Diabetologia (2004) 47:1668–1671 DOI 10.1007/s00125-004-1508-2
Short Communication
In the lipodystrophy associated with highly active antiretroviral therapy, pseudo-Cushing’s syndrome is associated with increased regeneration of cortisol by 11β-hydroxysteroid dehydrogenase type 1 in adipose tissue J. Sutinen1, 2, 6 · K. Kannisto3 · E. Korsheninnikova4 · T. Nyman4 · E. Ehrenborg3 · R. Andrew5 · D. J. Wake5 · A. Hamsten3 · B. R. Walker5 · H. Yki-Järvinen1, 3 1 Division
of Diabetes, Department of Medicine, University of Helsinki, Helsinki, Finland of Infectious Diseases, Department of Medicine, University of Helsinki, Helsinki, Finland 3 King Gustaf V Research Institute, Karolinska Institutet, Stockholm, Sweden 4 Minerva Research Institute, Helsinki, Finland 5 Endocrinology Unit, University of Edinburgh, Edinburgh, Scotland, UK 6 Division of Infections Diseases, Department of Medicine, University of Helsinki, Helsinki, Finland 2 Division
Abstract Aims/hypothesis. Highly active antiretroviral therapy (HAART) in patients infected with human immunodeficiency virus (HIV) is associated with a poorly understood lipodystrophic and hypertriglyceridaemic syndrome, which resembles Cushing’s syndrome, but in which plasma cortisol is not elevated. We tested the hypothesis that this HAART-associated lipodystrophy is explained by increased local regeneration of cortisol from inactive cortisone within adipose tissue, catalysed by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Methods. In this cross-sectional study, a previously described cohort of 30 HIV-infected patients with lipodystrophy were compared with 13 HIV-infected patients without lipodystrophy. Intra-abdominal and subcutaneous adipose tissue were quantified using magnetic resonance imaging. Gene expression in subcutaneous fat was measured using real-time PCR. Urine cortisol and its metabolites were analysed by gas chromatography/mass spectrometry. Received: 23 April 2004 / Accepted: 18 July 2004 Published online: 29 September 2004 © Springer-Verlag 2004 J. Sutinen (✉) Division of Infections Diseases, Department of Medicine, University of Helsinki, P.O. Box 348, 00029 HUS Helsinki, Finland E-mail:
[email protected] Tel.: +358-9-47175989, Fax: +358-9-47175900 Abbreviations: HAART, highly active antiretroviral therapy · HAL, HAART-associated lipodystrophy · HIV, human immunodeficiency virus · 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1 · MRI, magnetic resonance imaging · PPAR, peroxisome proliferator-activated receptor
Results. Patients with lipodystrophy had significantly higher 11β-HSD1 mRNA concentrations (relative to β2-microglobulin mRNA) in subcutaneous adipose tissue than non-lipodystrophic patients (0.29±0.20 vs 0.09±0.07, p=0.0004) and higher ratios of urinary cortisol : cortisone metabolites. Adipose tissue 11βHSD1 mRNA correlated with multiple features of insulin resistance and with mRNA concentrations for glucocorticoid receptor and angiotensinogen. Conclusions/interpretation. In adipose tissue of patients with HAART-associated lipodystrophy, 11βHSD1 mRNA is increased and its concentration is correlated with features of insulin resistance. We suggest that increased adipose tissue 11β-HSD1 may explain the pseudo-Cushing’s features in patients with HAART-associated lipodystrophy, and is a potential therapeutic target. Keywords Adipose tissue · Antiretroviral therapy · Cortisol · Glucocorticoid · HIV · 11β-Hydroxysteroid dehydrogenase type 1 · Lipodystrophy · Real-time PCR
Introduction Combined highly active antiretroviral therapy (HAART), comprising protease and reverse transcriptase inhibitors, is effective in preventing sequelae of human immunodeficiency virus (HIV) infection. However, some patients taking HAART develop a lipodystrophic syndrome, with loss of subcutaneous fat and accumulation of fat in the abdomen and nape of the neck. This syndrome is associated with hypertriglyceridaemia and insulin resistance [1]. The mechanisms underlying HAART-associated lipodystrophy (HAL) are unknown. The distribution of fat accumulation in
J. Sutinen et al.: In the lipodystrophy associated with highly active antiretroviral therapy
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Table 1. Characteristics of the study subjects Nonlipodystrophic patients (n=13) Age (years) 39±7 Body mass index (kg/m2) 22.4±3.7 Waist-to-hip ratio 0.89±0.10 Systolic blood pressure (mmHg) 121±10 Diastolic blood pressure (mmHg) 77±8 Subcutaneous fat by MRI (cm3) 1760±960 Intra-abdominal fat by MRI (cm3) 930±890 Total body fat by bioimpedance (%) 19±7 Plasma glucose (mmol/l) 5.0±0.5 Serum insulin (mU/l) 6.5±3.6 Serum triglycerides (mmol/l) 1.2±0.5 Serum HDL-cholesterol (mmol/l) 1.6±0.4 Serum total cholesterol (mmol/l) 4.9±0.7 Serum C-reactive protein (mg/l) 0.62±0.55 U cortisol : cortisone metabolite ratio 1.42±0.21 Adipose 11β-HSD1 mRNAb 0.09±0.07 a b
Lipodystrophic p a patients (n=30)
Correlation p with adipose 11β-HSD1 mRNA
Correlation p with U cortisol: cortisone metabolite ratio
43±10 23.6±2.8 0.99±0.07 125±12 78±8 1140±850 1920±1110 17±7 5.5±1.5 11.1±6.5 3.4±2.0 1.1±0.3 5.9±1.1 1.53±1.40 1.92±0.62 0.29±0.20
0.30 0.42 0.59 0.04 −0.07 0.09 0.58 0.17 0.30 0.51 0.58 −0.51 0.42 0.43 0.25
0.15 −0.02 0.17 0.14 −0.13 −0.52 0.28 −0.22 −0.12 0.18 0.37 −0.44 0.06 0.17
0.396 0.915 0.325 0.418 0.463 0.002 0.109 0.210 0.516 0.300 0.031 0.009 0.745 0.347
0.25
0.173
0.146 0.128 0.003 0.308 0.832 0.040 0.003 0.543 0.104 0.009
