed] [Google Scholar]
- 25.Brunner EJ, Hemingway H, Walker BR, Page M, Clarke P, Juneja M, Shipley MJ, Kumari M, Andrew R, Seckl JR, Papadopoulos A, Checkley S, Rumley A, Lowe GDO, Stansfield SA, Marmot MG. Adrenocortical, autonomic and inflammatory causes of the metabolic syndrome: nested case-control study. Circulation. 2002;106:2659–2665. doi: 10.1161/01.cir.0000038364.26310.bd. [DOI] [PubMed] [Google Scholar]
- 26.Rosmond R, Dallman MF, Bjorntorp P. Stress-related cortisol secretion in men: relationships with abdominal obesity and endocrine, metabolic and haemodynamic abnormalities. J Clin Endocrinol Metab. 1998;83:1853–1859. doi: 10.1210/jcem.83.6.4843. [DOI] [PubMed] [Google Scholar]
- 27.Bruehl H, Rueger M, Dziobek I, Sweat V, Tirsi A, Javier E, Arentoft A, Wolf OT, Convit A. Hypothalamic-pituitary-adrenal axis dysregulation and memory impairments in type 2 diabetes. J Clin Endocrinol Metab. 2007;92:2439–2445. doi: 10.1210/jc.2006-2540. [DOI] [PubMed] [Google Scholar]
- 28.Oltmanns KM, Dodt B, Schultes B, Raspe HH, Schweiger U, Born J, Fehm HL, Peters A. Cortisol correlates with metabolic disturbances in a population study of type 2 diabetic patients. Eur J Endocrinol. 2006;154:325–331. doi: 10.1530/eje.1.02074. [DOI] [PubMed] [Google Scholar]
- 29.Andrews RC, Walker BR. Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci. 1999;96:513–523. doi: 10.1042/cs0960513. [DOI] [PubMed] [Google Scholar]
- 30.Chandola T, Britton A, Brunner E, Hemingway H, Malik M, Kumari M, Badrick E, Kivimaki M, Marmot M. Work stress and coronary heart disease: what are the mechanisms? Eur Heart J. 2008;29:640–645. doi: 10.1093/eurheartj/ehm584. [DOI] [PubMed] [Google Scholar]
- 31.Andrews RC, Herlihy O, Livingstone DEW, Andrew R, Walker BR. Abnormal cortisol metabolism and tissue sensitivity to cortisol in patients with glucose intolerance. J Clin Endocrinol Metab. 2002;87:5587–5593. doi: 10.1210/jc.2002-020048. [DOI] [PubMed] [Google Scholar]
- 32.Strain GW, Zumoff B, Kream J, Strain JJ, Levin J, Fukushima D. Sex difference in the influence of obesity on the 24 hr mean plasma concentration of cortisol. Metabolism. 1982;31:209–212. doi: 10.1016/0026-0495(82)90054-3. [DOI] [PubMed] [Google Scholar]
- 33.Wake DJ, Stimson RH, Tan GD, Homer NZ, Andrew R, Karpe F, Walker BR. Effects of Peroxisome Proliferator-Activated Receptor-{alpha} and -{gamma} Agonists on 11{beta}-Hydroxysteroid Dehydrogenase Type 1 in Subcutaneous Adipose Tissue in Men. J Clin Endocrinol Metab. 2007;92:1848–1856. doi: 10.1210/jc.2006-2713. [DOI] [PubMed] [Google Scholar]
- 34.Travia D, Tosi F, Negri C, Faccini G, Moghetti P, Muggeo M. Sustained therapy with 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors does not impair steroidogenesis by adrenals and gonads. J Clin Endocrinol Metab. 1995;80:836–840. doi: 10.1210/jcem.80.3.7883839. [DOI] [PubMed] [Google Scholar]