Introduction: While stress associates with poor glycemic control, its relationship to incident diabetes (DM) risk is unclear. We imaged activity of the amygdala (AA: a validated measure of neural tissue response to stress) to test if it associates with incident DM independently of adiposity.Methods: 293 non-diabetics were studied: 61 in a cross-sectional study (mean age ± SD 63±9 yrs) and 232 (55±10 yrs) in a longitudinal events study. Individuals underwent FDG PET/CT with assessment of AA. In the biomarker study, metabolic markers were measured. In the longitudinal study, visceral adipose tissue (VAT) volumes were assessed (by CT), after which individuals were followed for 2 years for incident DM. Image analyses and DM adjudication were performed by mutually blinded investigators. Cox and log-rank tests were used.Results: Higher AA (upper vs. lower two tertiles) associated with higher HOMA-IR (1.2 vs. 0.7, p=0.045) and lower adiponectin (2.4 vs. 4.6 μg/ml, p=0.025). In the longitudinal study, 21 individuals developed DM over 2 yrs. Baseline AA (continuous variable) associated with VAT (p=0.002) and predicted incident DM (Cox HR [95% CI]: 1.46 [1.08-1.97], p=0.013), remaining significant after multivariate adjustments, including VAT (p=0.042). The combination of higher AA and higher VAT (≥ median values) produced the greatest risk of DM, while lower AA associated with lower risk of DM regardless of adiposity (Figure). Moreover, higher AA associated with markedly increased risk of DM even in the subset of individuals with high adiposity: those with ≥ median VAT (Cox HR: 6.57 [1.42-30.43], p=0.016), or BMI>25 (Cox HR: 6.37 [1.44-28.24], p=0.015).Conclusions: These findings provide new insights into the mechanism by which stress may predispose humans to obesity and DM. We show that stress (via AA) is an important co-inducer of DM across levels of adiposity and that obese individuals with low AA may be relatively protected from metabolic complications of adiposity.