Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes. Issue 1 (4th March 2020)

• Record Type: Journal Article
• Authors: Lang, Shan; Yang, Jin; Yang, Kun; Gu, Liangbiao; Cui, Xiaona; Wei, Tianjiao; Liu, Junling; Le, Yunyi; Wang, Haining; Wei, Rui; Hong, Tianpei
• Is Part Of: BMJ open diabetes research and care. Volume 8:Issue 1(2020)
• Publication Date: 2020-03-04
• Subjects: type 2 diabetes -- glucagon-like peptide-1 (GLP-1) -- glucagon receptor -- intestinal hormones; Diabetes -- Periodicals; 616.462005
• DOI: 10.1136/bmjdrc-2019-001025
• Languages: English
• ISSNs: 2052-4897

Abstract

Abstract : Objective: Glucagon receptor (GCGR) blockage improves glycemic control and increases circulating glucagon-like peptide-1 (GLP-1) level in diabetic animals and humans. The elevated GLP-1 has been reported to be involved in the hypoglycemic effect of GCGR blockage. However, the source of this elevation remains to be clarified. Research design and methods: REMD 2.59, a human GCGR monoclonal antibody (mAb), was administrated for 12 weeks in db/db mice and high-fat diet+streptozotocin (HFD/STZ)-induced type 2 diabetic (T2D) mice. Blood glucose, glucose tolerance and plasma GLP-1 were evaluated during the treatment. The gut length, epithelial area, and L-cell number and proliferation were detected after the mice were sacrificed. Cell proliferation and GLP-1 production were measured in mouse L-cell line GLUTag cells, and primary mouse and human enterocytes. Moreover, GLP-1 receptor (GLP-1R) antagonist or protein kinase A (PKA) inhibitor was used in GLUTag cells to determine the involved signaling pathways. Results: Treatment with the GCGR mAb lowered blood glucose level, improved glucose tolerance and elevated plasma GLP-1 level in both db/db and HFD/STZ-induced T2D mice. Besides, the treatment promoted L-cell proliferation and LK-cell expansion, and increased the gut length, epithelial area and L-cell number in these two T2D mice. Similarly, our in vitro study showed that the GCGR mAb promoted L-cell proliferation and increased GLP-1 production in GLUTag cells, and primary mouse and human enterocytes. Furthermore, either GLP-1R antagonist or PKA inhibitor diminished the effects of GCGR mAb on L-cell proliferation and GLP-1 production. Conclusions: The elevated circulating GLP-1 level by GCGR mAb is mainly due to intestinal L-cell proliferation and GLP-1 production, which may be mediated via GLP-1R/PKA signaling pathways. Therefore, GCGR mAb represents a promising strategy to improve glycemic control and restore the impaired GLP-1 production in T2D.