Diabetes, Vol 45, Issue 5 615-621, Copyright © 1996 by American Diabetes Association

ARTICLES

Mechanisms behind insulin resistance in rat skeletal muscle after oophorectomy and additional testosterone treatment

J Rincon, A Holmang, EO Wahlstrom, P Lonnroth, P Bjorntorp, JR Zierath and H Wallberg-Henriksson
Deopartment of Clinical Physiology, Karolinska Hospital, Stockholm, Sweden.

The absence of female sex hormones, as well as testosterone treatment of oophorectomized (OVX) female rats has been demonstrated to result in decreased whole-body insulin-mediated glucose uptake. The cellular mechanism behind this insulin resistance and the role of low levels of female sex hormones as a risk factor for development of peripheral insulin resistance are not yet fully clarified. We assessed the protein expression of GLUT4 and glycogen synthase, as well as insulin-induced translocation of GLUT4 to the plasma membrane, in soleus skeletal muscle from control rats, OVX rats, and OVX rats treated for 8 weeks with testosterone (OVX + T). Whole-body insulin-mediated glucose uptake assessed by the hyperinsulinemic-euglycemic clamp procedure was 25% lower in OVX rats (P < 0.001) and addition of testosterone treatment further decreased insulin-mediated glucose uptake in OVX + T rats by 48% (P < 0.001) compared with controls. GLUT4 protein expression in soleus muscles was unaltered in the OVX and OVX + T rats compared with controls. Insulin induced a 3.7-fold increase (P < 0.05) in the plasma membrane content of GLUT4 in soleus muscle from control rats, whereas plasma membrane content of GLUT4 in soleus muscle from OVX or OVX + T rats was unaltered in response to insulin. Glycogen synthase protein expression in muscle homogenates was decreased by 25% in the OVX group (P < 0.05) and by 37% in the OVX + T group (P < 0.05) when compared with the control group. Insulin receptor and tyrosine kinase activities in the basal and insulin-stimulated states did not differ between the OVX and OVX + T rats. In conclusion, the absence of female sex hormones appears to decrease insulin-mediated whole-body glucose uptake via an impaired insulin-stimulated translocation of GLUT4 to the plasma membrane and by decreased protein expression of glycogen synthase. Testosterone treatment further impairs whole-body insulin-mediated glucose uptake, presumably by additional impairment of glycogen synthase expression.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. J. Toth, B. C. Cooper, R. E. Pratley, A. Mari, D. E. Matthews, and P. R. Casson Effect of ovarian suppression with gonadotropin-releasing hormone agonist on glucose disposal and insulin secretion Am J Physiol Endocrinol Metab, June 1, 2008; 294(6): E1035 - E1045. [Abstract] [Full Text] [PDF]

				A. Moran, D. R. Jacobs Jr, J. Steinberger, L. M. Steffen, J. S. Pankow, C.-P. Hong, and A. R. Sinaiko Changes in Insulin Resistance and Cardiovascular Risk During Adolescence: Establishment of Differential Risk in Males and Females Circulation, May 6, 2008; 117(18): 2361 - 2368. [Abstract] [Full Text] [PDF]

				M. Yoshioka, A. Boivin, C. Bolduc, and J. St-Amand Gender difference of androgen actions on skeletal muscle transcriptome J. Mol. Endocrinol., August 1, 2007; 39(2): 119 - 133. [Abstract] [Full Text] [PDF]

				L. Manneras, S. Cajander, A. Holmang, Z. Seleskovic, T. Lystig, M. Lonn, and E. Stener-Victorin A New Rat Model Exhibiting Both Ovarian and Metabolic Characteristics of Polycystic Ovary Syndrome Endocrinology, August 1, 2007; 148(8): 3781 - 3791. [Abstract] [Full Text] [PDF]

				P. Ordonez, M. Moreno, A. Alonso, R. Fernandez, F. Diaz, and C. Gonzalez Neuroendocrinology/Endocrinology: Insulin sensitivity in streptozotocin-induced diabetic rats treated with different doses of 17{beta}-oestradiol or progesterone Exp Physiol, January 1, 2007; 92(1): 241 - 249. [Abstract] [Full Text] [PDF]

				T. Enoki, Y. Yoshida, J. Lally, H. Hatta, and A. Bonen Testosterone increases lactate transport, monocarboxylate transporter (MCT) 1 and MCT4 in rat skeletal muscle J. Physiol., November 15, 2006; 577(1): 433 - 443. [Abstract] [Full Text] [PDF]

				A. Gambineri, L. Patton, A. Vaccina, M. Cacciari, A. M. Morselli-Labate, C. Cavazza, U. Pagotto, and R. Pasquali Treatment with Flutamide, Metformin, and Their Combination Added to a Hypocaloric Diet in Overweight-Obese Women with Polycystic Ovary Syndrome: A Randomized, 12-Month, Placebo-Controlled Study J. Clin. Endocrinol. Metab., October 1, 2006; 91(10): 3970 - 3980. [Abstract] [Full Text] [PDF]

				E. L. Ding, Y. Song, V. S. Malik, and S. Liu Sex Differences of Endogenous Sex Hormones and Risk of Type 2 Diabetes: A Systematic Review and Meta-analysis JAMA, March 15, 2006; 295(11): 1288 - 1299. [Abstract] [Full Text] [PDF]

				S. H. Golden, J. Ding, M. Szklo, M. I. Schmidt, B. B. Duncan, and A. Dobs Glucose and Insulin Components of the Metabolic Syndrome Are Associated with Hyperandrogenism in Postmenopausal Women: The Atherosclerosis Risk in Communities Study Am. J. Epidemiol., September 15, 2004; 160(6): 540 - 548. [Abstract] [Full Text] [PDF]

				S. Fenkci, V. Fenkci, M. Yilmazer, M. Serteser, and T. Koken Effects of short-term transdermal hormone replacement therapy on glycaemic control, lipid metabolism, C-reactive protein and proteinuria in postmenopausal women with type 2 diabetes or hypertension Hum. Reprod., April 1, 2003; 18(4): 866 - 870. [Abstract] [Full Text] [PDF]

				L. Morin-Papunen, I. Vauhkonen, R. Koivunen, A. Ruokonen, H. Martikainen, and J. S. Tapanainen Metformin Versus Ethinyl Estradiol-Cyproterone Acetate in the Treatment of Nonobese Women with Polycystic Ovary Syndrome: A Randomized Study J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 148 - 156. [Abstract] [Full Text] [PDF]

				H. Nishizawa, I. Shimomura, K. Kishida, N. Maeda, H. Kuriyama, H. Nagaretani, M. Matsuda, H. Kondo, N. Furuyama, S. Kihara, et al. Androgens Decrease Plasma Adiponectin, an Insulin-Sensitizing Adipocyte-Derived Protein Diabetes, September 1, 2002; 51(9): 2734 - 2741. [Abstract] [Full Text] [PDF]

				A. S. Ryan, B. J. Nicklas, and D. M. Berman Hormone Replacement Therapy, Insulin Sensitivity, and Abdominal Obesity in Postmenopausal Women Diabetes Care, January 1, 2002; 25(1): 127 - 133. [Abstract] [Full Text] [PDF]

				S. Morimoto, C. Fernandez-Mejia, G. Romero-Navarro, N. Morales-Peza, and V. DÍaz-Sánchez Testosterone Effect on Insulin Content, Messenger Ribonucleic Acid Levels, Promoter Activity, and Secretion in the Rat Endocrinology, April 1, 2001; 142(4): 1442 - 1447. [Abstract] [Full Text]

				T.-S. TSAO, J. LI, K. S. CHANG, A. E. STENBIT, D. GALUSKA, J. E. ANDERSON, J. R. ZIERATH, R. J. MCCARTER, and M. J. CHARRON Metabolic adaptations in skeletal muscle overexpressing GLUT4: effects on muscle and physical activity FASEB J, April 1, 2001; 15(6): 958 - 969. [Abstract] [Full Text] [PDF]

				K. E. Friday, C. Dong, and R. U. Fontenot Conjugated Equine Estrogen Improves Glycemic Control and Blood Lipoproteins in Postmenopausal Women with Type 2 Diabetes J. Clin. Endocrinol. Metab., January 1, 2001; 86(1): 48 - 52. [Abstract] [Full Text]

				M. E. E. Jones, A. W. Thorburn, K. L. Britt, K. N. Hewitt, N. G. Wreford, J. Proietto, O. K. Oz, B. J. Leury, K. M. Robertson, S. Yao, et al. Aromatase-deficient (ArKO) mice have a phenotype of increased adiposity PNAS, November 7, 2000; 97(23): 12735 - 12740. [Abstract] [Full Text] [PDF]

				M. Niklasson, P. Daneryd, P. Lonnroth, and A. Holmang Effects of exercise on insulin distribution and action in testosterone-treated oophorectomized female rats J Appl Physiol, June 1, 2000; 88(6): 2116 - 2122. [Abstract] [Full Text] [PDF]

				J. W. RYDER, Y. KAWANO, D. GALUSKA, R. FAHLMAN, H. WALLBERG-HENRIKSSON, M. J. CHARRON, and J. R. ZIERATH Postexercise glucose uptake and glycogen synthesis in skeletal muscle from GLUT4-deficient mice FASEB J, December 1, 1999; 13(15): 2246 - 2256. [Abstract] [Full Text]

				A. Thorell, J. Nygren, M. F. Hirshman, T. Hayashi, K. S. Nair, E. S. Horton, L. J. Goodyear, and O. Ljungqvist Surgery-induced insulin resistance in human patients: relation to glucose transport and utilization Am J Physiol Endocrinol Metab, April 1, 1999; 276(4): E754 - E761. [Abstract] [Full Text] [PDF]

				N. Hjeltnes, D. Galuska, M. Björnholm, A.-k. Aksnes, A. Lannem, J. R. Zierath, and H. Wallberg-Henriksson Exercise-induced overexpression of key regulatory proteins involved in glucose uptake and metabolism in tetraplegic persons: molecular mechanism for improved glucose homeostasis FASEB J, December 1, 1998; 12(15): 1701 - 1712. [Abstract] [Full Text]

				A. Dunaif Insulin Resistance and the Polycystic Ovary Syndrome: Mechanism and Implications for Pathogenesis Endocr. Rev., December 1, 1997; 18(6): 774 - 800. [Abstract] [Full Text]

				B. Andersson, L.-A. Mattsson, L. Hahn, L. Lapidus, G. Holm, B.-A. Bengtsson, and P. Bjorntorp Estrogen Replacement Therapy Decreases Hyperandrogenicity and Improves Glucose Homeostasis and Plasma Lipids in Postmenopausal Women With Noninsulin-Dependent Diabetes Mellitus J. Clin. Endocrinol. Metab., February 1, 1997; 82(2): 638 - 643. [Abstract] [Full Text] [PDF]