Testosterone supplementation improves insulin responsiveness in HFD fed male T2DM mice and potentiates insulin signaling in the skeletal muscle and C2C12 myocyte cell line


Autoři: Madhuraka Pal aff001;  Jasim Khan aff002;  Ravi Kumar aff001;  Avadhesha Surolia aff003;  Sarika Gupta aff001
Působiště autorů: Molecular Science Laboratory, National Institute of Immunology, New Delhi, India aff001;  Molecular Toxicology Laboratory, Department of Medical Elementology and Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, India aff002;  Molecular Biophysics Unit, Indian Institute of Science, Bengaluru, Karnataka, India aff003
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0224162

Souhrn

Background

Type 2 Diabetes Mellitus (T2DM) is characterised by hyperglycemia due to the incidence of insulin resistance. Testosterone supplementation has been shown to have a positive co-relation with improved glycemic control in T2DM males. Clinical studies have reported that Androgen Replacement Therapy (ART) to hypogonadic males with T2DM resulted in improved glycemic control and metabolic parameters, but, these studies did not address in detail how testosterone acted on the key glucose homeostatic organs.

Method

In this study, we delineate the effect of testosterone supplementation to high-fat diet (HFD) induced T2DM in male C57BL6J mice and the effect of testosterone supplementation on the skeletal muscle insulin responsiveness. We also studied the effect of testosterone on the insulin signaling pathway proteins in C2C12 myocyte cells to validate the in vivo findings.

Results

We found that testosterone had a potentiating effect on the skeletal muscle insulin signaling pathway to improve glycaemic control. We demonstrate that, in males, testosterone improves skeletal muscle insulin responsiveness by potentiating the PI3K-AKT pathway. The testosterone treated animals showed significant increase in the skeletal muscle Insulin Receptor (IR), p85 subunit of PI3K, P-GSK3α (Ser-21), and P-AKT (Ser-473) levels as compared to the control animals; but there was no significant change in total AKT and GSK3α. Testosterone supplementation inhibited GSK3α in the myocytes in a PI3K/AKT pathway dependent manner; on the other hand GSK3β gene expression was reduced in the skeletal muscle upon testosterone supplementation.

Conclusion

Testosterone increases insulin responsiveness by potentiating insulin signaling in the skeletal muscle cells, which is in contrast to the increased insulin resistance in the liver of testosterone treated T2DM male animals.

Klíčová slova:

Androgens – Gene expression – Glycogens – Insulin – Insulin signaling – Skeletal muscles – Testosterone


Zdroje

1. Taylor S. Deconstructing Type 2 Diabetes. Cell. 1999; 97(1):9–12. doi: 10.1016/s0092-8674(00)80709-6 10199397

2. American Diabetes Association. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2004; 28(Supplement 1): S37–S42.

3. Traish A, Saad F, Guay A. The Dark Side of Testosterone Deficiency: II. Type 2 Diabetes and Insulin Resistance. J Androl. 2008; 30(1):23–32. doi: 10.2164/jandrol.108.005751 18772488

4. Kapoor D. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol. 2006; 154(6):899–906. doi: 10.1530/eje.1.02166 16728551

5. Pitteloud N, Mootha VK, Dwyer AA, Hardin M, Lee H, Eriksson KF et al. Relationship between Testosterone Levels, Insulin Sensitivity, and Mitochondrial Function in Men. Diabetes Care. 2005; 28(7):1636–1642. doi: 10.2337/diacare.28.7.1636 15983313

6. Sato K, Iemitsu M, Aizawa K, Ajisaka R. Testosterone and DHEA activate the glucose metabolism-related signaling pathway in skeletal muscle. Am J Physiol Endocrinol Metab. 2008 May;2 94(5): E961–8

7. Arha D, Ramakrishna E, Gupta AP, Rai AK, Sharma A, Ahmad I, et al. Isoalantolactone derivative promotes glucose utilization in skeletal muscle cells and increases energy expenditure in db/db mice via activating AMPK-dependent signalling. Mol Cell Endocrinol. 2018 Jan 15; 460:134–151. doi: 10.1016/j.mce.2017.07.015 28736255

8. Mitsuhashi K, Senmaru T, Fukuda T, Yamazaki M, Shinomiya K, Ueno M, et al. Testosterone stimulates glucose uptake and GLUT4 translocation through LKB1/AMPK signaling in 3T3-L1 adipocytes. Endocrine. 2016; 51: 174–184. doi: 10.1007/s12020-015-0666-y 26100787

9. Pal M, Gupta S. Testosterone supplementation improves glucose homeostasis despite increasing hepatic insulin resistance in male mouse model of type 2 diabetes mellitus. Nutr Diabetes. 2016; 6(12):e236. doi: 10.1038/nutd.2016.45 27941939

10. Roelandt P, Sancho-Bru P, Pauwelyn K, Verfaillie C. Differentiation of rat multipotent adult progenitor cells to functional hepatocyte-like cells by mimicking embryonic liver development. Nat Protoc. 2010; 5(7):1324–1336. doi: 10.1038/nprot.2010.80 20595960

11. DeFronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest. 1985; 76, 149–155. doi: 10.1172/JCI111938 3894418

12. Reis MA, Carneiro EM, Mello MA, Boschero AC, Saad MJ, Velloso LA. Glucose-induced insulin secretion is impaired and insulin-induced phosphorylation of the insulin receptor and insulin receptor substrate-1 are increased in protein-deficient rats. J Nutr. 1997; 127, 403–410. doi: 10.1093/jn/127.3.403 9082023

13. Singh R, Artaza J, Taylor W, Gonzalez-Cadavid N, Bhasin S. Androgens Stimulate Myogenic Differentiation and Inhibit Adipogenesis in C3H 10T1/2 Pluripotent Cells through an Androgen Receptor-Mediated Pathway. Endocrinology. 2003; 144(11):5081–5088. doi: 10.1210/en.2003-0741 12960001

14. Saltiel A, Kahn C. Insulin signalingand the regulation of glucose and lipid metabolism. Nature. 2001; 414(6865):799–806. doi: 10.1038/414799a 11742412

15. Elchebly M. Increased Insulin Sensitivity and Obesity Resistance in Mice Lacking the Protein Tyrosine Phosphatase-1B Gene. Science. 1999; 283(5407):1544–1548.

16. Nelson JF, Latham KR, & Finch CE. Plasma testosterone levels in C57BL/6J male mice: effects of age and disease. Acta Endocrinologica. 1975; 80(4): 744–752. doi: 10.1530/acta.0.0800744 1103542

17. O’Neill BT, Lee KY, Klaus K, Softic S, Krumpoch MT, Fentz J, et al. Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis. J Clin Invest. 2016; 126(9):3433–3446. doi: 10.1172/JCI86522 27525440

18. Cohen P. The twentieth century struggle to decipher insulin signalling. Nat Rev Mol Cell Biol. 2006; (11):867–873. doi: 10.1038/nrm2043 17057754

19. Samuel V, Shulman G. Mechanisms for Insulin Resistance: Common Threads and Missing Links. Cell. 2012; 148(5):852–871. doi: 10.1016/j.cell.2012.02.017 22385956

20. Liberman Z, Eldar-Finkelman H. Serine 332 Phosphorylation of Insulin Receptor Substrate-1 by Glycogen Synthase Kinase-3 Attenuates Insulin Signaling. J Biol Chem. 2004; 280(6):4422–4428. doi: 10.1074/jbc.M410610200 15574412

21. Nikoulina S, Ciaraldi T, Mudaliar S, Mohideen P, Carter L, Henry R. Potential role of glycogen synthase kinase-3 in skeletal muscle insulin resistance of type 2 diabetes. Diabetes. 2000; 49(2):263–271. doi: 10.2337/diabetes.49.2.263 10868943

22. van der Velden JL, Langen RC, Kelders MC, Wouters EF, Janssen-Heininger YM, Schols AM. Inhibition of glycogen synthase kinase-3beta activity is sufficient to stimulate myogenic differentiation. Am J Physiol Cell Physiol. 2006; 290(2): C453–62. doi: 10.1152/ajpcell.00068.2005 16162663

23. Léger B, Cartoni R, Praz M, Lamon S, Dériaz O, Crettenand A, et al. Akt signalingthrough GSK-3beta, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy. J Physiol. 2006; 576(Pt 3):923–33. doi: 10.1113/jphysiol.2006.116715 16916907

24. Feng H, Cheng AS, Tsang DP, Li MS, Go MY, Cheung YS, et al. Cell cycle–related kinase is a direct androgen receptor–regulated gene that drives β-catenin/T cell factor–dependent hepatocarcinogenesis. J Clin Invest. 2011; 121(8):3159–3175. doi: 10.1172/JCI45967 21747169

25. Ma Y, Fu S, Lu L, Wang X. Role of androgen receptor on cyclic mechanical stretch-regulated proliferation of C2C12 myoblasts and its upstream signals: IGF-1- mediated PI3K/Akt and MAPKs pathways. Mol Cell Endocrinol. 2017; 450: 83e93

26. Li Longlong, Yao Yao, Jiang Zhihao, Zhao Jinlong, Cao Ji, and Ma Haitian. Dehydroepiandrosterone Prevents H2O2-Induced BRL-3A Cell Oxidative Damage through Activation of PI3K/Akt Pathways rather than MAPK Pathways. Oxid Med Cell Longev. 2019; 2019: Article ID 2985956.

27. Rossetti Michael L., Steiner Jennifer L., Gordon Bradley S. Androgen-mediated regulation of skeletal muscle protein balance. Mol Cell Endocrinol. 2017; 447: 35–44 doi: 10.1016/j.mce.2017.02.031 28237723

28. Iguchi K, Fukami K, Ishii K, Otsuka T, Usui S, Sugimura Y, et al. Low Androgen Sensitivity Is Associated With Low Levels of Akt Phosphorylation in LNCaP-E9 Cells. J Androl. 2011; 33(4):660–666. doi: 10.2164/jandrol.111.013888 22016349

29. Heinlein CA, Chang C. The Roles of Androgen Receptors and Androgen-Binding Proteins in Nongenomic Androgen Actions. Mol Endocrinol. 2002; 16 (10): 2181–2187 doi: 10.1210/me.2002-0070 12351684

30. Bolton E. C., So A. Y., Chaivorapol C., Haqq C. M., Li H., and Yamamoto K. R. Cell- and gene-specific regulation of primary arget genes by the androgen receptor. Genes Dev. 2007; 21: 2005–2017 doi: 10.1101/gad.1564207 17699749

31. Xu W, Niu T, Xu B, Navarro G, Schipma MJ, Mauvais-Jarvis F. Androgen receptor deficient islet βcells exhibit alteration in genetic markers of insulin secretion and inflammation. A transcriptome analysis in the male mouse. J Diabetes Complications. 2017 May; 31(5):787–795. doi: 10.1016/j.jdiacomp.2017.03.002 28343791

32. Yu C, Lin H, Sparks JD, Yeh S, Chang C. Androgen Receptor Roles in Insulin Resistance and Obesity in Males: The Linkage of Androgen-Deprivation Therapy to Metabolic Syndrome. Diabetes 63 (10) 3180–3188. doi: 10.2337/db13-1505 25249645

33. Bassil N, Alkaade S, Morley JE. The benefits and risks of testosterone replacement therapy: a review. Ther. Clin. Risk Manag. 2009; 5: 427–448. doi: 10.2147/tcrm.s3025 19707253


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2019 Číslo 11