I-M-150847, a novel GLP-1 and GIP receptor dual agonist, improves glycemic control and reduces obesity in the rodent model of type 2 diabetes and obesity.

We report the discovery of a novel unimolecular glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor dual agonist that exhibits potent glycemic control and weight loss in diet-induced obese mice. The dual agonism of GLP-1 and GIP receptor was achieved by replacing the tryptophan cage of exendin-4 with the C-terminal undecapeptide sequence of oxyntomodulin along with a single amino acid substitution from histidine to tyrosine at the amino terminus of the peptide. The structural modification places lysine 30 of the novel incretin agonist in frame with the corresponding lysine residue in the native GIP sequence. The novel incretin receptor dual agonist, named I-M-150847, induces rapid redistribution of GLP-1R at the plasma membrane following activation ensuring the maintenance of the receptor in a sensitized state. I-M-150847 promotes glucose-stimulated insulin exocytosis in cultured pancreatic beta cells and augments insulin-stimulated glucose uptake in mouse adipocytes. Chronic administration of I-M-150847 enhances insulin sensitivity, improves glycemic control, and achieves significant weight loss relative to the control or exendin-4-treated DIO-mice demonstrating the therapeutic efficacy of dual agonist in ameliorating type 2 Diabetes and Obesity. Significance statement.O_LIReplacement of the Trp-cage with the C-terminal oxyntomodulin undecapeptide along with the tyrosine substitution at the amino terminus converts the selective GLP-1R agonist exendin-4 to a novel GLP-1R and GIPR dual agonist I-M-150847. C_LIO_LIThe GLP-1R and GIPR dual agonist I-M-150847 induces the expeditious redistribution of GLP-1R at the plasma membrane following initial activation thereby maintaining the receptor in a sensitized state. C_LIO_LIThe incretin receptor dual agonist I-M-150847 enhances insulin sensitivity and delivers superior glycemic control and weight loss compared to exendin-4 in the rodent model of diabetes and obesity. C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/471325v2_ufig1.gif" ALT="Figure 1"> View larger version (30K): org.highwire.dtl.DTLVardef@1e27480org.highwire.dtl.DTLVardef@4e88acorg.highwire.dtl.DTLVardef@1eee9e7org.highwire.dtl.DTLVardef@3e41c9_HPS_FORMAT_FIGEXP M_FIG C_FIG