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.

Satietogenic Protein from Tamarind Seeds Decreases Food Intake, Leptin Plasma and <b><i>CCK-1r</i></b> Gene Expression in Obese Wistar Rats

“…This peptide presents 68 amino acid residues and the insulin receptor binding protein of M. charantia (mcIRBP). It acts by activating insulin receptor signaling pathways and stimulating both the uptake and release of glucose in rat cells [56, 57]. Confirming these data, mcIRBP-19 was observed to be the peptide insulin receptor binding motif of mcIRBP with a similar ability for glucose uptake [58].…”

Bitter melon triterpenes work as insulin sensitizers and insulin substitutes in insulin-resistant cells

“…Several types of medicinal compounds have been isolated from the different parts of bitter melon, including triterpenoids, proteins, lipids, steroids, monoterpenes, alkaloids, etc. Some of them were shown to have hypoglycaemic effects, especially triterpenoids and proteins (Chang et al, , 2011Cheng et al, 2008;Lo et al, 2014;Zhang et al, 2014), whereas the action modes and mechanisms of most of these hypoglycaemic molecules, and whether they work under insulin-resistant conditions, remain undefined.…”

Effect of Momordica charantia, Camellia sinensis and Cinnamon Species on Insulin Resistance

“…Further studies are needed to shed light on the molecular mechanism involved in the p38 mitogen-activated protein kinase (p38MAPK) pathway activation of cell surface GLUT4. All of these findings point to at least two pathways which are implicated in bitter melon improved insulin resistance, and increased muscle glucose uptake resulting in a decrease of glucose levels [93].…”