Terminalin from African Mango (Irvingia gabonensis) Stimulates Glucose Uptake through Inhibition of Protein Tyrosine Phosphatases

Abstract

Protein tyrosine phosphatases (PTPs), along with protein tyrosine kinases, control signaling pathways involved in cell growth, metabolism, differentiation, proliferation, and survival. Several PTPs, such as PTPN1, PTPN2, PTPN9, PTPN11, PTPRS, and DUSP9, disrupt insulin signaling and trigger type 2 diabetes, indicating that PTPs are promising drug targets for the treatment or prevention of type 2 diabetes. As part of an ongoing study on the discovery of pharmacologically active bioactive natural products, we conducted a phytochemical investigation of African mango (Irvingia gabonensis) using liquid chromatography–mass spectrometry (LC/MS)-based analysis, which led to the isolation of terminalin as a major component from the extract of the seeds of I. gabonensis. The structure of terminalin was characterized by spectroscopic methods, including one-dimensional (1D) and two-dimensional (2D) nuclear magnetic resonance (NMR) and high-resolution (HR) electrospray ionization (ESI) mass spectroscopy. Moreover, terminalin was evaluated for its antidiabetic property; terminalin inhibited the catalytic activity of PTPN1, PTPN9, PTPN11, and PTPRS in vitro and led to a significant increase in glucose uptake in differentiated C2C12 muscle cells, indicating that terminalin exhibits antidiabetic effect through the PTP inhibitory mechanism. These findings suggest that terminalin derived from African mango could be used as a functional food ingredient or pharmaceutical supplement for the prevention of type 2 diabetes.

Flavonoids and Tannins from Anogeissus latifolia

“…The third one displayed five equivalent pairs of quaternary carbons at 123.2-107.8 ppm together with the most upfield last one that assigned at 106.7 for the protonated equivalent pair of carbons(C-10/17). Both 1 H and 13 C NMR data together with HRESI-MS results were in complete accordance with the previously published data of gallagic acid bilactone (terminalin) 23 .…”

Methyl Syringate Stimulates Glucose Uptake by Inhibiting Protein Tyrosine Phosphatases Relevant to Insulin Resistance

“…Considering that glucose uptake by insulin-sensitive tissues such as skeletal muscles, liver, and adipocytes leads to the maintenance of glucose homeostasis [ 30 , 31 , 32 ], we next investigated the antidiabetic effects of methyl syringate on glucose uptake. We previously reported that several natural compounds exhibit antidiabetic properties by inhibiting PTPs associated with insulin resistance [ 2 , 22 , 28 , 33 , 34 ]. To determine the appropriate concentration of methyl syringate for treatment of 3T3-L1 adipocytes, cell viability was evaluated.…”

Ethnomedicinal Uses, Phytochemistry, and Pharmacological Activity of the Irvingia Species

“…Furthermore, ellagic acid (16) was also identified in Irvingia gabonensis stem bark by Ojo et al [27]. More recently, Yoon et al [29] isolated the phenolic compound (tannin) terminalin (32) from Irvingia gabonensis seeds.…”

“…In 2012, Sun and Chen [26] used UHPLC/HRMS (ultra-high-performance liquid chromatography/high resolution mass spectrometry) analysis to identify the chemical constituents of Irvingia gabonensis seeds. Among the compounds identified, phenolics comprised: 3,3 ,4 -tri-O-methylellagic acid (4.04 mg/g of extract) (13); 3,4-di-O-methylellagic acid (0.58 mg/g of extract) (14); methyl gallate (15); ellagic acid (16), di-O-methyl-ellagic acid hexoside (17); methyl-ellagic acid (18); mono-Omethyl ellagic acid deoxyhexoside (19); di-O-methyl ellagic acid (20); di-O-methyl ellagic acid-O-pentoside (21); di-hexahydroxydiphenoyl-ellagic acid (22); di-O-methyl-ellagic acid deoxyhexoside (23); galloyl-hexahydroxydiphenoyl-methyl-ellagic acid (24); tri-O-methylellagic acid (25); mono-O-methyl-ellagic acid rhamnoside (26); mono-O-methyl-ellagic acid rhamnosyl-rhamnoside (27); galloyl-tri-O-methyl-ellagic acid hexoside (28); galloyl-HHDP-ellagic acid (29); di-O-methyl-ellagic acid deoxyhexide (30) [26] (Table 3). From the powdered seeds of African mango (I. gabonensis), 4-hydroxybenzoic acid (31) was also isolated and characterized.…”

“…In another study, the antidiabetic activity of terminalin (32), a phenolic compound isolated from the aqueous extract of Irvingia gabonensis seeds, was evaluated through the inhibition of protein tyrosine phosphate enzymes (PTPs). Terminalin (32) demonstrated antidiabetic activity via in vitro inhibition (80%) of the catalytic sites of PTPN1, PTPN9, PTPN11, and PTPRS, which hampered the glucose uptake in differentiated C2C12 myocytes [29].…”