1722-P: Suppression of Glucagon Signaling Promotes α-to-ß Reprogramming

The generation of surrogate β cells has attracted a lot of attention for the cure of diabetes. Recently, we have revealed that glucagon antibody induces α-cell neogenesis in adult mice, suggesting that the suppression of glucagon signaling could play a role in cellular plasticity in α-cell lineage. Therefore, we hypothesized that inhibiting glucagon signaling may affect the efficiency of α-to-β reprogramming. We generated a transgenic mouse line (αPdx1) that exogenously and inducibly expresses Pdx1 specifically in α cells, and treated the mice with glucagon receptor antagonist. As FLAG-tagged sequence is attached to Pdx1, the exogenous expression of Pdx1 can be distinguished from the endogenous Pdx1 gene. The reprogramming efficiency was evaluated by counting FLAG-tag/insulin double-positive cells, that is, α-cell-derived insulin-producing cells. Immunohistological analysis demonstrated that the number of α-cell-derived insulin-producing cells was significantly increased in αPdx1 mice treated with glucagon receptor antagonist (GRA), compared with the mice treated with vehicle (26.0 ± 1.6 vs 13.5 ± 1.3%, p < 0.0001). In addition, GRA significantly increased α-to-β reprogramming ratio in αPdx1 mice after β-cell ablation (73.7 ± 3.3 vs 52.0 ± 1.8%, p = 0.0004). Furthermore, when the mice were induced hyperglycemia by alloxan, the administration of GRA significantly improved hyperglycemia during intraperitoneal glucose tolerance test (IPGTT), compared αPdx1 mice administered by vehicle (p = 0.012). Notably, the insulin levels during IPGTT were significantly higher in the mice treated with GRA (p = 0.034). Thus, the suppression of glucagon signaling promotes α-to-β reprogramming in mice, which could lead to establishing efficient methods for generating surrogate β cells.