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Highly Selective Protein Tyrosine Phosphatase Inhibitor, 2,2 ',3,3 '-Tetrabromo-4,4 ',5,5 '-tetrahydroxydiphenylmethane, Ameliorates Type 2 Diabetes Mellitus in BKS db Mice
Li, Chao1,2,3,4; Luo, Jiao1,2,3,4; Guo, Shuju1,2,3; Jia, Xiaoling1,2,3; Guo, Chuanlong1,2,3,4; Li, Xiangqian1,2,3; Xu, Qi1,2,3,4; Shi, Dayong1,2,3,4,5
2019-05-01
Source PublicationMOLECULAR PHARMACEUTICS
ISSN1543-8384
Volume16Issue:5Pages:1839-1850
Corresponding AuthorShi, Dayong(shidayong@qdio.ac.cn)
AbstractProtein tyrosine phosphatase 1B (PTP1B) is a widely confirmed target of the type 2 diabetes mellitus (T2DM) treatment. Herein, we reported a highly specific PTP1B inhibitor 2,2',3,3'-tetrabromo-4,4',5,5'-tetrahydroxy-diphenylmethane (compound 1), which showed promising hypoglycemic activity in diabetic BKS db mice. With the IC50 value of 2.4 mu M, compound 1 could directly bind to the catalytic pocket of PTP1B through a series of hydrogen bonds. Surface plasmon resonance analysis revealed that the target PTP1B affinity [KD (equilibrium dissociation constant) value] of compound 1 binding to PTP1B was 2.90 mu M. Moreover, compound 1 could activate the insulin signaling pathway in C2C12 skeletal muscle cells. We further evaluated the long-term effects of compound 1 in diabetic BKS db mice. Notably, oral administration of compound 1 significantly reduced the blood glucose levels of diabetic mice with increasing insulin sensitivity. In addition, the dyslipidemia of diabetic mice was also significantly improved by compound 1 gavage. The histological experiments showed that compound 1 treatment significantly ameliorated the disordered hepatic and pancreatic architecture and increased the glycogen content in the liver tissues as well as improved the insulin secretion function of pancreas. Taken together, our results manifested that the natural product compound 1 was a highly specific PTP1B inhibitor, which could activate insulin signaling pathway and ameliorate hyperglycemia and dyslipidemia in diabetic BKS db mice.
Keywordtype 2 diabetes mellitus protein tyrosine phosphatase 1B insulin resistance hypoglycemic activity dyslipidemia
DOI10.1021/acs.molpharmaceut.8b01106
Indexed BySCI
Language英语
Funding ProjectNational Natural Science Foundation of China[81773586] ; National Natural Science Foundation of China[81703354] ; Key Research Program of Frontier Sciences, CAS[QYZDB-SSW-DQC014] ; Qingdao Marine Biomedical Science and Technology Innovation Center project[2017-CXZX01-1-1] ; Qingdao Marine Biomedical Science and Technology Innovation Center project[2017-CXZX01-3-9] ; Shandong Provincial Natural Science Foundation for Distinguished Young Scholars[JQ201722] ; National Program for Support of Top-notch Young Professionals ; Taishan scholar Youth Project of Shandong province
WOS Research AreaResearch & Experimental Medicine ; Pharmacology & Pharmacy
WOS SubjectMedicine, Research & Experimental ; Pharmacology & Pharmacy
WOS IDWOS:000467351300005
PublisherAMER CHEMICAL SOC
Citation statistics
Document Type期刊论文
Identifierhttp://ir.qdio.ac.cn/handle/337002/161338
Collection实验海洋生物学重点实验室
Corresponding AuthorShi, Dayong
Affiliation1.Chinese Acad Sci, Inst Oceanol, CAS Key Lab Expt Marine Biol, Qingdao 266071, Shandong, Peoples R China
2.Qngdao Natl Lab Marine Sci & Technol, Lab Marine Drugs & Bioprod, Qingdao 266237, Shandong, Peoples R China
3.Chinese Acad Sci, Ctr Ocean Mega Sci, 7 Nanhai Rd, Qingdao 266071, Shandong, Peoples R China
4.Univ Chinese Acad Sci, Beijing, Peoples R China
5.Shandong Univ, State Key Lab Microbial Technol, Qingdao, Shandong, Peoples R China
First Author AffilicationInstitute of Oceanology, Chinese Academy of Sciences
Corresponding Author AffilicationInstitute of Oceanology, Chinese Academy of Sciences
Recommended Citation
GB/T 7714
Li, Chao,Luo, Jiao,Guo, Shuju,et al. Highly Selective Protein Tyrosine Phosphatase Inhibitor, 2,2 ',3,3 '-Tetrabromo-4,4 ',5,5 '-tetrahydroxydiphenylmethane, Ameliorates Type 2 Diabetes Mellitus in BKS db Mice[J]. MOLECULAR PHARMACEUTICS,2019,16(5):1839-1850.
APA Li, Chao.,Luo, Jiao.,Guo, Shuju.,Jia, Xiaoling.,Guo, Chuanlong.,...&Shi, Dayong.(2019).Highly Selective Protein Tyrosine Phosphatase Inhibitor, 2,2 ',3,3 '-Tetrabromo-4,4 ',5,5 '-tetrahydroxydiphenylmethane, Ameliorates Type 2 Diabetes Mellitus in BKS db Mice.MOLECULAR PHARMACEUTICS,16(5),1839-1850.
MLA Li, Chao,et al."Highly Selective Protein Tyrosine Phosphatase Inhibitor, 2,2 ',3,3 '-Tetrabromo-4,4 ',5,5 '-tetrahydroxydiphenylmethane, Ameliorates Type 2 Diabetes Mellitus in BKS db Mice".MOLECULAR PHARMACEUTICS 16.5(2019):1839-1850.
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