1. Characterization of [125I]GLP-1(9-36), a novel radiolabeled analog of the major metabolite of glucagon-like peptide 1 to a receptor distinct from GLP1-R and function of the peptide in murine aorta.
- Author
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Kuc, Rhoda E., Maguire, Janet J., Siew, Keith, Patel, Sheena, Derksen, David R., Margaret Jackson, V., O'Shaughnessey, Kevin M., and Davenport, Anthony P.
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GLUCAGON-like peptide-1 receptor , *RADIOLABELING , *GHRELIN receptors , *BLOOD sugar , *TYPE 2 diabetes , *CD26 antigen - Abstract
Abstract: Aims: Glucagon-like peptide 1 (GLP-1) is an insulin secretagogue, released in response to meal ingestion and efficiently lowers blood glucose in Type 2 diabetic patients. GLP-1(7-36) is rapidly metabolized by dipeptidyl peptidase IV to the major metabolite GLP-1(9-36)-amide, often thought to be inactive. Inhibitors of this enzyme are widely used to treat diabetes. Our aim was to characterize the binding of GLP-1(9-36) to native mouse tissues and to cells expressing GLP1-R as well as to measure functional responses in the mouse aorta compared with GLP-1(7-36). Main methods: The affinity of [125I]GLP-1(7-36) and [125I]GLP-1(9-36) was measured in mouse tissues by saturation binding and autoradiography used to determine receptor distribution. The affinity of both peptides was compared in binding to recombinant GLP-1 receptors using cAMP and scintillation proximity assays. Vasoactivity was determined in mouse aortae in vitro. Key findings: In cells expressing GLP-1 receptors, GLP-1(7-36) bound with the expected high affinities (0.1nM) and an EC50 of 0.07nM in cAMP assays but GLP-1(9-36) bound with 70,000 and 100,000 fold lower affinities respectively. In contrast, in mouse brain, both labeled peptides bound with a single high affinity, with Hill slopes close to unity, although receptor density was an order of magnitude lower for [125I]GLP-1(9-36). In functional experiments both peptides had similar potencies, GLP-1(7-36), pD2 =7.40±0.24 and GLP-1(9-36), pD2 =7.57±0.64. Significance: These results suggest that GLP-1(9-36) binds and has functional activity in the vasculature but these actions may be via a pathway that is distinct from the classical GLP-1 receptor and insulin secretagogue actions. [Copyright &y& Elsevier] more...
- Published
- 2014
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