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The role of protein tyrosine phosphatase 1B (PTP1B) in the pathogenesis of type 2 diabetes mellitus and its complications

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Abstract

Insulin resistance, the most important characteristic of the type 2 diabetes mellitus (T2DM), is mostly caused by impairment in the insulin receptor (IR) signal transduction pathway. Protein tyrosine phosphatase 1B (PTP1B), one of the main negative regulators of the IR signaling pathway, is broadly expressed in various cells and tissues. PTP1B decreases the phosphorylation of the IR resulting in insulin resistance in various tissues. The evidence for the physiological role of PTP1B in regulation of metabolic pathways came from whole-body PTP1B-knockout mice. Whole-body and tissue-specific PTP1B-knockout mice showed improvement in adiposity, insulin resistance, and glucose tolerance. In addition, the key role of PTP1B in the pathogenesis of T2DM and its complications was further investigated in mice models of PTP1B deficient/overexpression. In recent years, targeting PTP1B using PTP1B inhibitors is being considered an attractive target to treat T2DM. PTP1B inhibitors improve the sensitivity of the insulin receptor and have the ability to cure insulin resistance-related diseases. We herein summarized the biological functions of PTP1B in different tissues in vivo and in vitro. We also describe the effectiveness of potent PTP1B inhibitors as pharmaceutical agents to treat T2DM.

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Abbreviations

ACC:

Acetyl-CoA carboxylase

AgRP:

Agouti-related protein

AMPK:

AMP-activated protein kinase

BP:

Blood pressure

BCR-ABL:

Breakpoint cluster region protein-Abelson murine leukemia

BAT:

Brown adipose tissue

CLK:

CDC-like kinase

CeA:

Central nucleus of the amygdala

DN:

Diabetic nephropathy

DR:

Diabetic retinopathy

Egr-1:

Early growth response 1

ER:

Endoplasmic reticulum

eNOS:

Endothelial nitric oxide synthase

EGFR:

Epidermal growth factor receptor

FAS:

Fatty acid synthase

FFA:

Free fatty acid

GLUT4:

Glucose transporter type 4

GSIS:

Glucose-stimulated insulin secretion

GK:

Goto–Kakizaki

Grb 14:

Growth factor receptor bound protein 14

HFD:

High fat diet

IR:

Insulin receptor

IRSI:

IR substrate 1

RTK:

IR tyrosine kinase

JAK2/STAT3:

Janus kinase 2/signal transducer and activator of transcription 3

JNK:

Jun N-terminal kinase

MCD:

Methionine/choline-deficient diet

MAPK:

Mitogen-activated protein kinase

MI:

Myocardial infarction

NPY:

Neuropeptide Y

NASH:

Nonalcoholic steatohepatitis

NF-kB:

Nuclear factor kappa B

PI3K:

Phosphatidylinositol 3-kinase

PEPCK:

Phosphoenolpyruvate carboxykinase

PDGF-R:

Platelet-derived growth factor receptors

PTM:

Post-translational modification

POMC:

Proopiomelanocortin

PGI2:

Prostaglandin I2

PKA:

Protein kinase A

Akt:

Protein kinase B

PKC:

Protein kinase C

PTP1B:

Protein tyrosine phosphatase

PTP:

Protein tyrosine phosphatases

ROS:

Reactive oxygen species

SIRT1:

Sirtuin 1

SUMO:

Small ubiquitin-related modifier

SREBP:

Sterol regulatory element-binding protein

TEM:

Transendothelial migration

T2DM:

Type 2 diabetes mellitus

VCAM-1:

Vascular adhesion molecule 1

YB1:

Y-box-binding protein 1

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Authors and Affiliations

  1. Department of Clinical Biochemistry, School of Allied Medical Sciences, Shahroud University of Medical Sciences, Shahroud, Iran

    Maryam Teimouri

  2. Department of Clinical Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

    Hossein Hosseini

  3. Department of Clinical Sciences, Faculty of Veterinary Science, Bu-Ali Sina University, Hamedan, Iran

    Zahra ArabSadeghabadi

  4. Department of Clinical Biochemistry, Faculty of Medicine, Tehran University of Medical Sciences, Tehran, Iran

    Reyhaneh Babaei-Khorzoughi & Reza Meshkani

  5. Department of Medical Laboratory Sciences, School of Allied Health Medicine, AJA University of Medical Sciences, Tehran, Iran

    Sattar Gorgani-Firuzjaee

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  1. Maryam Teimouri
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  2. Hossein Hosseini
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  3. Zahra ArabSadeghabadi
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  4. Reyhaneh Babaei-Khorzoughi
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  5. Sattar Gorgani-Firuzjaee
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  6. Reza Meshkani
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Contributions

RM designed the study and revised the manuscript. MT wrote the paper. HH and ZA made the literature selection. RB participates in drafting. SG-F revised the manuscript. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

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Correspondence to Reza Meshkani.

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Key points

• PTP1B serves as a negative regulator of the insulin signaling pathway.

• PTP1B upregulation plays critical role in the T2DM and its complications.

• PTP1B inhibition is a potential therapeutic approach for T2DM treatment.

• It remains a challenge to identify appropriate inhibitors for PTP1B.

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Teimouri, M., Hosseini, H., ArabSadeghabadi, Z. et al. The role of protein tyrosine phosphatase 1B (PTP1B) in the pathogenesis of type 2 diabetes mellitus and its complications. J Physiol Biochem 78, 307–322 (2022). https://doi.org/10.1007/s13105-021-00860-7

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  • DOI: https://doi.org/10.1007/s13105-021-00860-7

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