A novel PTP1B inhibitor extracted fromGanoderma lucidumameliorates insulin resistance by regulating IRS1-GLUT4 cascades in the insulin signaling pathway

Abstract

Insulin resistance caused by the overexpression of protein tyrosine phosphatase 1 B (PTP1B) as well as the dephosphorylation of its target is one of the main causes of type 2 diabetes (T2D). A newly discovered proteoglycan, Fudan-Yueyang Ganoderma lucidum (FYGL) extracted from Ganoderma lucidum, was first reported to be capable of competitively inhibiting PTP1B activity in vitro in our previous work. In the present study, we sought to reveal the mechanism of PTP1B inhibition by FYGL at the animal and cellular levels. We found that FYGL can decrease blood glucose, reduce body weight and ameliorate insulin resistance in ob/ob mice. Decrease of PTP1B expression and increase of the phosphorylation of PTP1B targets in the insulin signaling pathway of skeletal muscles were observed. In order to clearly reveal the underlying mechanism of the hypoglycemic effect caused by FYGL, we further investigated the effects of FYGL on the PTP1B-involved insulin signaling pathway in rat myoblast L6 cells. We demonstrated that FYGL had excellent cell permeability by using a confocal laser scanning microscope and a flow cytometer. We found that FYGL had a positive effect on insulin-stimulated glucose uptake by using the 2-deoxyglucose (2-DG) method. FYGL could inhibit PTP1B expression at the mRNA level, phosphorylating insulin receptor substrate-1 (IRS1), as well as activating phosphatidylinositol-3 kinase (PI3K) and protein kinase B (Akt). Finally, FYGL increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) and consequently up-regulated the expression of glucose transporter type 4 (GLUT4), promoting GLUT4 transportation to the plasma membrane in PTP1B-transfected L6 cells. Our study provides theoretical evidence for FYGL to be potentially used in T2D management.

Role of PI3K/AKT Pathway in Insulin-Mediated Glucose Uptake

“…Since this protein was found to be overexpressed in insulinsensitive peripheral tissues (fat, muscle) and in hepatic cells during insulin-resistant state, searching for PTP1B inhibitors has become an important area of research in the treatment of impairment of insulin transmission pathway. FYGL (Fudan-Yueyang G. lucidum extract) appears to be a promising substance showing PTP1B inhibitory activity with weak cell permeability and bioavailability [26,27].…”

Infliximab ameliorates tumor necrosis factor‐alpha‐induced insulin resistance by attenuating PTP1B activation in 3T3L1 adipocytes in vitro

“…38 Interestingly, FYGL was also shown to improve insulin-stimulated glucose uptake and activation of IRS-1, PI3K and AKT by blocking PTP1B activation in rat myoblast L6 cells. 38 Consistent with previous evidence, we found that infliximab also acts as PTP1B inhibitor by exerting the ability to improve insulin signalling pathway and consequently glucose homeostasis in 3T3L1 adipocytes exposed to TNF-alpha in vitro.…”

“…In this sense, Yi‐ming Ma and coworkers previously showed that CCF06240, a PTP1B inhibitor, restores insulin sensitivity in HFD‐fed mice and promotes phosphorylation of IRS‐1 in HepG2 cells in vitro . Similarly, a recent study reported a decrease in blood glucose and insulin resistance in ob/ob mice receiving Fudan‐Yueyang‐Ganoderma‐lucidum (FYGL), a proteoglycan with the ability to inhibit PTP1B . Interestingly, FYGL was also shown to improve insulin‐stimulated glucose uptake and activation of IRS‐1, PI3K and AKT by blocking PTP1B activation in rat myoblast L6 cells .…”

“…37 Similarly, a recent study reported a decrease in blood glucose and insulin resistance in ob/ob mice receiving Fudan-Yueyang-Ganoderma-lucidum (FYGL), a proteoglycan with the ability to inhibit PTP1B. 38 Interestingly, FYGL was also shown to improve insulin-stimulated glucose uptake and activation of IRS-1, PI3K and AKT by blocking PTP1B activation in rat myoblast L6 cells. 38 Consistent with previous evidence, we found that infliximab also acts as PTP1B inhibitor by exerting the ability to improve insulin signalling pathway and consequently glucose homeostasis in 3T3L1 adipocytes exposed to TNF-alpha in vitro.…”

Adipose Tissue and Inflammation

“…IRS-1 and IRS-2 are widely distributed in mammalian tissue, while IRS-4 restricts its expression to the hypothalamus [85], these proteins are adapter molecules for the kinase activity of the phosphorylated insulin receptor, in turn phosphorylating the p85 regulatory subunit of phosphoinositide 3-kinase (PI3K). The phosphorylation of the latter induces a conformational change of this protein which leads to the binding of the catalytic subunit (p110) activating PI3K; once activated, this protein phosphorylates phosphatidylinositol-3,4-diphosphate (PIP2) into the second messenger phosphatidylinositol-3,4,5-triphosphate (PIP3) [86,87], and these lipid products induce the recruitment and the interaction of the protein kinase (PDK)-1 and serine/threonine-specific protein kinase (Akt). The activation of PDK-1 phosphorylates some isoforms of protein kinase C, such as PKCλ/ζ, which is responsible for phosphorylating vesicles that contain the glucose transporter type 4 (GLUT4), promoting migration and fusion with the cell surface, which increases glucose uptake as well as your metabolism [88] (Figure 6A).…”