Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes

BMJ Open Diabetes Research & Care
Shan LangTianpei Hong

Abstract

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. 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. 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, epithe...Continue Reading

Citations

Feb 16, 2021·World Journal of Stem Cells·Kang-Li WangRui Wei
Feb 4, 2021·Endocrinology·Emily W SunDamien J Keating
Jun 29, 2021·The Lancet. Diabetes & Endocrinology·Michael A NauckJuris J Meier
Jul 22, 2021·ChemMedChem·Xi Khai Wong, Keng Yoon Yeong

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Methods Mentioned

BETA
ELISA
protein assay
electrophoresis
flow cytometry
reverse transcription PCR

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