DESCRIPTION (provided by applicant): Diabetes Mellitus (DM) is a metabolic disease that causes microvascular and neurologic complications and affects 20-30% of Veterans. Evidence supports a link between DM and hearing loss. A growing body of evidence-including from our own laboratory-suggests that DM-related harmful effects alter the cochlea, auditory nerve, and brain, impacting auditory processing at peripheral, central, and cognitive levels. Because ofthe documented adverse effects of hearing loss on an individual's social, emotional and economic well-being, the insidious nature of even a mild peripheral hearing loss when combined with central and cognitive declines,and the potential for dual sensory loss of vision and hearing in this population, it is important that the pathophysiologic and histopathologic mechanisms of DM-related auditory senescence be revealed. Like most previous studies considering hearing loss and DM, initial findings originating from the NCRAR were established in cross-sectional studies. Our published results support the notion that DM effects are more notable in a younger population, reminiscent of changes from presbycusis among non-diabetics who are much older, and among Veterans with more severe disease, requiring insulin (Austin et al 2009; Konrad-Martin et al., 2010). However, historically, we did not address progression in auditory dysfunction over time, or how these hearing changes impact speech understanding or quality of life. We are currently in the last year of a 4-year longitudinal study of auditory function among Veterans with and without DM, some of whom were first seen in our DM studies 5-17 years ago, thereby providing additional longitudinal contrasts. Like many cohort studies, this longitudinal study becomes more valuable the longer the observation is continued. We propose to continue longitudinal surveillance in this valuable cohort of Veterans with DM-related auditory and cognitive changes and to augment findings with a longitudinal assessment of DM-related auditory senescence in a mouse model of type 2 DM. Proposed research aims to more precisely determine the longitudinal changes from DM compared to changes from aging alone in humans and mice, including estimating effect sizes and the age of onset of key measures of auditory and cognitive dysfunction. We introduce measures of temporal processing in both species because of its importance for speech understanding in humans and because, in animal models, impaired temporal processing at neural and behavioral levels has been linked to peripheral-auditory changes that may occur prematurely with DM. Specific Aim (1) Benchmark longitudinal changes in auditory function among Veterans with type 2 DM and estimate the differences from normal aging. Specific Aim (2) Determine the extent to which type 2 DM exacerbates presbycusis in the mouse cochlea. Specific Aim (3) Determine the DM characteristics and comorbidities that are risk...