Article: Pathophysiology The immune marker soluble urokinase plasminogen activator receptor is associated with new-onset diabetes in non-smoking women and men S. B. Haugaard 1,2,3 , O. Andersen 1 , T. W. Hansen 4 , J. Eugen-Olsen 1 , A. Linneberg 5 , S. Madsbad 2,6 , M. H. Olsen 5,6 , T. Jørgensen 5,6 , K. Borch-Johnsen 7,8 and J. Jeppesen 6,9 1 Clinical Research Centre, Copenhagen University, 2 Department of Endocrinology, Copenhagen University, Hvidovre Hospital, 3 Department of Internal Medicine, Copenhagen University Hospital, Amager, 4 Department of Clinical Physiology, Nuclear Medicine and PET, Copenhagen University Hospital, Faculty of Health Sciences, Rigshospitalet, Copenhagen, 5 Research Centre for Prevention and Health, Copenhagen University Hospital, Glostrup, 6 Faculty of Health Science, University of Copenhagen, 7 Research Center for Quality in Health Care, National Institute of Public Health, University of Southern Denmark, Odense, 8 Faculty of Health Science, University of Aarhus and 9 Department of Medicine, Copenhagen University Hospital, Glostrup, Denmark Accepted 1 November 2011 Abstract Aim To explore the putative association of new-onset diabetes and the soluble urokinase plasminogen activator receptor (suPAR), which is a new and stable plasma marker of immune function and low-grade inflammation. This association has been previously suggested by using the less sensitive International Classification of Disease system to detect incident diabetes in the Danish MONICA 10 cohort. Methods The Danish National Diabetes Register enabled more accurate identification of incident diabetes during a median follow-up of 13.8 years in the Danish MONICA 10 cohort (n = 2353 generally healthy individuals). The soluble urokinase plasminogen activator receptor was measured by the ELISA method. To fulfil model assumptions, outcome analyses were stratified by age, and further by smoking, owing to the interaction between the soluble urokinase plasminogen activator receptor and smoking on new-onset diabetes (P < 0.0001). Results New-onset diabetes (n = 182) was associated with increased soluble urokinase plasminogen activator receptor levels (P = 0.013). Among 699 middle-aged (41 and 51 years) and 564 older (61 and 71 years) non-smokers, participants in the upper soluble urokinase plasminogen activator receptor quartile had a sex- and age-adjusted relative risk of 6.01 (95% CI 2.17–16.6, P < 0.0006) and relative risk of 3.25 (95% CI 1.51–6.98, P = 0.0025), respectively, for new-onset diabetes compared with participants in the lowest quartile. This relationship remained significant after additional adjustments for C-reactive protein and leukocytes or fasting glucose and insulin or BMI (P < 0.05). The soluble urokinase plasminogen activator receptor was not related to incident diabetes among smokers (P ‡ 0.85). Conclusions In these explorative analyses, the soluble urokinase plasminogen activator receptor associated independently with incident diabetes in non-smokers, supporting an immune origin of Type 2 diabetes. Competing disease risk may explain lack of association among smokers. Diabet. Med. 29, 479–487 (2012) Keywords immune function, incident diabetes, insulin resistance, low-grade inflammation, soluble urokinase plasminogen activator receptor Abbreviations CRP, C-reactive protein; MONICA, Monitoring Trends and Determinants of Cardiovascular Disease study; suPAR, soluble urokinase plasminogen activator receptor Introduction With the current epidemic of Type 2 diabetes in westernized communities, there is an urgent need for ways in which to predict those who are likely to develop diabetes, so that early prevention Correspondence to: Steen B Haugaard MD DMSc, Clinical Research Centre, Copenhagen University Hospital, Hvidovre, DK-2650, Copenhagen, Denmark. E-mail: sbhau@dadlnet.dk DIABETICMedicine DOI: 10.1111/j.1464-5491.2011.03513.x ª 2011 The Authors. Diabetic Medicine ª 2011 Diabetes UK 479