Combination of GLP-1 Receptor Activation and Glucagon Blockage Promotes Pancreatic beta-Cell Regeneration In Situ in Type 1 Diabetic Mice

Pancreatic beta-cell neogenesis in vivo holds great promise for cell replacement therapy in diabetic patients, and discovering the relevant clinical therapeutic strategies would push it forward to clinical application. Liraglutide, a widely used antidiabetic glucagon-like peptide-1 (GLP-1) analog, has displayed diverse beta-cell-protective effects in type 2 diabetic animals. Glucagon receptor (GCGR) monoclonal antibody (mAb), a preclinical agent that blocks glucagon pathway, can promote the recovery of functional beta-cell mass in type 1 diabetic mice. Here, we conducted a 4-week treatment of the two drugs alone or in combination in type 1 diabetic mice. Although liraglutide neither lowered the blood glucose level nor increased the plasma insulin level, the immunostaining showed that liraglutide expanded beta-cell mass through self-replication, differentiation from precursor cells, and transdifferentiation from pancreatic alpha cells to beta-cells. The pancreatic beta-cell mass increased more significantly after GCGR mAb treatment, while the combination group did not further increase the pancreatic beta-cell area. However, compared with the GCGR mAb group, the combined treatment reduced the plasma glucagon level and increased the proportion of beta-cells/alpha-cells. Our study evaluated the effects of liraglutide, GCGR mAb monotherapy, and combined strategy in glucose control and islet beta-cell regeneration and provided useful clues for the future clinical application in type 1 diabetes.