Article Text
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.
- type 2 diabetes
- glucagon-like peptide-1 (GLP-1)
- glucagon receptor
- intestinal hormones
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Footnotes
Correction notice This article has been corrected since it was published. The GLUTag cells were used in the lab of Professor Xiaopei Cao (Department of Endocrinology, Sun Yat-sen University, Guangzhou, China), and the cell line was provided by Professor Daniel J Drucker (Mt. Sinai Hospital, University of Toronto, ON, Canada).
Contributors SL, RW and TH designed the research. SL, JY, KY, LG, XC and TW performed the experiments. SL, JL, YL, HW, RW and TH analyzed the data. SL and RW wrote the paper. TH reviewed and edited the manuscript. RW and TH are the guarantors of this work, and as such had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Funding This work was supported by the National Key Research and Development Program of China (2016YFA0100501), the National Natural Science Foundation of China (81830022, 81770768, 81970671, 91749101, 81800730 and 81670701), and the Natural Science Foundation of Beijing (7192225).
Disclaimer The funding sources had no role in study design, collection, analysis and interpretation of data, writing of the report, and decision to submit the article for publication.
Competing interests None declared.
Patient consent for publication Not required.
Ethics approval All animal experimental procedures were approved by the Animal Care and Use Committee of Peking University. The use of human intestinal tissues was approved by the Ethics Committee of Peking University Third Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information. The data sets generated during the current study are available from the corresponding authors upon reasonable request.