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

Pancreatic β -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 β -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 β -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 β -cell mass through self-replication, differentiation from precursor cells, and transdifferentiation from pancreatic α cells to β -cells. The pancreatic β -cell mass increased more significantly after GCGR mAb treatment, while the combination group did not further increase the pancreatic β -cell area. However, compared with the GCGR mAb group, the combined treatment reduced the plasma glucagon level and increased the proportion of β -cells/ α -cells. Our study evaluated the effects of liraglutide, GCGR mAb monotherapy, and combined strategy in glucose control and islet β -cell regeneration and provided useful clues for the future clinical application in type 1 diabetes.