Glucagon is an essential regulator of glucose homeostasis, particularly in type 2 diabetes (T2D). Blocking the glucagon receptor (GCGR) in diabetic animals and humans has been shown to alleviate hyperglycemia and increase circulating glucagon-like peptide-1 (GLP-1) levels. However, the origin of the upregulated GLP-1 remains to be clarified. Here, we administered high-fat diet + streptozotocin-induced T2D mice and diabetic db/db mice with REMD 2.59, a fully competitive antagonistic human GCGR monoclonal antibody (mAb) for 12 weeks. GCGR mAb treatment decreased fasting blood glucose levels and increased plasma GLP-1 levels in the T2D mice. In addition, GCGR mAb upregulated preproglucagon gene expression and the contents of gut proglucagon-derived peptides, particularly GLP-1, in the small intestine and colon. Notably, T2D mice treated with GCGR mAb displayed a higher L-cell density in the small intestine and colon, which was associated with increased numbers of LK-cells coexpressing GLP-1 and glucose-dependent insulinotropic polypeptide and reduced L-cell apoptosis. Furthermore, GCGR mAb treatment upregulated GLP-1 production in the pancreas, which was detected at lower levels than in the intestine. Collectively, these results suggest that GCGR mAb can increase intestinal GLP-1 production and L-cell number by enhancing LK-cell expansion and inhibiting L-cell apoptosis in T2D.
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http://dx.doi.org/10.1016/j.peptides.2020.170349 | DOI Listing |
J Diabetes
December 2023
Department of Endocrinology and Metabolism, Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
Introduction: The role of cardiac microvascular endothelial cells (CMECs) in diabetic cardiomyopathy is not fully understood. We aimed to investigate whether a glucagon receptor (GCGR) monoclonal antibody (mAb) ameliorated diabetic cardiomyopathy and clarify whether and how CMECs participated in the process.
Research Design And Methods: The db/db mice were treated with GCGR mAb or immunoglobulin G (as control) for 4 weeks.
Diabetes
May 2023
Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China.
Unlabelled: Dysfunction of glucagon-secreting α-cells participates in the progression of diabetes, and glucagon receptor (GCGR) antagonism is regarded as a novel strategy for diabetes therapy. GCGR antagonism upregulates glucagon and glucagon-like peptide 1 (GLP-1) secretion and, notably, promotes β-cell regeneration in diabetic mice. Here, we aimed to clarify the role of GLP-1 receptor (GLP-1R) activated by glucagon and/or GLP-1 in the GCGR antagonism-induced β-cell regeneration.
View Article and Find Full Text PDFAm J Physiol Endocrinol Metab
January 2023
Department of Endocrinology and Metabolism, https://ror.org/04wwqze12Peking University Third Hospital, Beijing, China.
Glucagon-secreting pancreatic α-cells play pivotal roles in the development of diabetes. Glucagon promotes insulin secretion from β-cells. However, the long-term effect of glucagon on the function and phenotype of β-cells had remained elusive.
View Article and Find Full Text PDFDiabetologia
March 2023
Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, China.
Aims/hypothesis: Glucagon receptor (GCGR) antagonism ameliorates hyperglycaemia and promotes beta cell regeneration in mouse models of type 2 diabetes. However, the underlying mechanisms remain unclear. The present study aimed to investigate the mechanism of beta cell regeneration induced by GCGR antagonism in mice.
View Article and Find Full Text PDFActa Diabetol
January 2023
Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing, 100191, China.
Aims: To investigate whether treatment with γ-aminobutyric acid (GABA) alone or in combination with glucagon receptor (GCGR) monoclonal antibody (mAb) exerted beneficial effects on β-cell mass and α-cell mass, and to explore the origins of the regenerated β-cells in mice with type 1 diabetes (T1D).
Methods: Streptozotocin (STZ)-induced T1D mice were treated with intraperitoneal injection of GABA (250 μg/kg per day) and/or REMD 2.59 (a GCGR mAb, 5 mg/kg per week), or IgG dissolved in PBS for 8 weeks.
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