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

Abstract

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 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 effect of liraglutide, GCGR mAb monotherapy, or combined strategy in glucose control and islet β-cell regeneration and provided useful clues for the future clinical application in type 1 diabetes.

Glucagon Acting at the GLP-1 Receptor Contributes to β-Cell Regeneration Induced by Glucagon Receptor Antagonism in Diabetic Mice

“…However, the effect of GLP-1R on β-cell regeneration has not yet been investigated. Our recent report showed that the combination of GCGR mAb and liraglutide (a GLP-1R agonist) could not further increase β-cell area compared with GCGR mAb alone ( 48 ), suggesting that GCGR mAb itself already activated pancreatic GLP-1R sufficiently. By using the GLP-1R antagonist Ex9 and global and pancreatic Glp1r -knockout mice, our studies demonstrated that GLP-1R signaling contributed to GCGR antagonism–induced β-cell regeneration.…”

Emerging Anti-Diabetic Drugs for Beta-Cell Protection in Type 1 Diabetes

“…REMD 2.59 is another human GCGR mAb that differs from volagidemab by one amino acid and has shown reduced gluconeogenesis and blood glucose, improved insulin action and glucose tolerance, enhanced lipid oxidation, protection against diabetic cardiomyopathy, and increased GLP-1 production and L-cell number in mouse models of type 2 diabetes [55][56][57]. REMD 2.59 has also been reported to decrease blood glucose, increase plasma glucagon, somatostatin, and insulin, increase α-cell mass and δ-cell number, which could potentially transdifferentiate into β-cells, and induce β-cell regeneration in normoglycemic and type 1 and 2 diabetic mouse models [58][59][60][61][62][63]. Additionally, this GCGR mAb has been tested for benefits in mouse models of myocardial infarction [64,65].…”

Regeneration of β cells from cell phenotype conversion among the pancreatic endocrine cells

“…Moreover, we also show that dapagliflozin, an SGLT2 inhibitor, promotes α‐to‐β cell conversion in type 2 diabetic mice, although this conversion only accounts for a small fraction of the regenerated β cells. 12 Enhancement of GLP‐1 signaling by several approaches, including transfection of recombinant adenovirus expressing GLP‐1, GLP‐1 receptor agonists or dipeptidyl peptidase 4 (DPP‐4) inhibitors (which prevent degradation of GLP‐1 by DPP‐4), can induce α‐to‐β cell conversion in type 1 and type 2 diabetic rodents, 13 , 27 , 28 and increase β cell‐like gene expression in a subcluster of human α cells. 13 Either glucagon receptor blockage or dapagliflozin can upregulate GLP‐1 levels in the circulation and islets, which is suggestive of the importance of GLP‐1 in mediating α‐to‐β cell conversion.…”