Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes
ObjectiveGlucagon 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...
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doaj-35696900d26a4b52afb435e6b306131e2021-06-10T10:02:39ZengBMJ Publishing GroupBMJ Open Diabetes Research & Care2052-48972020-04-018110.1136/bmjdrc-2019-001025Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetesShan Lang0Liangbiao Gu1Xiaona Cui2Tianjiao Wei3Junling Liu4Yunyi Le5Rui Wei6Tianpei Hong7Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, ChinaDepartment of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, ChinaDepartment of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, ChinaDepartment of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, ChinaDepartment of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, ChinaDepartment of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, ChinaDepartment of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, ChinaDepartment of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, ChinaObjectiveGlucagon 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 methodsREMD 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.ResultsTreatment 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.ConclusionsThe 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.https://drc.bmj.com/content/8/1/e001025.full |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shan Lang Liangbiao Gu Xiaona Cui Tianjiao Wei Junling Liu Yunyi Le Rui Wei Tianpei Hong |
spellingShingle |
Shan Lang Liangbiao Gu Xiaona Cui Tianjiao Wei Junling Liu Yunyi Le Rui Wei Tianpei Hong 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 |
author_facet |
Shan Lang Liangbiao Gu Xiaona Cui Tianjiao Wei Junling Liu Yunyi Le Rui Wei Tianpei Hong |
author_sort |
Shan Lang |
title |
Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes |
title_short |
Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes |
title_full |
Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes |
title_fullStr |
Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes |
title_full_unstemmed |
Glucagon receptor antagonist upregulates circulating GLP-1 level by promoting intestinal L-cell proliferation and GLP-1 production in type 2 diabetes |
title_sort |
glucagon receptor antagonist upregulates circulating glp-1 level by promoting intestinal l-cell proliferation and glp-1 production in type 2 diabetes |
publisher |
BMJ Publishing Group |
series |
BMJ Open Diabetes Research & Care |
issn |
2052-4897 |
publishDate |
2020-04-01 |
description |
ObjectiveGlucagon 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 methodsREMD 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.ResultsTreatment 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.ConclusionsThe 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. |
url |
https://drc.bmj.com/content/8/1/e001025.full |
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