Molecular Biology Reports

, 36:1703 | Cite as

Resistin induces rat insulinoma cell RINm5F apoptosis



Beta-cell apoptosis induced by adipokines may result in beta-cell dysfunction in type 2 diabetes. Resistin, an adipokine-linked obesity with type 2 diabetes, impairs glucose-stimulated insulin secretion (GSIS) in beta-cells. Presently, the effects of resistin on rat insulinoma cells RINm5F were examined. Treatment of RINm5F with resistin induced cell damage. Tissue Inhibitor of Metalloproteinase-1 (TIMP-1) protected resistin-mediated cytotoxicity in RINm5F. Incubation with resistin up-regulated caspase-3 activity and induced the formation of a DNA ladder. TIMP-1 attenuated these effects. The molecular mechanism of TIMP-1 inhibition of resistin-mediated cytotoxicity appeared to involve Akt phosphorylation and activation of IkB-α phosphorylation. Resistin treatment suppressed Akt phosphorylation and activated IkB-α phosphorylation, which could be attenuated by TIMP-1. We conclude that resistin can induce beta-cell apoptosis and that resistin-related beta-cell apoptosis can be prevented by TIMP-1.


Resistin TIMP-1 Beta-cell Apoptosis 



This study was supported by the National Natural Science Foundation of China (No 30371502; 30571978), the Natural Science Foundation of Jiangsu Province (No BK2001120), and a grant from Jiangsu Province Health Department (No RC2002061).


  1. 1.
    Porte D Jr, Kahn SE (2001) Beta-cell dysfunction and failure in type 2 diabetes: potential mechanisms. Diabetes 50(Suppl 1):S160–S163. doi: 10.2337/diabetes.50.2007.S160 PubMedCrossRefGoogle Scholar
  2. 2.
    O’Rahilly S (2002) Insights into obesity and insulin resistance from the study of extreme human phenotypes. Eur J Endocrinol/Eur Federation Endocr Soc 147:435–441Google Scholar
  3. 3.
    Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G (2001) Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol 280:E745–E751Google Scholar
  4. 4.
    Zhao YF, Feng DD, Chen C (2006) Contribution of adipocyte-derived factors to beta-cell dysfunction in diabetes. Int J Biochem Cell Biol 38:804–819. doi: 10.1016/j.biocel.2005.11.008 PubMedCrossRefGoogle Scholar
  5. 5.
    Boden G, Lebed B, Schatz M, Homko C, Lemieux S (2001) Effects of acute changes of plasma free fatty acids on intramyocellular fat content and insulin resistance in healthy subjects. Diabetes 50:1612–1617. doi: 10.2337/diabetes.50.7.1612 PubMedCrossRefGoogle Scholar
  6. 6.
    Rachdaoui N, Nagy LE (2003) Endothelin-1-stimulated glucose uptake is desensitized by tumor necrosis factor-alpha in 3T3–L1 adipocytes. Am J Physiol 285:E545–E551Google Scholar
  7. 7.
    Lee JW, Romsos DR (2003) Leptin administration normalizes insulin secretion from islets of Lep(ob)/Lep(ob) mice by food intake-dependent and -independent mechanisms. Exp Biol Med (Maywood, NJ) 228:183–187Google Scholar
  8. 8.
    Kwon G, Xu G, Marshall CA, McDaniel ML (1999) Tumor necrosis factor alpha-induced pancreatic beta-cell insulin resistance is mediated by nitric oxide and prevented by 15-deoxy-Delta12, 14-prostaglandin J2 and aminoguanidine. A role for peroxisome proliferator-activated receptor gamma activation and inos expression. J Biol Chem 274:18702–18708. doi: 10.1074/jbc.274.26.18702 PubMedCrossRefGoogle Scholar
  9. 9.
    Park H, Ahn Y, Park CK, Chung HY, Park Y (2003) Interleukin-6 protects MIN6 beta cells from cytokine-induced apoptosis. Ann N Y Acad Sci 1005:242–249. doi: 10.1196/annals.1288.036 PubMedCrossRefGoogle Scholar
  10. 10.
    Steppan CM, Bailey ST, Bhat S et al (2001) The hormone resistin links obesity to diabetes. Nature 409:307–312. doi: 10.1038/35053000 PubMedCrossRefGoogle Scholar
  11. 11.
    Steppan CM, Brown EJ, Wright CM et al (2001) A family of tissue-specific resistin-like molecules. Proc Natl Acad Sci USA 98:502–506. doi: 10.1073/pnas.98.2.502 PubMedCrossRefGoogle Scholar
  12. 12.
    Moon B, Kwan JJ, Duddy N, Sweeney G, Begum N (2003) Resistin inhibits glucose uptake in L6 cells independently of changes in insulin signaling and GLUT4 translocation. Am J Physiol 285:E106–E115Google Scholar
  13. 13.
    Steppan CM, Wang J, Whiteman EL, Birnbaum MJ, Lazar MA (2005) Activation of SOCS-3 by resistin. Mol Cell Biol 25:1569–1575. doi: 10.1128/MCB.25.4.1569-1575.2005 PubMedCrossRefGoogle Scholar
  14. 14.
    Liu F, Yang T, Wang B et al (2008) Resistin induces insulin resistance, but does not affect glucose output in rat-derived hepatocytes. Acta Pharmacol Sin 29:98–104PubMedCrossRefGoogle Scholar
  15. 15.
    Minn AH, Patterson NB, Pack S et al (2003) Resistin is expressed in pancreatic islets. Biochem Biophys Res Commun 310:641–645. doi: 10.1016/j.bbrc.2003.09.061 PubMedCrossRefGoogle Scholar
  16. 16.
    Nakata M, Okada T, Ozawa K, Yada T (2007) Resistin induces insulin resistance in pancreatic islets to impair glucose-induced insulin release. Biochem Biophys Res Commun 353:1046–1051. doi: 10.1016/j.bbrc.2006.12.134 PubMedCrossRefGoogle Scholar
  17. 17.
    Brown JE, Onyango DJ, Dunmore SJ (2007) Resistin down-regulates insulin receptor expression, and modulates cell viability in rodent pancreatic beta-cells. FEBS Lett 581:3273–3276. doi: 10.1016/j.febslet.2007.06.031 PubMedCrossRefGoogle Scholar
  18. 18.
    Han X, Sun Y, Scott S, Bleich D (2001) Tissue inhibitor of metalloproteinase-1 prevents cytokine-mediated dysfunction and cytotoxicity in pancreatic islets and beta-cells. Diabetes 50:1047–1055. doi: 10.2337/diabetes.50.5.1047 PubMedCrossRefGoogle Scholar
  19. 19.
    Janjic D, Wollheim CB (1992) Islet cell metabolism is reflected by the MTT (tetrazolium) colorimetric assay. Diabetologia 35:482–485. doi: 10.1007/BF02342448 PubMedCrossRefGoogle Scholar
  20. 20.
    Zhang Z, Jin L, Qian X et al (2007) Novel Bcl-2 inhibitors: discovery and mechanism study of small organic apoptosis-inducing agents. ChemBioChem 8:113–121. doi: 10.1002/cbic.200600305 PubMedCrossRefGoogle Scholar
  21. 21.
    Li L, El-Kholy W, Rhodes CJ, Brubaker PL (2005) Glucagon-like peptide-1 protects beta cells from cytokine-induced apoptosis and necrosis: role of protein kinase B. Diabetologia 48:1339–1349. doi: 10.1007/s00125-005-1787-2 PubMedCrossRefGoogle Scholar
  22. 22.
    Cnop M, Welsh N, Jonas JC, Jorns A, Lenzen S, Eizirik DL (2005) Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 54(Suppl 2):S97–S107. doi: 10.2337/diabetes.54.suppl_2.S97 PubMedCrossRefGoogle Scholar
  23. 23.
    Kim EK, Kwon KB, Han MJ et al (2007) Inhibitory effect of Artemisia capillaris extract on cytokine-induced nitric oxide formation and cytotoxicity of RINm5F cells. Int J Mol Med 19:535–540PubMedGoogle Scholar
  24. 24.
    Li S, E M, Yu B (in press) Adriamycin induces myocardium apoptosis through activation of nuclear factor kappaB in rat. Mol Biol Rep. doi: 10.1007/s11033-007-9112-4
  25. 25.
    Karin M, Delhase M (2000) The I kappa B kinase (IKK) and NF-kappa B: key elements of proinflammatory signalling. Semin Immunol 12:85–98. doi: 10.1006/smim.2000.0210 PubMedCrossRefGoogle Scholar
  26. 26.
    Fan HQ, Gu N, Liu F et al (2007) Prolonged exposure to resistin inhibits glucose uptake in rat skeletal muscles. Acta Pharmacol Sin 28:410–416. doi: 10.1111/j.1745-7254.2007.00523.x PubMedCrossRefGoogle Scholar
  27. 27.
    LeRoith D (2002) Beta-cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities. Am J Med 113(Suppl 6A):3S–11S. doi: 10.1016/S0002-9343(02)01276-7 PubMedCrossRefGoogle Scholar
  28. 28.
    Banerjee RR, Lazar MA (2001) Dimerization of resistin and resistin-like molecules is determined by a single cysteine. J Biol Chem 276:25970–25973. doi: 10.1074/jbc.M103109200 PubMedCrossRefGoogle Scholar
  29. 29.
    Liu F, Fan HQ, Qiu J et al (2008) A paradox: insulin inhibits expression and secretion of resistin which induces insulin resistance. World J Gastroenterol 14:95–100. doi: 10.3748/wjg.14.95 PubMedCrossRefGoogle Scholar
  30. 30.
    Lee SJ, Yoo HJ, Bae YS, Kim HJ, Lee ST (2003) TIMP-1 inhibits apoptosis in breast carcinoma cells via a pathway involving pertussis toxin-sensitive G protein and c-Src. Biochem Biophys Res Commun 312:1196–1201. doi: 10.1016/j.bbrc.2003.11.050 PubMedCrossRefGoogle Scholar
  31. 31.
    Jiang H, Zhu H, Chen X et al (2007) TIMP-1 transgenic mice recover from diabetes induced by multiple low-dose streptozotocin. Diabetes 56:49–56. doi: 10.2337/db06-0710 PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2008

Authors and Affiliations

  • Chun-lin Gao
    • 1
    • 2
  • De-yu Zhao
    • 3
  • Jie Qiu
    • 2
  • Chun-mei Zhang
    • 2
  • Chen-bo Ji
    • 2
  • Xiao-hui Chen
    • 1
    • 2
  • Feng Liu
    • 2
    • 3
  • Xi-rong Guo
    • 1
    • 2
  1. 1.Department of PediatricsNanjing Maternity & Child Health Hospital of Nanjing Medical UniversityNanjingChina
  2. 2.Institute of Pediatrics of Nanjing Medical UniversityNanjingChina
  3. 3.Department of Respiratory MedicineNanjing Children’s Hospital Affiliated to Nanjing Medical UniversityNanjingChina

Personalised recommendations