title: A novel insulin receptor-binding protein from Momordica charantia enhances glucose uptake and glucose clearance in vitro and in vivo through triggering insulin receptor signaling pathway.
abstract: Diabetes, a common metabolic disorder, is characterized by hyperglycemia. Insulin is the principal mediator of glucose homeostasis. In a previous study, we identified a trypsin inhibitor, named Momordica charantia insulin receptor (IR)-binding protein (mcIRBP) in this study, that might interact with IR. The physical and functional interactions between mcIRBP and IR were clearly analyzed in the present study. Photo-cross-linking coupled with mass spectrometry showed that three regions (17-21, 34-40, and 59-66 residues) located on mcIRBP physically interacted with leucine-rich repeat domain and cysteine-rich region of IR. IR-binding assay showed that the binding behavior of mcIRBP and insulin displayed a cooperative manner. After binding to IR, mcIRBP activated the kinase activity of IR by (5.87 ± 0.45)-fold, increased the amount of phospho-IR protein by (1.31 ± 0.03)-fold, affected phosphoinositide-3-kinase/Akt pathways, and consequently stimulated the uptake of glucose in 3T3-L1 cells by (1.36 ± 0.12)-fold. Intraperitoneal injection of 2.5 nmol/kg mcIRBP significantly decreased the blood glucose levels by 20.9 ± 3.2% and 10.8 ± 3.6% in normal and diabetic mice, respectively. Microarray analysis showed that mcIRBP affected genes involved in insulin signaling transduction pathway in mice. In conclusion, our findings suggest that mcIRBP is a novel IRBP that binds to sites different from the insulin-binding sites on IR and stimulates both the glucose uptake in cells and the glucose clearance in mice.
authors.affiliation: Graduate Institute of Chinese Medicine, China Medical University , Taichung 40402, Taiwan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Lo
authors.forename: Tin-Yun
authors.initials: TY
authors.lastname: Ho
authors.forename: Chia-Cheng
authors.initials: CC
authors.lastname: Li
authors.forename: Jaw-Chyun
authors.initials: JC
authors.lastname: Chen
authors.forename: Jau-Jin
authors.initials: JJ
authors.lastname: Liu
authors.forename: Chien-Yun
authors.initials: CY
authors.lastname: Hsiang
mesh_terms: D041721:3T3-L1 Cells; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000302:isolation & purification / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental; D005947:Glucose / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D015394:Molecular Structure; D029777:Momordica charantia / Q000737:chemistry; D010940:Plant Proteins / Q000494:pharmacology*; D011485:Protein Binding; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014361:Trypsin Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*
chemical_list: D002352:Carrier Proteins; D007004:Hypoglycemic Agents; C093458:Momordica charantia trypsin inhibitor II'; D010940:Plant Proteins; D014361:Trypsin Inhibitors; D011972:Receptor, Insulin; D005947:Glucose
keywords: Momordica charantia; diabetes; glucose homeostasis; insulin receptor-binding protein