.  Eugen‐Olsen J, Andersen O, Linneberg A, Ladelund S, Hansen TW, Langkilde A, Petersen J, Pielak T, Møller LN, Jeppesen J, Lyngbæk S, Fenger M, Olsen MH, Hildebrandt PR, Borch‐Johnsen K, Jørgensen T, Haugaard SB (Copenhagen University, Hvidovre Hospital, Hvidovre; Copenhagen University Hospital, Glostrup; Copenhagen University Hospital, Copenhagen; Copenhagen University Hospital, Glostrup; Copenhagen University, Hvidovre Hospital, Hvidovre; Steno Diabetes Center, Gentofte; University of Aarhus, Aarhus; University of Copenhagen, Copenhagen; Copenhagen University, Hvidovre Hospital, Hvidovre, Denmark). Circulating soluble urokinase plasminogen activator receptor predicts cancer, cardiovascular disease, diabetes and mortality in the general population. J Intern Med 2010; 268: 296–308. Background.  Low‐grade inflammation is thought to contribute to the development of cardiovascular disease (CVD), type‐2 diabetes mellitus (T2D), cancer and mortality. Biomarkers of inflammation may aid in risk prediction and enable early intervention and prevention of disease. Objective.  The aim of this study was to investigate whether plasma levels of the inflammatory biomarker soluble urokinase plasminogen activator receptor (suPAR) are predictive of disease and mortality in the general population. Design.  This was an observational prospective cohort study. Cohort participants were included from June 1993 to December 1994 and followed until the end of 2006. Setting.  General adult Caucasian population. Participants.  The MONICA10 study, a population‐based cohort recruited from Copenhagen, Denmark, included 2602 individuals aged 41, 51, 61 or 71 years. Measurements.  Blood samples were analysed for suPAR levels using a commercially available enzyme‐linked immunosorbent assay. Risk of cancer (n = 308), CVD (n = 301), T2D (n = 59) and mortality (n = 411) was assessed with a multivariate proportional hazards model using Cox regression. Results.  Elevated baseline suPAR level was associated with an increased risk of cancer, CVD, T2D and mortality during follow‐up. suPAR was more strongly associated with cancer, CVD and mortality in men than in women, and in younger compared with older individuals. suPAR remained significantly associated with the risk of negative outcome after adjustment for a number of relevant risk factors including C‐reactive protein levels. Limitation.  Further validation in ethnic populations other than Caucasians is needed. Conclusion.  The stable plasma protein suPAR may be a promising biomarker because of its independent association with incident cancer, CVD, T2D and mortality in the general population.

Human immunodeficiency virus (HIV)-associated lipodystrophy syndrome (HALS) is a side effect of highly active antiretroviral therapy of HIV-infected patients; however, the mechanism of the lipodystrophy and insulin resistance seen in this syndrome remains elusive. Adiponectin, an adipocyte-specific protein, is thought to play an important role in regulating insulin sensitivity. We investigated circulating levels and gene expression of adiponectin in subcutaneous abdominal adipose tissue (AT) from 18 HIV-infected patients with HALS compared with 18 HIV-infected patients without HALS. Implications of cytokines for adiponectin levels were investigated by determining circulating levels of TNF-α, IL-6, and IL-8 as well as gene expression of these cytokines in AT. HALS patients exhibited 40% reduced plasma adiponectin levels ( P < 0.05) compared with non-HALS subjects. Correspondingly, adiponectin mRNA levels in AT were reduced by >50% ( P = 0.06). HALS patients were insulin resistant, and a positive correlation was found between plasma adiponectin and insulin sensitivity ( r = 0.55, P < 0.01) and percent limb fat ( r = 0.61, P < 0.01). AT mRNA of TNF-α, IL-6, and IL-8 was increased in AT of HALS subjects ( P < 0.05), and both AT TNF-α mRNA and plasma TNF-α were negatively correlated to plasma adiponectin ( P < 0.05). Finally, TNF-α was found in vitro to inhibit human AT adiponectin mRNA by 80% ( P < 0.05). In conclusion, HALS patients have reduced levels of plasma adiponectin and adiponectin mRNA in AT. Increased cytokine mRNA in AT is hypothesized to exert an inhibitory effect on adiponectin gene expression and, consequently, to play a role in the reduced plasma adiponectin levels found in HALS patients.

Circulating soluble urokinase plasminogen activator receptor (suPAR) reflects the immune and pro-inflammatory status of the HIV-infected patient. Highly active antiretroviral therapy (HAART) suppresses suPAR. Independent of the immune response to HAART, suPAR remains elevated in some HIV-infected patients, reflecting possibly a low-grade pro-inflammatory state. Low-grade inflammation has been implicated in insulin resistance and other features of dysmetabolism. Accordingly it is hypothesized that circulating suPAR is associated with the metabolic status of HIV-infected patients on HAART. Fasting plasma suPAR was determined in 36 normoglycaemic HIV-infected patients on HAART (n = 18 lipodystrophic, and n = 18 non-lipodystrophic) who had estimated insulin sensitivity (Rd) and non-oxidative glucose disposal (NOGM) by euglycaemic hyperinsulinaemic clamps, indirect calorimetry, and glucose tracer infusion. Five patients had circadian suPAR concentrations measured (24 hr, 20 min-intervals). suPAR and non-HDL-cholesterol were higher and Rd, NOGM, and limb fat were lower in lipodystrophic patients than in non-lipodystrophic patients (P < 0.05). suPAR correlated positively with non-HDL-cholesterol and inversely with Rd, NOGM and limb fat (P < 0.005, n = 36). suPAR also correlated positively with leukocyte count and TNF-alpha (P < 0.01, n = 36) but not with IL-6. In multiple regression analyses suPAR was a stronger predictor of dysmetabolism than TNF-alpha and IL-6. Circadian suPAR did not systematically fluctuate. In conclusion, suPAR may reflect the metabolic status of the HIV-infected patient on HAART, thus linking low-grade inflammation, immune constitution, lipid and glucose metabolism, and fat redistribution. Circadian suPAR concentration appeared stable, suggesting that sampling schedule does not affect measurement. Further studies addressing whether suPAR predicts lipodystrophy and dysmetabolism in HIV-infected patients are warranted.

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