Phloridzin Acts as an Inhibitor of Protein-Tyrosine Phosphatase MEG2 Relevant to Insulin Resistance.

Abstract

Inhibition of the megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2, also named PTPN9) activity has been shown to be a potential therapeutic strategy for the treatment of type 2 diabetes. Previously, we reported that PTP-MEG2 knockdown enhances adenosine monophosphate activated protein kinase (AMPK) phosphorylation, suggesting that PTP-MEG2 may be a potential antidiabetic target. In this study, we found that phloridzin, isolated from Ulmus davidiana var. japonica, inhibits the catalytic activity of PTP-MEG2 (half-inhibitory concentration, IC50 = 32 ± 1.06 μM) in vitro, indicating that it could be a potential antidiabetic drug candidate. Importantly, phloridzin stimulated glucose uptake by differentiated 3T3-L1 adipocytes and C2C12 muscle cells compared to that by the control cells. Moreover, phloridzin led to the enhanced phosphorylation of AMPK and Akt relevant to increased insulin sensitivity. Importantly, phloridzin attenuated palmitate-induced insulin resistance in C2C12 muscle cells. We also found that phloridzin did not accelerate adipocyte differentiation, suggesting that phloridzin improves insulin sensitivity without significant lipid accumulation. Taken together, our results demonstrate that phloridzin, an inhibitor of PTP-MEG2, stimulates glucose uptake through the activation of both AMPK and Akt signaling pathways. These results strongly suggest that phloridzin could be used as a potential therapeutic candidate for the treatment of type 2 diabetes.

• Authors: Sun-Young Yoon, Jae Sik Yu, Ji Young Hwang, Hae Min So, Seung Oh Seo, Jung Kyu Kim, Tae Su Jang, Sang J Chung, Ki Hyun Kim
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 26 Issue 6 (Mar 14 2021) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 33799458 (Publication Type: Journal Article)

Chemical References

• Hypoglycemic Agents
• Insulin
• Palmitates
• Phlorhizin
• Protein Tyrosine Phosphatases
• Protein Tyrosine Phosphatases, Non-Receptor
• Ptpn9 protein, mouse
• Glucose

Topics

• 3T3 Cells
• Adipocytes (drug effects, metabolism)
• Animals
• Cell Differentiation (drug effects)
• Cell Line
• Diabetes Mellitus, Type 2 (drug therapy, metabolism)
• Glucose (metabolism)
• Hypoglycemic Agents (pharmacology)
• Insulin (metabolism)
• Insulin Resistance (physiology)
• Mice
• Palmitates (pharmacology)
• Phlorhizin (pharmacology)
• Phosphorylation (drug effects)
• Protein Tyrosine Phosphatases (antagonists & inhibitors)
• Protein Tyrosine Phosphatases, Non-Receptor (antagonists & inhibitors)
• Signal Transduction (drug effects)