Context Emotional stress may be a risk factor for type 2 diabetes (T2D) but the relation between phobic stress symptom scores and risk of T2D is SLIT3 uncertain. at baseline and updated in 2004 for NHS in 2005 for NHS II and in 2000 for HPFS. Incident T2D was confirmed by a validated supplementary questionnaire. We used Cox proportional hazards analysis to evaluate associations with incident T2D. Results During 3 110 248 person-years of follow-up we documented 12 876 incident T2D cases. In multivariable Cox regression models with adjustment for major way of life and dietary risk factors the HRs of T2D across categories of increasing levels of CCI (scores= 2-<3 KN-62 3 4 6 compared with a score of <2 were increased significantly by KN-62 6% 10 11 and 13% (=0.0005) for NHS; and by 19% 11 22 and 29% (<0.0001) for NHS II. Each score increment in CCI was associated with 3% higher risk of T2D in NHS (HRs 1.03 95 and 4% higher risk of T2D in NHS II (HRs 1.04 95 Further adjustment for self-reported depression and antidepressant use did not change the results. In HPFS the association between CCI and T2D was not significant after adjusting for way of life variables. Conclusion Our results suggest that higher phobic stress symptom scores are associated with an increased risk of T2D in women. INTRODUCTION The prevalence of type 2 diabetes (T2D) is usually increasing at alarming rates in the US and worldwide (1 2 In addition to well-known diabetic risk factors such as diet obesity physical inactivity age race and a family history of T2D (3 4 recent studies have suggested a role of emotional stress in the etiology of T2D (5-7). The epidemiological studies support the concept that different forms of emotional stress particularly depressive disorder general emotional stress stress anger/hostility and sleeping problems (6) contribute to an elevated risk of T2D. Stress disorders are the most prevalent mental disorders and lifetime prevalence of specific phobia and interpersonal phobia is over 12% in the U.S. (8 9 Emotional stress may influence behavioral factors and thereby increase the risk of T2D through unhealthy dietary intake excessive alcohol consumption smoking and low exercise levels (7 10 11 Additional evidence also suggests the association between phobic stress symptoms and increasing inflammatory biomarkers such as C-reactive protein tumor necrosis factor α leptin soluble E-selectin and soluble intercellular adhesion molecule (12 13 which are well-known risk factors for T2D (14). Importantly phobic stress is usually treatable; thus any potential impacts on T2D incidence may be amendable through early identification and intervention. An association between phobic stress symptoms scores and increased risk of coronary heart disease (CHD) in men and women has been previously reported in our and other cohorts (15-17) to date however the relationship between phobic stress symptoms scores and T2D incidence has not been directly examined. Therefore using data from three prospective cohorts the Nurses’ Health Study (NHS) Nurses’ Health Study II (NHS II) and Health Professional Follow-up Study (HPFS) we examined KN-62 the association between phobic stress symptoms scores as measured by Crown-Crisp index (CCI) and T2D incidence in women and men. RESEARCH DESIGN AND METHODS Study Population We used data from 3 prospective cohort studies: NHS (started in 1976; n=121 704 age range at baseline: 30-55 y enrolled from 11 US says) NHS II (established in 1989; n=116 643 age range at baseline: 24-43 y; enrolled from 14 US says) and HPFS (initiated in 1986 n=51 529 age range at baseline: 40-75 y; enrolled from 50 US says). In all the 3 cohorts questionnaires were administered at baseline and biennially thereafter to collect and update information on lifestyle practices and occurrence of chronic diseases. Information on phobic stress was first obtained around the 1988 questionnaire in NHS (n=103 614 around the 1993 questionnaire in NHS II (n=87 238 and on the 1988 HPFS questionnaire (n=48 834 this served as the baseline populations for our analyses. Participants were excluded if they had T2D cancer CHD or stroke at baseline (n=16 255 in NHS n=5935 in NHS II and n=7370 KN-62 in HPFS) missing information on T2D diagnosis date (n=3355 in NHS n=937 in NHS II and n=1524 in HPFS) age (n=48 in NHS and n=182 in NHS II) or phobic stress symptoms score data (n = 14 620 in NHS n =64 in NHS II and n=9110 in HPFS). After exclusions data from 69 336 women in NHS 80 120 women in NHS II and 30 830 men in HPFS were available for the analysis. The study protocol was approved by the institutional review boards of Brigham and Women’s.