Diabetes is a serious medical condition resulting from failure of insulin action and/or insufficient insulin secretion from the pancreatic β-cells. Diabetes affects approximately 20% of the Veterans that receive health care through the Veterans Health Administration. Therefore, efforts to understand the pathophysiology of this debilitating disease are highly relevant to future developments in care and therapeutics of this disease. The PI has been conducting diabetes research for nearly 30 years. His current investigations are aimed at understanding the molecular and cellular mechanisms underlying β-cell dysfunction leading to the onset of diabetes. Seminal contributions from his laboratory have defined novel roles for Rac1, a small G-protein, in the pathogenesis of islet β-cell dysfunction under metabolic stress and diabetic conditions. His current studies are based on the hypothesis that metabolic stress promotes functional and transcriptional activation of Rac1 to promote intracellular oxidative stress, mitochondrial and nuclear damage/ collapse leading to the loss of functional β-cell mass. His team is also aiming to identify key signaling proteins/factors in the Rac1 activation- deactivation cycle that might contribute to the metabolic and functional defects in the pancreatic β-cell. These studies employ state-of-the art microscopic, molecular biological, proteomics and lipidomics approaches involving islets derived from animal models of impaired insulin secretion as well as islets from T2D human donors. In addition to his ongoing investigations (above), during the next renewal period, the PI will continue collaborative studies toward the development of novel small molecule and peptide-based inhibitors for halting metabolic defects of the islet β-cell in in vitro and in vivo models of metabolic stress and diabetes. The long-standing expertise of the PI and his collaborators in this field will provide a unique opportunity to address these important aspects of islet function in health and diabetes. Furthermore, the PI will continue his ongoing, highly productive, collaborative studies to decipher the molecular and cellular mechanisms involved in the pathogenesis of diabetic retinopathy. Lastly, the PI proposes to establish new collaborations with researchers at the JDD VAMC to assess islet β-cell function in animal models of TBI and PTSD. Significant knowledge gaps exist in this area, which is highly relevant to the VA healthcare mission. Collectively, data accrued from these complementary investigations will provide actionable insights that will impact the prevention and treatment of diabetes and its associated complications in humans, including our Veterans. In support of the proposed investigations, the PI has already established numerous collaborations with VA and non-VA investigators. He is highly productive with a large number of publications in high impact journals; the majority of which are coauthored by his trainees and collaborators. ...