Molecular Medicine

, Volume 17, Issue 1–2, pp 4–11 | Cite as

Modulation of Insulin Sensitivity and Caveolin-1 Expression by Orchidectomy in a Nonobese Type 2 Diabetes Animal Model

  • Yoon Sin Oh
  • Tae Sup Lee
  • Gi Jeong Cheon
  • Ik-Soon Jang
  • Hee-Sook Jun
  • Sang Chul Park
Research Article


Previously, we found that male JYD mice developed type 2 diabetes but female mice did not, and that decreased expression levels of caveolin-1 were correlated with the development of a diabetic phenotype in these mice. Therefore, we hypothesized that sex hormones affect the expression of caveolin-1 and contribute to the development of insulin resistance and hyperglycemia in JYD mice. We used glucose and insulin tolerance tests to examine insulin sensitivity in male, female and orchidectomized male JYD mice. Glucose uptake was analyzed by using 18F-fluorodeoxyglucose positron emission tomography. We also examined insulin-signaling molecules and caveolin proteins in various tissues in these mice by Western blotting. In addition, we examined changes of caveolin-1 expression in L6 skeletal muscle cells treated with 17-β estradiol or dihydroxytestosterone. We found that glucose and insulin tolerance were impaired and hyperglycemia developed in male, but not female, JYD mice. Expression of insulin-signaling molecules such as insulin receptor, protein kinase B, and glucose transporter-4 were decreased in male JYD mice compared with female mice. Orchidectomized JYD male mice showed improved glucose and insulin tolerance with a concomitant increase in the expression of insulin-signaling molecules and caveolin-1 in adipose tissue and skeletal muscle. Moreover, 17-β-estradiol treatment increased the expression of caveolin-1 in differentiated skeletal muscle cells. We conclude that sex hormones modulate the expression of caveolin-1 and insulin-signaling molecules, subsequently affecting insulin sensitivity and the development of type 2 diabetes in JYD mice.



This study was supported by grants from the Aging and Apoptosis Research Center of the Korea Science and Engineering Foundation (RII-2002-097-05001-0, RII-2002-097-00001-0), National Research Foundation (NRF) of Korea funded by the Ministry of Education, Science and Technology (MEST) (M20702010002-08N0201-00200), and the Innovative Research Institute for Cell Therapy (A062260), Korea. We thank S-K Woo for technical assistance with imaging analysis and A Kyle for editorial assistance.


  1. 1.
    Meneilly GS, Tessier D. (2001) Diabetes in elderly adults. J. Gerontol. A. Biol. Sci. Med. Sci. 56:M5–13.CrossRefGoogle Scholar
  2. 2.
    Ding EL, et al. (2009) Sex hormone-binding globulin and risk of type 2 diabetes in women and men. N. Engl. J. Med. 361:1152–63.CrossRefGoogle Scholar
  3. 3.
    Ding EL, Song Y, Manson JE, Rifai N, Buring JE, Liu S. (2007) Plasma sex steroid hormones and risk of developing type 2 diabetes in women: a prospective study. Diabetologia 50:2076–84.CrossRefGoogle Scholar
  4. 4.
    Ding EL, Song Y, Malik VS, Liu S. (2006) Sex differences of endogenous sex hormones and risk of type 2 diabetes: a systematic review and meta-analysis. JAMA 295:1288–99.CrossRefGoogle Scholar
  5. 5.
    Dunaif A. (1993) Insulin resistance in polycystic ovarian syndrome. Ann. N. Y. Acad. Sci. 687:60–4.CrossRefGoogle Scholar
  6. 6.
    Legro RS, Kunselman AR, Dodson WC, Dunaif A. (1999) Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J. Clin. Endocrinol. Metab. 84:165–9.PubMedGoogle Scholar
  7. 7.
    Regitz-Zagrosek V, Lehmkuhl E, Mahmoodzadeh S. (2007) Gender aspects of the role of the metabolic syndrome as a risk factor for cardiovascular disease. Gend. Med. 4(Suppl B):S162–77.CrossRefGoogle Scholar
  8. 8.
    Diamond MP, Grainger D, Diamond MC, Sherwin RS, Defronzo RA. (1998) Effects of methyl-testosterone on insulin secretion and sensitivity in women. J. Clin. Endocrinol. Metab. 83:4420–5.PubMedGoogle Scholar
  9. 9.
    Kumagai S, Holmang A, Bjorntorp P. (1993) The effects of oestrogen and progesterone on insulin sensitivity in female rats. Acta Physiol. Scand. 149:91–7.CrossRefGoogle Scholar
  10. 10.
    Sargiacomo M, et al. (1995) Oligomeric structure of caveolin: implications for caveolae membrane organization. Proc. Natl. Acad. Sci. U. S. A. 92:9407–11.CrossRefGoogle Scholar
  11. 11.
    Schnitzer JE, Allard J, Oh P. (1995) NEM inhibits transcytosis, endocytosis, and capillary permeability: implication of caveolae fusion in endothelia. Am. J. Physiol. 268:H48–55.PubMedGoogle Scholar
  12. 12.
    Okamoto T, Schlegel A, Scherer PE, Lisanti MP. (1998) Caveolins, a family of scaffolding proteins for organizing “preassembled signaling complexes” at the plasma membrane. J. Biol. Chem. 273:5419–22.CrossRefGoogle Scholar
  13. 13.
    Razandi M, Oh P, Pedram A, Schnitzer J, Levin ER. (2002) ERs associate with and regulate the production of caveolin: implications for signaling and cellular actions. Mol. Endocrinol. 16:100–15.CrossRefGoogle Scholar
  14. 14.
    Lu ML, Schneider MC, Zheng Y, Zhang X, Richie JP. (2001) Caveolin-1 interacts with androgen receptor. A positive modulator of androgen receptor mediated transactivation. J. Biol. Chem. 276:13442–51.CrossRefGoogle Scholar
  15. 15.
    Nadal A, Diaz M, Valverde MA. (2001) The estrogen trinity: membrane, cytosolic, and nuclear effects. News Physiol. Sci. 16:251–5.PubMedGoogle Scholar
  16. 16.
    Oh YS, et al. (2006) Regulation of insulin response in skeletal muscle cell by caveolin status. J. Cell Biochem. 99:747–58.CrossRefGoogle Scholar
  17. 17.
    Oh YS, et al. (2007) Exercise type and muscle fiber specific induction of caveolin-1 expression for insulin sensitivity of skeletal muscle. Exp. Mol. Med. 39:395–401.CrossRefGoogle Scholar
  18. 18.
    Oh YS, et al. (2008) A potential role for skeletal muscle caveolin-1 as an insulin sensitivity modulator in ageing-dependent non-obese type 2 diabetes: studies in a new mouse model. Diabetologia. 51:1025–34.CrossRefGoogle Scholar
  19. 19.
    Wolfe AM, Wray S, Westphal H, Radovick S. (1996) Cell-specific expression of the human gonadotropin-releasing hormone gene in transgenic animals. J. Biol. Chem. 271:20018–23.CrossRefGoogle Scholar
  20. 20.
    Torizuka T, Fisher SJ, Brown RS, Wahl RL. (1998) Effect of insulin on uptake of FDG by experimental mammary carcinoma in diabetic rats. Radiology. 208:499–504.CrossRefGoogle Scholar
  21. 21.
    Wahl RL, Henry CA, Ethier SP. (1992) Serum glucose: effects on tumor and normal tissue accumulation of 2-[F-18]-fluoro-2-deoxy-D-glucose in rodents with mammary carcinoma. Radiology. 183:643–7.CrossRefGoogle Scholar
  22. 22.
    Ogi M, et al. (2003) Distribution and localization of caveolin-1 in sinusoidal cells in rat liver. Med. Electron Microsc. 36:33–40.CrossRefGoogle Scholar
  23. 23.
    Denker SP, McCaffery JM, Palade GE, Insel PA, Farquhar MG. (1996) Differential distribution of alpha subunits and beta gamma subunits of heterotrimeric G proteins on Golgi membranes of the exocrine pancreas. J. Cell Biol. 133:1027–40.CrossRefGoogle Scholar
  24. 24.
    Nevins AK, Thurmond DC. (2006) Caveolin-1 functions as a novel Cdc42 guanine nucleotide dissociation inhibitor in pancreatic beta-cells. J. Biol. Chem. 281:18961–72.CrossRefGoogle Scholar
  25. 25.
    Saltiel AR. (2001) New perspectives into the molecular pathogenesis and treatment of type 2 diabetes. Cell. 104:517–29.CrossRefGoogle Scholar
  26. 26.
    Kim JH, et al. (2001) Genetic analysis of a new mouse model for non-insulin-dependent diabetes. Genomics. 74:273–86.CrossRefGoogle Scholar
  27. 27.
    Iwase M, et al. (1996) Effect of gonadectomy on the development of diabetes mellitus, hypertension, and albuminuria in the rat model. Metabolism. 45:155–61.CrossRefGoogle Scholar
  28. 28.
    Zimmet P, Alberti KG, Shaw J. (2001) Global and societal implications of the diabetes epidemic. Nature. 414:782–7.CrossRefGoogle Scholar
  29. 29.
    Haring R, et al. (2009) Prediction of metabolic syndrome by low serum testosterone levels in men: results from the study of health in Pomerania. Diabetes. 58:2027–31.CrossRefGoogle Scholar
  30. 30.
    Singh AB, et al. (2002) The effects of varying doses of T on insulin sensitivity, plasma lipids, apolipoproteins, and C-reactive protein in healthy young men. J. Clin. Endocrinol. Metab. 87:136–43.CrossRefGoogle Scholar
  31. 31.
    Friedl KE, Jones RE, Hannan CJ Jr, Plymate SR. (1989) The administration of pharmacological doses of testosterone or 19-nortestosterone to normal men is not associated with increased insulin secretion or impaired glucose tolerance. J. Clin. Endocrinol. Metab. 68:971–5.CrossRefGoogle Scholar
  32. 32.
    Basu R, et al. (2007) Effect of 2 years of testosterone replacement on insulin secretion, insulin action, glucose effectiveness, hepatic insulin clearance, and postprandial glucose turnover in elderly men. Diabetes Care. 30:1972–8.CrossRefGoogle Scholar
  33. 33.
    Jedrzejuk D, Medras M, Milewicz A, Demissie M. (2003) Dehydroepiandrosterone replacement in healthy men with age-related decline of DHEAS: effects on fat distribution, insulin sensitivity and lipid metabolism. Aging Male. 6:151–6.CrossRefGoogle Scholar
  34. 34.
    Holmang A, Bjorntorp P. (1992) The effects of testosterone on insulin sensitivity in male rats. Acta Physiol. Scand. 146:505–10.CrossRefGoogle Scholar
  35. 35.
    Koricanac G, Milosavljevic T, Stojiljkovic M, Zakula Z, Ribarac-Stepic N, Isenovic ER. (2008) Insulin signaling in the liver and uterus of ovariectomized rats treated with estradiol. J. Steroid Biochem. Mol. Biol. 108:109–16.CrossRefGoogle Scholar
  36. 36.
    Schlegel A, Lisanti MP. (2000) A molecular dissection of caveolin-1 membrane attachment and oligomerization. Two separate regions of the caveolin-1 C-terminal domain mediate membrane binding and oligomer/oligomer interactions in vivo. J. Biol. Chem. 275:21605–17.CrossRefGoogle Scholar
  37. 37.
    Cohen AW, Combs TP, Scherer PE, Lisanti MP. (2003) Role of caveolin and caveolae in insulin signaling and diabetes. Am. J. Physiol. Endocrinol. Metab. 285:E1151–60.CrossRefGoogle Scholar
  38. 38.
    Nasu Y, et al. (1998) Suppression of caveolin expression induces androgen sensitivity in metastatic androgen-insensitive mouse prostate cancer cells. Nat. Med. 4:1062–4.CrossRefGoogle Scholar
  39. 39.
    Cohen AW, et al. (2003) Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue. Am. J. Physiol. Cell Physiol. 285:C222–35.CrossRefGoogle Scholar
  40. 40.
    Haynes MP, et al. (2000) Membrane estrogen receptor engagement activates endothelial nitric oxide synthase via the PI3-kinase-Akt pathway in human endothelial cells. Circ. Res. 87:677–82.CrossRefGoogle Scholar

Copyright information

© The Feinstein Institute for Medical Research 2011

Authors and Affiliations

  1. 1.Lee Gil Ya Cancer and Diabetes InstituteGachon University of Medicine and ScienceYeonsu-ku, IncheonKorea
  2. 2.Molecular Imaging Research CenterKorea Institute of Radiological and Medical SciencesSeoulKorea
  3. 3.Korea Basic Science InstituteDaegeonKorea
  4. 4.Department of Biochemistry and Molecular BiologySeoul National University College of MedicineChongno Ku, SeoulKorea

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