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B-hGLP1R mice
Strain Name C57BL/6-Glp1rtm1(GLP1R)/Bcgen Common Name  B-hGLP1R mice
Background C57BL/6 Catalog number  170164
Related Genes 
GLP-1; GLP-1R; GLP-1-R

Gene description

The glucagon-like peptide-1 receptor (GLP1R) is a class B family G protein-coupled receptor, primarily expressed in the pancreas especially in  pancreas islet B cell and central nervous system (CNS), as well as variable levels in the peripheral nervous system, heart, kidney, and lung. GLP-1 can binds to GLP1R, which is activated and stimulating the insulin secretion and inhibition of glucagon release. GLP-1 also exerts central effects to decrease appetite and promote satiety. However the GLP-1 is susceptible to N-terminal proteolysis by action of the serine exopeptidase dipeptidyl peptidase-4 (DPP-4), which removes the terminal dipeptide to abolish biological activity. This proteolytic lability severely limits the circulating half-life of the active hormone. As a result, the agonists of GLP1R has potential in an anti-obesity and diabetes therapeutic.


mRNA and protein expression analysis

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The mRNA of human GLP1R was detectable in the lung of the homozygous B-hGLP1R mice,but not detectable in wildtype mice. While the mouse GLP1R mRNA was not detectable in homozygous B-hGLP1R mice. Also we proved that the protein could be expressed normally by western blot analysis. Human and mouse cross-reactive antibodies were used to detect the GLP1R of the wildtype and humanized GLP1R mice.


Protein expression analysis


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IHC for human GLP1R expression. Pancreata from wild-type (+/+) and B-hGLP1R mice (H/H) were stained using an antibody specific for human GLP1R. and only the pancreas from B-hGLP1R mice (H/H) showed hGLP1R positive signal in plasma membrane.

Analysis of leukocytes cell subpopulation in B-hGLP1R mice


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Analysis of leukocyte subpopulations by FACS. Splenocytes were isolated from female C57BL/6 and B-hGLP1R mice (n=3, 9-week-old). Flow cytometry analysis of the splenocytes were performed to assess leukocyte subpopulations. A. Representative FACS plots. Single live cells were gated for the CD45+ population and used for further analysis as indicated here. B. Results of FACS analysis. Percent of T cells, B cells, NK cells, monocytes, dendritic cells, granulocytes and macrophages in homozygous B-hGLP1R mice were similar to those in the C57BL/6 mice, demonstrating that GLP1R humanized does not change the overall development, differentiation or distribution of these cell types in spleen. The same results were observed in blood and lymph node, data was not shown. Values are expressed as mean ± SEM.


Analysis of leukocytes cell subpopulation in B-hGLP1R mice



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Analysis of T cell subpopulation in spleen by FACS. The lymphocytes were isolated from spleen in C57BL/6 and B-hGLP1R mice (n=3, 9-week-old). The proportion of T cells subpopulation was tested by flow cytometry. There were no differences between C57BL/6 and B-hGLP1R mice, demonstrating that humanized of GLP1R does not change the overall development, differentiation or distribution of these T cell subtypes. The same results were observed in blood and lymph node, data was not shown. Values are expressed as mean ± SEM.


Dulaglutide reduces blood glucose in B-hGLP1R mice

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Dulaglutide reduces blood glucose in B-hGLP1R mice. Blood was collected from C57BL/6 mice and B-hGLP1R mice (male, 7-8w, n=5) at multiple time points after injection of Dulaglutide (in house) or PBS for analysis. (A). Body weight. (B). Non-fasting blood glucose. (C). Fasting blood glucose. (D). IPGTT. (E). Area under the curve for the IPGTT. The body weight has no significant change during the experiment. Dulaglutide reduced the non-fasting blood glucose and fasting blood glucose compared to the PBS in C57BL/6 and B-hGLP1R mice. For the IPGTT results, B-hGLP1R mice and wild-type mice display similar physiological responses for glucose metabolism. Values are expressed as mean ± SEM. IPGTT, Intraperitoneal glucose tolerance test.


Dulaglutide reduces food instake in B-hGLP1R mice


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Dulaglutide decreased food intake in B-hGLP1R mice. Food intake was monitored in C57BL/6 and B-hGLP1R mice (male, 15w, n=5) after treatment with dulaglutide for 24 and 48 hours separately, then calculated for each cage and corrected for food intake per mouse. (A). Food intake in 24h. (B). Food intake in 48h. Dulaglutide decreased food intake both in C57BL/6 and B-hGLP1R mice. Values are expressed as mean ± SEM.


Model schematic and antibody evaluation scheme


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Schedule for in vivo efficacy of Dulaglutide. B-hGLP1R (male, n=10) mice were fed with high-fat diet for 12 weeks to induce mice obesity. Then, the mice were randomized according to body weight. About 24 hours before or after injected drugs,  measured and calculated the food intake. The Dulaglutide (in house) was subcutaneous injection every two days from Day 1 to 8 after grouping. Blood was collected to measure blood glucose and IPGTT on the days shown in the schematic diagram and the table. Measure plasma insulin during the IPGTT.


Dulaglutide reduces blood glucose in B-hGLP1R mice with obesity

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Dulaglutide reduces blood glucose in B-hGLP1R mice with obesity. Blood was collected from B-hGLP1R mice (male, n=10) at multiple time points after injection of Dulaglutide (in house) or PBS for analysis. (A). Body weight. (B). Non-fasting blood glucose. (C). Fasting blood glucose. (D). Serum glucose levels following intraperitoneal glucose challenge. (E). Area under the curve (AUC) for the IPGTT. (F). Food intake. Dulaglutide resulted in no weight loss during the experiment, and reduced the non-fasting blood glucose and fasting blood glucose compared to PBS. For the IPGTT results, glucose tolerance was improved by dulaglutide compared to PBS. The results show that B-hGLP1R mice provide an efficacious preclinical animal model for evaluating related drugs. Values are expressed as mean ± SEM. IPGTT, Intraperitoneal glucose tolerance test.


Dulaglutide decreased food intake/glucagon and increased insulin/GLP-1 secretion in B-hGLP1R mice with obesity

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Dulaglutide regulated blood glucose by increasing insulin and decreased glucagon secretion in B-hGLP1R obesity mice, and influenced the food intake. Food intake was measured in C57BL/6 and B-hGLP1R mice (male, n=10) after treatment with dulaglutide for 24h, then calculated for each cage and corrected for food intake per mice. The plasma insulin was measured during the IPGTT. And collected the serum for GLP-1 and glucagon analysis. (A) Food intake in 24h after treatment. (B). Plasma insulin secretion. (C). The area under the curve for plasma insulin during 0-30 minutes. (D). Serum GLP-1. (E). Serum Glucagon. Dulaglutide decreased food intake in B-hGLP1R mice. Meanwhile, Insulin and GLP-1 increased, glucagon secretion decreased after treatment with Dulaglutide, which is consistent with the mechanisms of control blood glucose. Values expressed as mean ± SEM. IPGTT, Intraperitoneal glucose tolerance test.


PF-06882961 improved glucose tolerance in B-hGLP1R mice with obesity

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PF-06882961 improved glucose tolerance in B-hGLP1R mice with obesity. (A). Serum glucose levels following intraperitoneal glucose challenge (IPGTT). (B). Area under the curve (AUC) for the IPGTT. Glucose tolerance was improved by PF-06882961 compared to vehicle in B-hGLP1R mice but not in wild-type C57BL/6 mice. The results show that B-hGLP1R mice provide an efficacious preclinical animal model for evaluating species-specific new 'biological' medicines. Values are expressed as mean ± SEM. (PF-08882961 is a small molecule agonist for human GLP1R).