GcgRA ΔNull and GcgRA ΔVilCre, respectively (n=15M WT and GcgRA ΔNull/drug treatment 15M Vil Cre and GcgRA ΔVilCre/drug treatment). Ex9 (50ug) impaired oral ( H–I) and IP ( J–K) glucose tolerance over saline (100μl) in WT and Vil Cre vs. Vil Cre and GcgRA ΔVilCre **p<0.05 Vil Cre vs. IP glucose tolerance (2g/kg) was not significantly different between GcgRA ΔNull, GcgRA ΔVilCre, and WT mice (n=10M Vil Cre & GcgRA ΔNull 9M GcgRA ΔVilCre). WT mice (n=10M Vil Cre & GcgRA ΔNull 9M GcgRA ΔVilCre). Oral glucose tolerance (2g/kg) was significantly lower at 15, 30 and 45 min in both GcgRA ΔNull and GcgRA ΔVilCre mice vs. Plasma glucagon levels 15min after 1U/kg of insulin were undetectable in GcgRA Δvilcre (n=8 GcgRA ΔVilCre and n=10 Vil Cre mice). Pancreatic protein levels of glucagon were undetectable in GcgRA ΔNull and GcgRA ΔVilCre mice (n=10M Vil Cre & GcgRA ΔNull 9M GcgRA ΔVilCre). Circulating levels of active GLP-1 15 min after a glucose (3 g/kg) gavage was similar between Vil Cre and GcgRA Δvilcre mice and undetectable in GcgRA ΔNull (n=7F 5M/genotype). GcgRA Δvilcre and were undetectable in the pancreas of GcgRA Δvilcre and in all tissues of the GcgRA ΔNull mice (n=9M/genotype). Tissue GLP-1 levels were not significantly different in the duodenum and ileum in Vil Cre vs. Gcg expression was undetectable in the GcgRA Δvilcre in the pancreas and hindbrain and in all tissues in the GcgRA ΔNull mice (n=7F 5M/genotype). GcgRA Δvilcre in the duodenum but similar in the jejunum, ileum, and colon. Gcg expression was significantly greater in Vil Cre vs. Signifcance in D–H was determine using a Two-way Anova for genotype and time. Significance in C was determined using a One-way ANOVA. insulin response to an IV glucose load (0.5 g/kg) were similar between WT and GcgRA ΔNull (n=8M-WT 7M- GcgRA ΔNull). Glucose clearance was similar in WT and GcgRA ΔNull at baseline and during the final 30 minutes of the hyperinsulinemic euglycemic clamp (main effect of time p<0.05). Endogenous glucose production (EGP) during baseline and during the final 30min of a hyperinsulinemic euglycemic clamp (n=6M/genotype) was similar in WT and GcgRA ΔNull (main effect of time p<0.05). Glucose response to Ensure® (200μl) was significantly lower at 15 and 30min after the gavage in GcgRA ΔNull vs. Gcg gene expression relative to GAPDH was nearly undetectable in GcgRA ΔNull vs. In the absence of Cre recombinase, expression of the targeted allele is suppressed generating a null allele.
A Lox P flanked transcriptional blocking cassette consisting of a splice acceptor (SA), an internal ribosomal entry site (IRES), and a green fluorescent protein (GFP) with a poly-A signal (pA) and was inserted into the intron between exons 2 and 3 of the Gcg gene. These findings suggest an alternative model whereby islet GLP-1 also plays an important role in regulating glucose homeostasis.Ĭopyright © 2017 Elsevier Inc.
In contrast, pancreatic reactivation of Gcg fully restored the effect of Ex9 to impair both oral and i.p. Unexpectedly, Ex-9 had no effect on blood glucose in mice with restoration of intestinal Gcg. Ex9 impaired glucose tolerance in wild-type mice but had no impact on Gcg-null or GLP-1R KO mice, suggesting that Ex9 is a true and specific GLP-1R antagonist. To test the relative importance of intestinal versus pancreatic sources of GLP-1 for physiological regulation of glucose, we administered a GLP-1R antagonist, exendin- (Ex9), to mice with tissue-specific reactivation of the preproglucagon gene (Gcg). Glucagon-like peptide 1 (GLP-1) is necessary for normal gluco-regulation, and it has been widely presumed that this function reflects the actions of GLP-1 released from enteroendocrine L cells.
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