ABSTRACT While evaluating the potential for glucagon receptor antagonists (GRAs) to maintain glucose homeostasis in T1D rodents, we noted that GRAs promote β−cell survival and regeneration. Remarkably, GRA-treated mice maintained normal blood glucose, even after the treatment was withdrawn. Our recently published data suggest that: 1) ablation or antagonism of the glucagon receptor (GcgR) blunts apoptosis and stimulates regeneration of functional β-cell mass in mice; 2) much of this new insulin+ mass derives from the conversion of α−cell precursors into insulin-producing cells; and 3) GRAs restore sustainable euglycemia and insulin production in diabetic NOD mice and in mice grafted with human islets. Our preliminary results suggest that the β-cytotrophic effects of GRAs occur through both islet autonomous effects and through a well described liver- α-cell axis4-7 which triggers α-cell hyperplasia through AA-dependent mechanisms (Figure 1). We have identified Foxn3, a glucagon-responsive transcriptional repressor and novel mediator of glycemia8-11, as the previously-undefined integrator by which glucagon alters amino acid metabolism. In parallel, we have identified the GRA-driven upregulation of fibroblast growth factor 2 (FGF2), a target of the proliferative transcriptional co-factor Yes-associated protein 1 (YAP1) that is expressed in Sox9+ ductal cells, as a key contributor to GRA-mediated revival of a regenerative niche within the islet. We hypothesize that impaired glucagon action promotes hepatic Foxn3-mediated α-cell hyperplasia via changes in amino acid metabolism and an FGF2-mediated regenerative niche within the islet to allow α-cell to β-cell conversion in T1D. We will evaluate our hypothesis using a cadre of novel, validated, and uniquely-suited mouse models which facilitate our genetic dissection of the mechanisms linking the loss of glucagon signaling to altered hepatic utilization of amino acids, α-cell hyperplasia, and the restoration of functional β-cell mass via two aims. 1) Using PANIC- ATTAC diabetic mice, cultured murine islets, and cultured human islets, we will examine the islet-autonomous effects of glucagon receptor antagonism or ablation on β-cell survival and β-cell regeneration. 2) We will examine α-cell hyperplasia, β-cell survival and the regeneration of functional β−cell mass after liver-specific deletion or overexpression of Foxn3.