A Novel PTP1B Inhibitor-Phosphate of Polymannuronic Acid Ameliorates Insulin Resistance by Regulating IRS-1/Akt Signaling.

Dan Li,Shixin Wang,Cheng Yang,Chunxia Li,Ximing Xu,Quancai Li,Jiejie Hao,Shuai Zhang

doi:10.3390/ijms222312693

Abstract

Protein tyrosine phosphatase 1B (PTP1B) is a critical negative modulator of insulin signaling and has attracted considerable attention in treating type 2 diabetes mellitus (T2DM). Low-molecular-weight polymannuronic acid phosphate (LPMP) was found to be a selective PTP1B inhibitor with an IC50 of 1.02 ± 0.17 μM. Cellular glucose consumption was significantly elevated in insulin-resistant HepG2 cells after LPMP treatment. LPMP could alleviate oxidative stress and endoplasmic reticulum stress, which are associated with the development of insulin resistance. Western blot and polymerase chain reaction (PCR) analysis demonstrated that LPMP could enhance insulin sensitivity through the PTP1B/IRS/Akt transduction pathway. Furthermore, animal study confirmed that LPMP could decrease blood glucose, alleviate insulin resistance, and exert hepatoprotective effects in diabetic mice. Taken together, LPMP can effectively inhibit insulin resistance and has high potential as an anti-diabetic drug candidate to be further developed.

Highlights

Academic Editor: Key Laboratory of Marine Drugs of Ministry of Education, Shandong Provincial Key Laboratory of Glycoscience and Glycoengineering, School of Medicine and Pharmacy, Ocean University of China, Laboratory of Marine Glycodrug Research and Development, Marine Biomedical Research Institute of Qingdao, Qingdao 266071, China
Low-molecularweight polymannuronic acid phosphate (LPMP) was previously synthesized in our laboratory by the phosphoric acid urine method [35,36]
To evaluate whether LPMP could bind to Protein tyrosine phosphatase 1B (PTP1B), we investigated the interaction of LPMP with PTP1B using a surface plasmon resonance biosensor (SPR)

Summary

Introduction

Protein tyrosine phosphatase 1B (PTP1B) is a critical negative modulator of insulin signaling and has attracted considerable attention in treating type 2 diabetes mellitus (T2DM). LPMP could alleviate oxidative stress and endoplasmic reticulum stress, which are associated with the development of insulin resistance. Animal study confirmed that LPMP could decrease blood glucose, alleviate insulin resistance, and exert hepatoprotective effects in diabetic mice. LPMP can effectively inhibit insulin resistance and has high potential as an anti-diabetic drug candidate to be further developed. Type 2 Diabetes Mellitus (T2DM) is a hyperglycemic metabolic disease that is difficult to treat and hugely impacts daily life. Interfering with the production and function of liver insulin could lead to the development of T2DM, and insulin resistance (IR) is inextricably linked with the development of diabetes [2]

Methods

Results

Conclusion