Liver-islet and intra-islet cross talk in alpha cell hyperplasia and beta cell regeneration

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 Remarkably, GRA-treated mice maintained normal blood glucose, even after the treatment was withdrawn.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.