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Reduced incretin receptor trafficking upon activation enhances glycemic control and reverses obesity in diet-induced obese mice.
- Source :
-
American journal of physiology. Cell physiology [Am J Physiol Cell Physiol] 2024 Jul 01; Vol. 327 (1), pp. C74-C96. Date of Electronic Publication: 2024 May 13. - Publication Year :
- 2024
-
Abstract
- Activation of incretin receptors by their cognate agonist augments sustained cAMP generation both from the plasma membrane as well as from the endosome. To address the functional outcome of this spatiotemporal signaling, we developed a nonacylated glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) receptor dual agonist I-M-150847 that reduced receptor internalization following activation of the incretin receptors. The incretin receptor dual agonist I-M-150847 was developed by replacing the tryptophan cage of exendin-4 tyrosine substituted at the amino terminus with the C-terminal undecapeptide sequence of oxyntomodulin that placed lysine 30 of I-M-150847 in frame with the corresponding lysine residue of GIP. The peptide I-M-150847 is a partial agonist of GLP-1R and GIPR; however, the receptors, upon activation by I-M-150847, undergo reduced internalization that promotes agonist-mediated iterative cAMP signaling and augments glucose-stimulated insulin exocytosis in pancreatic β cells. Chronic administration of I-M-150847 improved glycemic control, enhanced insulin sensitivity, and provided profound weight loss in diet-induced obese (DIO) mice. Our results demonstrated that despite being a partial agonist, I-M-150847, by reducing the receptor internalization upon activation, enhanced the incretin effect and reversed obesity. NEW & NOTEWORTHY Replacement of the tryptophan cage (Trp-cage) with the C-terminal oxyntomodulin undecapeptide along with the tyrosine substitution at the amino terminus converts the selective glucagon-like peptide-1 receptor (GLP-1R) agonist exendin-4 to a novel GLP-1R and GIPR dual agonist I-M-150847. Reduced internalization of incretin receptors upon activation by the GLP-1R and GIPR dual agonist I-M-150847 promotes iterative receptor signaling that enhances the incretin effect and reverses obesity.
- Subjects :
- Animals
Mice
Male
Protein Transport drug effects
Glycemic Control methods
Mice, Obese
Receptors, Gastrointestinal Hormone agonists
Receptors, Gastrointestinal Hormone metabolism
Insulin-Secreting Cells metabolism
Insulin-Secreting Cells drug effects
Humans
Diet, High-Fat adverse effects
Blood Glucose metabolism
Blood Glucose drug effects
Insulin metabolism
Exenatide pharmacology
Signal Transduction drug effects
Cyclic AMP metabolism
Obesity metabolism
Obesity drug therapy
Glucagon-Like Peptide-1 Receptor agonists
Glucagon-Like Peptide-1 Receptor metabolism
Mice, Inbred C57BL
Incretins pharmacology
Incretins metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1522-1563
- Volume :
- 327
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- American journal of physiology. Cell physiology
- Publication Type :
- Academic Journal
- Accession number :
- 38738303
- Full Text :
- https://doi.org/10.1152/ajpcell.00474.2023