Basic Information
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Gene targeting strategy
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Gene targeting strategy for B-hGLP1R/hGCGR mice. The full coding sequence of human GLP1R gene was inserted into mouse Glp1r gene in B-hGLP1R/hGCGR mice. The exons 2-14 of mouse Gcgr gene that encode the full-length protein were replaced by human GCGR exons 2-14 in B-hGLP1R/hGCGR mice.
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mRNA expression analysis
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Species-specific GLP1R gene expression analysis in wild-type and humanized B-hGLP1R/hGCGR mice by RT-PCR. Mouse Glp1r mRNA was detected in lung and liver tissues from wild-type (+/+) mice, while human GLP1R mRNA was detected in homozygous B-hGLP1R/hGCGR (H/H) mice.
Species-specific GCGR gene expression analysis in wild-type and humanized B-hGLP1R/hGCGR mice by RT-PCR. Mouse Gcgr mRNA was detected in kidney and liver tissues from wild-type C57BL/6 (+/+) mice, while human GCGR mRNA was detected in homozygous B-hGLP1R/hGCGR (H/H) mice.
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Protein Expression Analysis
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GLP1R expression analysis in wild-type mice and B-hGLP1R/hGCGR mice by western blotting. GLP1R protein was detectable in the lung, brain and liver of wild-type mice (+/+) and homozygous B-hGLP1R/hGCGR mice (H/H). As the antibody used in the experiments is cross reactive between human and mouse, mRNA data should be considered. As mouse Glp1r mRNA is not expressed in humanized mice, it is predicted that the expressed protein in B-hGLP1R/hGCGR mice is human GLP1R.
GCGR expression analysis in wild-type mice and B-hGLP1R/hGCGR mice by western blotting. GCGR protein was detectable in the kidney and liver of wild-type mice (+/+) and homozygous B-hGLP1R/hGCGR mice (H/H). As for the antibody used in the experiments is cross reactive between human and mouse, mRNA data should be considered. As mouse Gcgr mRNA is not expressed in humanized mice, it is predicted that the expressed protein in B-hGLP1R/hGCGR mice is human GCGR.
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In vivo efficacy of cotadutide in B-hGLP1R/hGCGR mice
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In vivo efficacy of cotadutide on B-hGLP1R/hGCGR mice DIO model. (A,C) Body weight and its’ change from baseline (%) during HFD induced. (B) Body weight before grouping. (D) Body weight change in grouping day and (E) experiment endpoint. (F) Random blood glucose on day 0, 3, 7, 10 after grouping. (G) Blood glucose profile following intraperitoneal injection of 1.25 g/kg glucose on day 12 after dosing. (H) Area under the IPGTT curve. (I) Cumulative food intake over the first 4 day of dosing. (J) Plasma insulin, (K) glucagon, (L) TG (triglycerides) and TC (cholesterol) level of liver on 20 hours after administration of the final dose. As shown in the panel, mouse body weight has increased under a high-fat diet. Following dosing with reagents in the panel, body weight and random blood glucose have reduced in the 30nM cotadutide treatment group but not obviously in the 10nM cotadutide group. During intraperitoneal glucose tolerance test (IPGTT), cotadutide reduced blood glucose. Whereas food intake has no difference among groups, and cotadutide shows a trend in reducing liver TG and TC levels in 10nM dose without statistical differences. As well as, the plasma insulin and glucagon show decreases trends. (ANOVA results, *:P<0.05,**:P<0.01, ***:p<0.001, ****:p<0.0001)
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