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To the Editor: In Cushing syndrome, elevated plasma cortisol levels cause insulin resistance, hyperglycemia, hypertension, and dyslipidemia. In patients without Cushing syndrome, these cardiovascular risk factors are associated with more subtle elevations in plasma cortisol concentrations¹ and enhanced tissue responsiveness to glucocorticoids.² We explored the possibility that insulin resistance in patients without Cushing syndrome involves dysregulation of glucocorticoid receptor (GR) expression in muscle.

Methods
We obtained biopsies of vastus lateralis skeletal muscle under local anesthesia from 23 men without fasting hyperglycemia participating in the the Uppsala Longitudinal Study of Adult Men.³ As previously described, participants underwent a 75-g oral glucose tolerance test, euglycemic hyperinsulinemic clamp, and ambulatory blood pressure recording. Height, weight, and waist and hip circumferences were measured. Glucocorticoid receptor messenger RNA (mRNA) levels were measured in muscle total RNA using a quantitative reverse transcriptase (RT) polymerase chain reaction (PCR) assay with synthetic RNA competitors for GR mRNA and 18S mRNA as internal control. Both competitors contained 83 base pair deletions to distinguish PCR products derived from endogenous and synthetic RNAs.⁴ The interassay coefficient of variation was 12%. Stata v5.0 (Stata Corp, College Station, Tex) was used for all analyses.

Results
Results are shown in Table 1. After adjusting for body mass index (BMI), higher levels of skeletal muscle GR mRNA were associated with hypertension, higher insulin levels after a glucose load, and insulin resistance in a euglycemic hyperinsulinemic clamp. Muscle GR mRNA was not associated with plasma lipids, glucose, or BMI alone.

View this table: [in this window] [in a new window] Table. Associations of GR mRNA Levels With Cardiovascular Risk Factors*

Comment
These data show that men with insulin resistance and hypertension have increased GR mRNA levels and, by inference, increased numbers of GRs in skeletal muscle. Glucocorticoid receptors mediate diverse effects on insulin sensitivity (in liver, adipose tissue, and skeletal muscle) and blood pressure (in kidney, blood vessels, and brain). Increased numbers of receptors in these sites could contribute to the association between features of the insulin resistance syndrome, and explain enhanced responsiveness to glucocorticoids.² Glucocorticoid receptors also contribute to negative feedback regulation of the hypothalamic-pituitary-adrenal axis. If receptor expression were similarly increased in central feedback sites, it might be expected that lower circulating cortisol levels would compensate for peripheral hypersensitivity.

However, dysregulation of GR expression appears to be tissue-specific. In an animal model of insulin resistance, dysregulation of GR expression was associated with increased GR mRNA in the liver but decreased GR mRNA in central negative feedback sites.⁵ Further understanding of tissue-specific variations in GR expression and function may offer fundamental insights into the pathophysiology of insulin resistance and its association with hypertension.

AUTHOR INFORMATION
Acknowledgment: Dr Reynolds is a Wellcome Trust Cardiovascular Research Initiative Clinical Training Fellow. Dr Walker is a British Heart Foundation Senior Research Fellow.

Rebecca M. Reynolds, MRCP; Karen E. Chapman, PhD; Jonathan R. Seckl, PhD; Brian R. Walker, MD
Molecular Medicine Centre
University of Edinburgh
Western General Hospital
Edinburgh, Scotland

Paul M. McKeigue, PhD
London School of Hygiene and Tropical Medicine
London, England

Hans O. Lithell, PhD
Department of Geriatrics
Uppsala University
Uppsala, Sweden

1. Phillips DIW, Walker BR, Reynolds RM, et al. Low birthweight and elevated plasma cortisol concentrations in adults from three populations. Hypertension. 2000;35:1301-1306. FREE FULL TEXT 2. Walker BR, Phillips DIW, Noon JP, et al. Increased glucocorticoid activity in men with cardiovascular risk factors. Hypertension. 1998;31:891-895. FREE FULL TEXT 3. McKeigue PM, Lithell HO, Leon DA. Glucose tolerance and resistance to insulin-stimulated glucose uptake in men aged 70 years in relation to size at birth. Diabetologia. 1998;41:1133-1138. FULL TEXT | ISI | PUBMED 4. Forster E. An improved general method to generate internal standards for competitive PCR. Biotechniques. 1994;16:18-20. ISI | PUBMED 5. Nyirenda MJ, Lindsay RS, Kenyon CJ, Burchell A, Seckl JR. Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. J Clin Invest. 1998;101:2174-2181. ISI | PUBMED

Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.

JAMA. 2002;287:2505-2506.

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