Psychological stress-related processes are thought to contribute to the development and progression of type 2 diabetes, but the biological mechanisms involved are poorly understood. Here, we tested the notion that people with type 2 diabetes experience chronic allostatic load, manifest as dynamic disturbances in reactivity to and recovery from stress across multiple (cardiovascular, neuroendocrine, inflammatory, metabolic) biological systems, coupled with heightened experience of chronic life stress. We carried out an experimental comparison of 140 men and women aged 50-75 y with type 2 diabetes and 280 nondiabetic individuals matched on age, sex, and income. We monitored blood pressure (BP) and heart rate, salivary cortisol, plasma interleukin (IL)-6, and total cholesterol in response to standardized mental stress, and assessed salivary cortisol over the day. People with type 2 diabetes showed impaired poststress recovery in systolic and diastolic BP, heart rate and cholesterol, and blunted stress reactivity in systolic BP, cortisol, cholesterol, and IL-6. Cortisol and IL-6 concentrations were elevated, and cortisol measured over the day was higher in the type 2 diabetes group. Diabetic persons reported greater depressive and hostile symptoms and greater stress experience than did healthy controls. Type 2 diabetes is characterized by disruption of stress-related processes across multiple biological systems and increased exposure to life stress. Chronic allostatic load provides a unifying perspective with implications for etiology and patient management.ype 2 diabetes has a heterogeneous pathophysiology in which β-cell dysfunction and insulin resistance play pivotal roles (1). Stress-related factors may contribute to risk of type 2 diabetes through their impact on inflammatory, metabolic, cardiovascular, and neuroendocrine regulation (2). Socioeconomic adversity over the life course predicts type 2 diabetes in later life (3), whereas stress at work and more general indicators of perceived stress are associated with future diabetes (4, 5). There appears to be a bidirectional relationship between type 2 diabetes and depressive symptoms (6), and people with type 2 diabetes may report greater social isolation and more limited social support (7).These diverse associations between stress-related processes and diabetes are only partly accounted for by lifestyle factors such as physical inactivity, alcohol consumption, or adiposity, suggesting that direct psychobiological pathways may be involved. A helpful concept in this regard is allostatic load. Allostasis refers to the dynamic process of adaptation to environmental challenges through adjustments in multiple biological systems, including the hypothalamic-pituitary-adrenocortical (HPA) axis, autonomic nervous system, and metabolic and immune systems (8). Allostasis is essential for maintaining homeostasis, but repeated or sustained stimulation leads to allostatic load, the wear-and-tear that results from dysregulation of mediating processes. Allostatic load is freque...