Summary Type 2 Diabetes (T2D) results from a combination of insulin resistance, most often brought about by obesity, and a gradual and unrelenting erosion of the ability of pancreatic beta cells to secrete sufficient insulin to meet the increased metabolic demand for insulin. A major mediator of beta cell dysfunction is glucose toxicity, mediated by sustained hyperglycemia. During the pathogenesis of T2D a vicious cycle ensues, where insulin resistance increases the demand for more insulin, but beta cells become “exhausted” and unable to secret enough insulin to maintain glucose homeostasis, leading to increased hyperglycemia, more beta cell exhaustion and death, erosion of beta cell mass, and eventually the need for insulin therapy. Therefore, there is an urgent need for new therapies that block the vicious cycle and preserve beta cell mass. We believe we have uncovered a molecular mechanism that explains the vicious cycle that erodes beta cell function and beta cell mass during T2D. This proposal will explore the molecular details of this mechanism and test the feasibility of therapeutic interventions that preserve rodent and human beta cells in models of glucose toxicity and T2D. The overarching hypothesis of this proposal is that the feed-forward mechanism of ChREBPβ expression becomes dysregulated in T2D and drives glucose toxicity through expression of the pro-oxidative activity of Txnip, the effects of which can be mitigated by the activation of Nrf2. Furthermore, maneuvers that break the vicious cycle of ChREBPβ production, or mitigate its actions through Txnip inhibition, or Nrf2 activation, protects beta cell mass and alleviates diabetic burden. This proposal will test this hypothesis by exploring the molecular regulatory mechanisms between these 3 factors, and by depleting either ChREBPβ or Txnip, or elevating NRF2, in mouse models of diabetes or glucotoxicity, or in glucotoxic or T2D human islets. Specific Aim 1 will explore the regulatory relationships between ChREBPβ, Txnip, and NRF2 that determine beta cell fate. Specific Aim 2 will examine how depletion of ChREBPβ, or Txnip, or activation of NRF2 affects beta cell function and glucose homeostasis in diabetic and glucotoxic mouse models. Specific Aim 3 will test if depletion of ChREBPβ, or TXNIP, or activation of NRF2 affects beta cell function and survival in glucotoxic or T2D human islets. Our results will inform the design of therapies that will mitigate beta cell glucose toxicity and may result in very specific drugs that target beta cells to preserve beta cell mass and function and alleviate diabetic symptoms and complications.