PTP1B Inhibitor Improves Both Insulin Resistance and Lipid Abnormalities in Vivo and in Vitro

Overview

Journal Mol Cell Biochem

Publisher Springer

Specialty Biochemistry

Date 2011 May 24

PMID 21603884

Citations 23

Authors

Yi-Ming Ma

Rong-ya Tao

Qian Liu

Juan Li

Jin-Ying Tian

Xiao-Lin Zhang

Zhi-Yan Xiao

Fei Ye

Affiliations

Soon will be listed here.

Abstract

PTP1B is a negative regulator of insulin signaling pathway. This study investigated the effects of compound CCF06240, a PTP1B inhibitor, on insulin sensitivity and lipid metabolic abnormalities in vivo and in vitro, respectively. The insulin resistant IRM mouse model was induced by HFD. The responses to insulin were determined by OGTT, ITT, and hyperinsulinemic-euglycemic clamp test. The body weight and the levels of serum TC and TG were measured to estimate the lipid metabolism in vivo. Recombinant human GST-PTP1B protein was used to measure the inhibition of CCF06240 on PTP1B activity. The hepatocyte lipid accumulation was induced by high concentrations of FFA and insulin in HepG(2) cells, and evaluated by the Oil Red O method. In IRM mice, the insulin resistance was improved; the body weight and the levels of TC and TG were also reduced by oral CCF06240 administration. In lipid accumulated model cells, CCF06240 was found to reverse the increased PTP1B activity, enhance the insulin-induced tyrosine phosphorylation in insulin signaling pathway, attenuate the FFA-insulin-induced cellular lipid accumulation, and down-regulate the expressions of genes related fatty acid synthesis. These results demonstrated that the PTP1B inhibitor, compound CCF06240, could increase insulin sensitivity through the regulation of insulin signaling pathway, and decrease FFA-insulin-induced hepatocytes lipid accumulation by reducing fatty acid syntheses.

Citing Articles

Effect of Zinc Supplementation on Glycemic Control in Newly Diagnosed Patients With Type 2 Diabetes Mellitus.

Chhina G, Chhabra A, Luthra S, Khattar S, Singh P, Luthra S Cureus. 2024; 16(9):e69180.

PMID: 39398666 PMC: 11468580. DOI: 10.7759/cureus.69180.

An Arylbenzofuran, Stilbene Dimers, and Prenylated Diels-Alder Adducts as Potent Diabetic Inhibitors from Leaves.

Ju S, Ali M, Ko S, Ryu J, Choi J, Jung H Antioxidants (Basel). 2023; 12(4).

PMID: 37107213 PMC: 10134988. DOI: 10.3390/antiox12040837.

The PTP1B inhibitor MSI-1436 ameliorates liver insulin sensitivity by modulating autophagy, ER stress and systemic inflammation in Equine metabolic syndrome affected horses.

Bourebaba L, Serwotka-Suszczak A, Pielok A, Sikora M, Mularczyk M, Marycz K Front Endocrinol (Lausanne). 2023; 14:1149610.

PMID: 37020593 PMC: 10067883. DOI: 10.3389/fendo.2023.1149610.

miR-140-5p Aggravates Insulin Resistance via Directly Targeting GYS1 and PPP1CC in Insulin-Resistant HepG2 Cells.

Li X, Ye Y, Wang B, Zhao S Diabetes Metab Syndr Obes. 2021; 14:2515-2524.

PMID: 34113143 PMC: 8187005. DOI: 10.2147/DMSO.S304055.

Evaluation of the Hypoglycemic Activity of by Targeting Protein Tyrosine Phosphatase 1B.

Begum N, Nasir A, Parveen Z, Muhammad T, Ahmed A, Farman S Front Pharmacol. 2021; 12:661803.

PMID: 34093192 PMC: 8173442. DOI: 10.3389/fphar.2021.661803.

References

Johnson T, Ermolieff J, Jirousek M . Protein tyrosine phosphatase 1B inhibitors for diabetes. Nat Rev Drug Discov. 2002; 1(9):696-709. DOI: 10.1038/nrd895. View

Farrell G, Larter C . Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006; 43(2 Suppl 1):S99-S112. DOI: 10.1002/hep.20973. View

Rector R, Thyfault J, Wei Y, Ibdah J . Non-alcoholic fatty liver disease and the metabolic syndrome: an update. World J Gastroenterol. 2008; 14(2):185-92. PMC: 2675112. DOI: 10.3748/wjg.14.185. View

Kumar A, Ahmad P, Maurya R, Singh A, Srivastava A . Novel 2-aryl-naphtho[1,2-d]oxazole derivatives as potential PTP-1B inhibitors showing antihyperglycemic activities. Eur J Med Chem. 2008; 44(1):109-16. DOI: 10.1016/j.ejmech.2008.03.009. View

Saltiel A, Kahn C . Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001; 414(6865):799-806. DOI: 10.1038/414799a. View

Zhang Z . Protein tyrosine phosphatases: structure and function, substrate specificity, and inhibitor development. Annu Rev Pharmacol Toxicol. 2002; 42:209-34. DOI: 10.1146/annurev.pharmtox.42.083001.144616. View

Bloomgarden Z . Insulin resistance, dyslipidemia, and cardiovascular disease. Diabetes Care. 2007; 30(8):2164-70. DOI: 10.2337/dc07-zb08. View

Bruce K, Hanson M . The developmental origins, mechanisms, and implications of metabolic syndrome. J Nutr. 2010; 140(3):648-52. DOI: 10.3945/jn.109.111179. View

Weickert M, Pfeiffer A . Signalling mechanisms linking hepatic glucose and lipid metabolism. Diabetologia. 2006; 49(8):1732-41. DOI: 10.1007/s00125-006-0295-3. View

10.

Ye F, Tao R, Cong W, Tian J, Liu Q . Utilization of fluorescence tracer in hyperinsulinemic-euglycemic clamp test in mice. J Biochem Biophys Methods. 2008; 70(6):978-84. DOI: 10.1016/j.jprot.2008.01.003. View

11.

Araya J, Rodrigo R, Videla L, Thielemann L, Orellana M, Pettinelli P . Increase in long-chain polyunsaturated fatty acid n - 6/n - 3 ratio in relation to hepatic steatosis in patients with non-alcoholic fatty liver disease. Clin Sci (Lond). 2004; 106(6):635-43. DOI: 10.1042/CS20030326. View

12.

Cong W, Tao R, Tian J, Liu G, Ye F . The establishment of a novel non-alcoholic steatohepatitis model accompanied with obesity and insulin resistance in mice. Life Sci. 2008; 82(19-20):983-90. DOI: 10.1016/j.lfs.2008.01.022. View

13.

Delibegovic M, Bence K, Mody N, Hong E, Ko H, Kim J . Improved glucose homeostasis in mice with muscle-specific deletion of protein-tyrosine phosphatase 1B. Mol Cell Biol. 2007; 27(21):7727-34. PMC: 2169063. DOI: 10.1128/MCB.00959-07. View

14.

Xue B, Kim Y, Lee A, Toschi E, Bonner-Weir S, Kahn C . Protein-tyrosine phosphatase 1B deficiency reduces insulin resistance and the diabetic phenotype in mice with polygenic insulin resistance. J Biol Chem. 2007; 282(33):23829-40. DOI: 10.1074/jbc.M609680200. View

15.

Koteish A, Diehl A . Animal models of steatosis. Semin Liver Dis. 2001; 21(1):89-104. DOI: 10.1055/s-2001-12932. View

16.

Van Gaal L, Mertens I, De Block C . Mechanisms linking obesity with cardiovascular disease. Nature. 2006; 444(7121):875-80. DOI: 10.1038/nature05487. View

17.

Klaman L, Boss O, Peroni O, Kim J, Martino J, Zabolotny J . Increased energy expenditure, decreased adiposity, and tissue-specific insulin sensitivity in protein-tyrosine phosphatase 1B-deficient mice. Mol Cell Biol. 2000; 20(15):5479-89. PMC: 85999. DOI: 10.1128/MCB.20.15.5479-5489.2000. View

18.

Fukuda H, Iritani N, Sugimoto T, Ikeda H . Transcriptional regulation of fatty acid synthase gene by insulin/glucose, polyunsaturated fatty acid and leptin in hepatocytes and adipocytes in normal and genetically obese rats. Eur J Biochem. 1999; 260(2):505-11. DOI: 10.1046/j.1432-1327.1999.00183.x. View

19.

Zinker B, Rondinone C, Trevillyan J, Gum R, Clampit J, Waring J . PTP1B antisense oligonucleotide lowers PTP1B protein, normalizes blood glucose, and improves insulin sensitivity in diabetic mice. Proc Natl Acad Sci U S A. 2002; 99(17):11357-62. PMC: 123261. DOI: 10.1073/pnas.142298199. View

20.

Towle H, Kaytor E, Shih H . Regulation of the expression of lipogenic enzyme genes by carbohydrate. Annu Rev Nutr. 1997; 17:405-33. DOI: 10.1146/annurev.nutr.17.1.405. View