Targeting glucagon‐like peptide‐1 and α2 adrenergic receptor combination using GLP‐1/yohimbine to achieve β‐cell specific targeting and therapy (1095.19)

Coupling multiple receptor binding domains into a single molecule enhances ligand binding affinity, and if the domains target different receptors, only cells expressing the complementary receptor combination will bind this agent. Pancreatic β‐cells express Glucagon Like Peptide‐1 (GLP‐1R) and α2Adrenergic Receptors (α2AR) that, as a combination, are relatively unique to the β‐cell. Moreover, activation of GLP‐1R and α2AR inversely affect β‐cell signaling. We propose that linking GLP‐1 to Yohimbine (Yhb; α2AR antagonist) may provide an agent with enhanced affinity, β‐cell specificity and possibly unique therapeutic potential. Using microscopy, we established that GLP‐1/Yhb bound to β‐cells with high affinity at nM concentrations and was rapidly internalized. In cells where either GLP‐1R or α2AR were knocked down (using siRNA), binding of GLP‐1/Yhb was significantly reduced (蠄 half of cells with both receptors), demonstrating specificity. Over a range of concentrations (0.01 – 5 nM ), GLP‐1/Yhb had similar activity as monomeric GLP‐1 for increasing cAMP production. Conversely, measurement of Glucose Stimulated Insulin Secretion (GSIS) showed that, at both 1nM and 100 nM, GLP‐1/Yhb potentiates GSIS more than GLP‐1 alone. Thus, due to its specificity for β‐cells and positive impact on β‐cell function, bivalent agents like GLP‐1/Yhb may provide a unique approach for successful β‐cell specific targeting and therapy. Grant Funding Source : Supported by: Juvenile Diabetes Research Foundation and American Diabetes Association