Objective: Based on the clear role for glucagon in the pathogenesis of diabetes, glucagon-blocking therapies have been pursued as a therapeutic strategy for this disease. Here, we used REMD 2.59, a human antagonistic glucagon receptor (GCGR) monoclonal antibody (mAb), to clarify the effects of GCGR mAb in promoting pancreatic β cell regeneration in type 2 diabetes (T2D), and its potential mechanism.
Methods: GCGR mAb was administrated weekly for 4 weeks in db/db mice and HFD/STZ-induced T2D mice, including different lineage-tracing mice. The plasma insulin and glucagon were determined by using ELISA. The evaluation of islet morphology was performed with immunofluorescent analysis. GCGR mAb was also treated in the systemic Fgf21 gene knockout (Fgf21-/-) and hepatocyte-specific Fgf21 gene knockout (Fgf21Hep-/-) T2D mice.
Results: Treatment with GCGR mAb lowered blood glucose, improved glucose tolerance, and elevated plasma glucagon and insulin levels in both db/db mice and HFD/STZ-induced T2D mice. The β cell dedifferentiation as indicated by β cell lineage-tracing was blocked by GCGR mAb. The β cell proliferation as indicated by insulin+ and BrdU+ cells was boosted by GCGR mAb. The α-to-β cell conversion, as evaluated by glucagon+ insulin+ cells and confirmed by α cell lineage-tracing, was facilitated by GCGR mAb. After GCGR mAb treatment, some insulin+ cells were located in the duct region or even colocalized with duct cell markers, suggestive of duct-derived β cell neogenesis that was also verified by Ngn3+ cell lineage-tracing. Notably, GCGR mAb could still improve glucose tolerance and increase β cell mass, but these effects were attenuated in Fgf21-/- and Fgf21Hep-/- T2D mice compared with WT T2D mice.
Conclusions: GCGR mAb promotes β cell regeneration via inhibiting β cell dedifferentiation and promoting β cell self-replication, α-to-β cell conversion and duct-derived β cell neogenesis in T2D mice, which is partly mediated by liver-derived FGF21.
X. Cui: None. T. Wei: None. J. Feng: None. J. Yang: None. H. Yan: Board Member; Self; REMD Biotherapeutics, Other Relationship; Spouse/Partner; REMD Biotherapeutics. R. Wei: None. T. Hong: Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi.
National Natural Science Foundation of China (81830022)