Natural Compound α-PGG and Its Synthetic Derivative 6Cl-TGQ Alter Insulin Secretion: Evidence for Diminishing Glucose Uptake as a Mechanism

Abstract

Purpose Previously we showed that natural compound α-penta-galloyl-glucose (α-PGG) and its synthetic derivative 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-D-glucopyranose (6Cl-TGQ) act to improve insulin signaling in adipocytes by increasing glucose transport. In this study, we investigated the mechanism of actions of α-PGG and 6Cl-TGQ on insulin secretion. Methods Mouse islets and/or INS-1832/13 beta-cells were used to test the effects of our compounds on glucose-stimulated insulin secretion (GSIS), intracellular calcium [Ca 2+ ] i using fura-2AM, glucose transport activity via a radioactive glucose uptake assay, intracellular ATP/ADP, and extracellular acidification (ECAR) and mitochondrial oxygen consumption rates (OCAR) using Seahorse metabolic analysis. Results Both compounds reduced GSIS in beta-cells without negatively affecting cell viability. The compounds primarily diminished glucose uptake into islets and beta-cells. Despite insulin-like effects in the peripheral tissues, these compounds do not act through the insulin receptor in islets. Further interrogation of the stimulus-secretion pathway showed that all the key metabolic factors involved in GSIS including ECAR, OCAR, ATP/ADP ratios, and [Ca 2+ ] i of INS-1832/13 cells were diminished after the compound treatment. Conclusion The compounds suppress glucose uptake of the beta-cells, which consequently slows down the rates of glycolysis and ATP synthesis, leading to decrease in [Ca 2+ ] i and GSIS. The difference between adipocytes and beta-cells in effects on glucose uptake is of great interest. Further structural and functional modifications could produce new compounds with optimized therapeutic potentials for different target cells. The higher potency of synthetic 6Cl-TGQ in enhancing insulin signaling in adipocytes but lower potency in reducing glucose uptake in beta-cells compared to α-PGG suggests the feasibility of such an approach.

Structure‐based survey of ligand binding in the human insulin receptor

“…There are currently 7 known small molecule ligands (and their derivatives) believed to bind to the EC domain of InsR. These are pentagalloyl‐glucopyranose (PGG) (Cao et al, 2013, 2014; Chen et al, 2021; Li, Kim et al, 2005; Ren et al, 2006), 4548 g05 (Qiang et al, 2014), thymolphtalein (Schlein et al, 2001), NPC43 (Lan et al, 2020), compound 4 (Tan et al, 2004), Rutaecarpin (Xie et al, 2020) and NT23 (Nakamura et al, 2010). Their evidence for binding and biological activity are described further below.…”

“…There are currently 7 known small molecule ligands (and their derivatives) believed to bind to the EC domain of InsR. These are pentagalloyl-glucopyranose (PGG) (Cao et al, 2013(Cao et al, , 2014Chen et al, 2021;Li, Kim et al, 2005 Ligands are discussed in the chronological order of their publications.…”

“…Detailed structure-activity relationship studies later identified a chlorinated derivative with even higher activity (Cao et al, 2014) and a smaller K D of 19 μM (Cao et al, 2014). The biological consequences of PGG action have been studied in detail recently (Chen et al, 2021).…”

Pentagalloyl Glucose: A Review of Anticancer Properties, Molecular Targets, Mechanisms of Action, Pharmacokinetics, and Safety Profile

“…Penta-O-galloyl-D-glucose, also known as pentagalloyl glucose (PGG), is classified as a gallotannin; it is a hydrolyzable tannin abundant in many plants, including Rhus chinensis, Paeonia suffruticosa, Bouea macrophylla, and Toona sinensis [ 10 , 11 , 12 , 13 ]. The naturally occurring polyphenolic compound PGG exists in beta-PGG form, whereas an anomeric alpha-PGG is rarely found in nature [ 14 ]. However, both compounds can be chemically synthesized, and a highly purified material is obtained after crystallization [ 15 ].…”