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Molecular Biology Reports

, Volume 46, Issue 5, pp 4953–4965 | Cite as

Endogenous SHBG levels correlate with that of glucose transporters in insulin resistance model cells

  • Chong Feng
  • Zhen JinEmail author
  • Lei Sun
  • Xiaoyan Wang
  • Xinshu Chi
  • Xuan Zhang
  • Siyu Lian
Original Article

Abstract

Gestational diabetes mellitus (GDM) is defined as glucose intolerance of any degree that occurs after onset of pregnancy. Sex hormone binding globulin (SHBG) plays an important regulatory role in insulin resistance and is a risk factor in GDM. In the current study, we aimed to examine whether SHBG can regulate glucose metabolism through glucose transporters (GLUTs). SHBG was transfected into established human insulin model cells and the expression of SHBG, GLUT1, GLUT3, and GLUT4 was detected and analyzed in normal cells, model cells, and all groups of transfected cells by real-time PCR and western blotting. Further, immunofluorescence staining was performed on cells from each group to observe protein expression. In insulin resistance model cells, the expression of SHBG was low, whereas that of GLUT1 was high and of GLUT3 and GLUT4 was low, when compared with expression in control cells. Moreover, the overexpression of SHBG inhibited the expression of GLUT1 mRNA and protein, and promoted the expression of GLUT3 and GLUT4. Our results indicate that SHBG could be involved in glucose metabolism through its regulation of multiple GLUTs. Transfection of SHBG into insulin-resistant cells may partially improve the level of GLUTs, providing a potential therapeutic approach for the treatment of insulin resistance in GDM. Although SHBG can regulate glucose metabolism through GLUTs and thus cause insulin resistance and induce gestational diabetes, the regulation mechanism of GLUTs mediated by SHBG has not been elucidated, which will be the focus of further studies.

Keywords

Gestational diabetes mellitus (GDM) Glucose transporters (GLUTs) Sex hormone binding globulin (SHBG) Insulin resistance GLUT4 translocation HTR8/SVneo 

Abbreviations

SHBG

Sex hormone binding globulin

GDM

Gestational diabetes mellitus

GLUTs

Glucose transporters

IADPSG

The International Association of the Diabetes and Pregnancy Study Group

T2D

Type II diabetes

apoB

Apolipoprotein B

BMI

Body Mass Index

HDL

High density lipoprotein

NIDDM

Non-insulin-resistant diabetes in women

EVT

Extravillous trophoblasts

Notes

Acknowledgements

Author Agreement: All authors have seen and approved the final version of the manuscript being submitted. We all warrant that the article is the authors’ original work, hasn’t received prior publication and isn’t under consideration for publication elsewhere.

Author contributions

CF executed the study and drafted the manuscript, ZJ designed the study, LS analysed the experimental data, XW and XC made the critical discussion, XZ and SL revised it critically for important intellectual content.

Funding

This study was supported by the National Natural Science Foundation of China (Nos. 81300511 and 81170591).

Compliance with ethical standards

Conflict of interest

There’s no financial/personal interest or belief that could affect our objectivity.

References

  1. 1.
    Goedegebure EAR, Koning SH, Hoogenberg K, Korteweg FJ, Lutgers HL, Diekman MJM, Stekkinger E, van den Berg PP, Zwart JJ (2018) Pregnancy outcomes in women with gestational diabetes mellitus diagnosed according to the WHO-2013 and WHO-1999 diagnostic criteria: a multicentre retrospective cohort study. BMC Pregn Childbirth 18(No.1):152CrossRefGoogle Scholar
  2. 2.
    Geng H, Ding X, Duan B (2017) Influence of standardized treatment for GDM on maternal blood glucose level, pregnancy outcomes and morbidity in mother and infant. Int J Clin Exp Med 10(11):15504–15509Google Scholar
  3. 3.
    Xu T, He Y, Dainelli L, Yu K, Detzel P, Silva-Zolezzi I, Volger S, Fang H (2017) Healthcare interventions for the prevention and control of gestational diabetes mellitus in China: a scoping review. BMC Pregn Childbirth. 17(1):171CrossRefGoogle Scholar
  4. 4.
    Xu X, Liu Y, Liu D, Li X, Rao Y, Sharma M, Zhao Y (2017) Prevalence and determinants of gestational diabetes mellitus: a cross-sectional study in China. Int J Environ Res Public Health. 14(12):1532PubMedCentralCrossRefGoogle Scholar
  5. 5.
    Li L, Jiang H, Chen Z, Liu P, Liu Y, Sun Z (2017) Analyses of the prevalence and risk factors of gestational diabetes mellitus using novel diagnostic criteria. West Indian Med J. 66(1):41–45Google Scholar
  6. 6.
    Waters TP, Dyer AR et al (2016) Maternal and neonatal morbidity for women who would be added to the diagnosis of GDM using IADPSG criteria: a secondary analysis of the hyperglycemia and adverse pregnancy outcome study. Diabetes Care. 39(12):2204–2210PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Park YM et al (2017) Gestational diabetes mellitus may be associated with increased risk of breast cancer. Br J Cancer. 116(7):960PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Minooee S et al (2017) Diabetes incidence and influencing factors in women with and without gestational diabetes mellitus: a 15 year population-based follow-up cohort study. Diabetes Res Clin Pract 128:24–31PubMedCrossRefGoogle Scholar
  9. 9.
    Saez-Lopez C, Rivera-Gimenez M, Hernandez C, Simó R, Selva DM (2015) SHBG-C57BL/ksJ-db/db: a new mouse model to study SHBG expression and regulation during obesity development. Endocrinology 156:4571–4581PubMedCrossRefGoogle Scholar
  10. 10.
    Chen L et al (2016) Gestational diabetes mellitus: its epidemiology and implication beyond pregnancy. Curr Epidemiol Rep 3:1–11CrossRefGoogle Scholar
  11. 11.
    Waters TP et al (2016) Maternal and neonatal morbidity for women who would be added to the diagnosis of GDM using IADPSG criteria: a secondary analysis of the hyperglycemia and adverse pregnancy outcome study. Diabetes Care 39:2204–2210PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Tam WH et al (2017) In utero exposure to maternal hyperglycemia increases childhood cardiometabolic risk in offspring. Diabetes Care 40:679–686PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Sherif K, Kushner H, Falkner BE (1998) Sex hormone-binding globulin and insulin resistance in African-American women. Metabolism 47(1):70–74PubMedCrossRefGoogle Scholar
  14. 14.
    Haffner SM et al (1993) Decreased sex hormone-binding globulin predicts noninsulin dependent diabetes mellitus in women but not in men. Endocr Soc 77:56–60Google Scholar
  15. 15.
    Heald AH et al (2005) Low sex hormone binding globulin is a potential marker for the metabolic syndrome in different ethnic groups. Exp Clin Endocrinol Diabetes 113(9):522–528PubMedCrossRefGoogle Scholar
  16. 16.
    Tawfeek MA et al (2017) Sex hormone binding globulin as a valuable biochemical marker in predicting gestational diabetes mellitus. BMC Womens Health 17(1):18PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    McElduff A, Hitchman R, McElduff P (2006) Is sex hormone-binding globulin associated with glucose tolerance? Diabet Med 23(3):306–312PubMedCrossRefGoogle Scholar
  18. 18.
    Chen Y et al (2016) Wnt5a inhibited human trophoblast cell line HTR8/SVneo invasion: implications for early placentation and preeclampsia. J Maternal-Fetel Neonatal Med 29:3532–3538CrossRefGoogle Scholar
  19. 19.
    Jiang L et al (2017) Elevated microRNA-520g in pre-eclampsia inhibits migration and invasion of trophoblasts. Placenta 51:70–75PubMedCrossRefGoogle Scholar
  20. 20.
    Bulla R, Bossi F, Agostinis C, Radillo O, Colombo F, De Seta F, Tedesco F (2009) Complement production by trophoblast cells at the feto-maternal interface. J Reprod Immunol. 82(2):119–125PubMedCrossRefGoogle Scholar
  21. 21.
    Beith JL, Alejandro EU, Johnson JD (2008) Insulin stimulates primary beta-cell proliferation via Raf-1 kinase. Endocrinology 149(No.5):2251–2260PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Barbour LA, Shao JH, Qiao LP (2004) Human placental growth hormone increases expression of the p85 regulatory unit of phosphatidylinositol 3-kinase and triggers severe insulin resistance in skeletal muscle. Endocrinology 145(3):1144–1150PubMedCrossRefGoogle Scholar
  23. 23.
    Feng C, Jin Z, Chi X, Zhang B, Wang X, Sun L, Fan J, Sun Q, Zhang X (2018) SHBG expression is correlated with PI3K/AKT pathway activity in a cellular model of human insulin resistance. Gynecol Endocrinol. 34(No.7):567–573PubMedCrossRefGoogle Scholar
  24. 24.
    AlEssa HB, Malik VS, Yuan C (2017) Dietary patterns and cardiometabolic and endocrine plasma biomarkers in US women. Am J Clin Nutr 105(2):432–441PubMedCrossRefGoogle Scholar
  25. 25.
    Keevil BG, Adaway J, Fiers T, Moghetti P, Kaufman JM (2018) The free androgen index is inaccurate in women when the SHBG concentration is low. Clin Endocrinol. 88:706–710CrossRefGoogle Scholar
  26. 26.
    Buyalos RP et al (1993) The influence of luteinizing hormone and insulin on sex steroids and sex hormone-binding globulin in the polycystic ovarian syndrome. Fertil Steril 60:626–633PubMedCrossRefGoogle Scholar
  27. 27.
    Xia H, Zhang R, Sun X (2016) Risk factors for preeclampsia in infertile Chinese women with polycystic ovary syndrome: a prospective cohort study. J Clin Hypertens 19:504–509CrossRefGoogle Scholar
  28. 28.
    Daan NM, Koster MP, de Wilde MA (2016) Biomarker profiles in women with PCOS and PCOS offspring; a pilot study. PLoS ONE 11(11):e0165033PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Mohammed M (2018) Impact of metabolic syndrome factors on testosterone and SHBG in type 2 diabetes mellitus and metabolic syndrome. J Diabet Res.  https://doi.org/10.1155/2018/4926789 CrossRefGoogle Scholar
  30. 30.
    Al-Kuraishy HM, Al-Gareeb AI (2016) Erectile dysfunction and low sex drive in men with type 2 DM: the potential role of diabetic pharmacotherapy. J Clin Diagn Res 10(No.12):21–26Google Scholar
  31. 31.
    Mattack N, Devi R, Kutum T, Patgiri D (2015) The evaluation of serum levels of testosterone in type 2 diabetic men and its relation with lipid profile. J Clin Diagn Res 9(No.1):BC04–BC07PubMedPubMedCentralGoogle Scholar
  32. 32.
    Liu S, Sun Q (2016) Sex differences, endogenous sex-hormone hormones, sex-hormone binding globulin, and exogenous disruptors in diabetes and related metabolic outcomes. J Diabetes 10:428–441CrossRefGoogle Scholar
  33. 33.
    Xita N, Georgiou I, Lazaros L (2008) The role of sex hormone-binding globulin and androgen receptor gene variants in the development of polycystic ovary syndrome. Human Reprod 23(3):693–698CrossRefGoogle Scholar
  34. 34.
    Sullivan PM, Petrusz P, Szpirer C, Joseph DR (1991) Alternative processing of androgen-binding protein RNA transcripts in fetal rat liver. Identification of a transcript formed by trans splicing. J Biol Chem 266(1):143–154PubMedGoogle Scholar
  35. 35.
    Hammond GL (1992) Novel testicular products of the human SHBG/ABP gene. Follicle stimulating hormone. Springer, New York, pp 246–253CrossRefGoogle Scholar
  36. 36.
    Joseph DR, Becchis M, Fenstermacher DA (1996) The alternate N-terminal sequence of rat androgen-binding protein/sex hormone-binding globulin contains a nuclear targeting signal. Endocrinology 137(3):1138–1143PubMedCrossRefGoogle Scholar
  37. 37.
    Simpson IA, Vannucci SJ, DeJoseph MR et al (2001) Glucose transporter asymmetries in the bovine blood-brain barrier. J Biol Chem 276:12725–12729PubMedCrossRefGoogle Scholar
  38. 38.
    Bannasch D, Safra N, Young A et al (2008) Mutations in the SLC2A9 gene cause hyperuricosuria and hyperuricemia in the dog. PLoS Genet 4:e1000246PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Baschnagel AM, Wobb JL, Dilworth JT et al (2015) The association of 18F-FDG PET and glucose metabolism biomarkers GLUT1 and HK2 in p16 positive and negative head and neck squamous cell carcinomas. Radiother Oncol. 117(No.1):118–124PubMedCrossRefGoogle Scholar
  40. 40.
    Komaki S, Sugita Y, Furuta T et al (2019) Expression of GLUT1 in pseudopalisaded and perivascular tumor cells is an independent prognostic factor for patients with glioblastomas. J Neuropathol Exp Neurol. 78(No.5):389–397PubMedCrossRefGoogle Scholar
  41. 41.
    Ferré-Dolcet L, Yeste M, Vendrell M, Rigau T, Rodríguez-Gil JE, Álamo MM (2018) Placental and uterine expression of GLUT3, but not GLUT1, is related with serum progesterone levels during the first stages of pregnancy in queens. Theriogenology 121:82–90PubMedCrossRefGoogle Scholar
  42. 42.
    Shao J, Qiao LP, Catalano PM, Draznin S, Friedman JE (2001) Impaired IRS-1 associated PI 3-kinase activity with increased akt and PKC lambda/zeta activity in skeletal muscle from gestational diabetic C57BL/KsJ-(db/+) mice and humans. Diabetes 50:A295Google Scholar
  43. 43.
    Beith JL, Alejandro EU, Johnson JD (2008) Insulin stimulates primary β-cell proliferation via Raf-1 kinase. Endocrinology 149(5):2251–2260PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Cline GW, Petersen KF, Krssak M (1997) Impaired glucose transport as a cause of decreased insulin-stimulated muscle glycogen synthesis in type 2 diabetes. N Engl J Med 99(9):2219–2224Google Scholar
  45. 45.
    Garvey WT et al (1992) Gene-expression of Glut4 in skeletal-muscle from insulin-resistant patients with obesity, Igt, Gdm, and Niddm. Diabetes 41(4):465–475PubMedCrossRefGoogle Scholar
  46. 46.
    Nishiumi S, Ashida H (2007) Rapid preparation of a plasma membrane fraction from adipocytes and muscle cells: Application to detection of translocated glucose transporter 4 on the plasma membrane. Biosci Biotechnol Biochem 71(9):2343–2346PubMedCrossRefGoogle Scholar
  47. 47.
    Palanivel R, Maida A, Liu Y (2006) Regulation of insulin signalling, glucose uptake and metabolism in rat skeletal muscle cells upon prolonged exposure to resistin. Diabetologia 49(1):183–190PubMedCrossRefGoogle Scholar
  48. 48.
    Garvey WT, Maianu L, Zhu JH (1993) Multiple defects in the adipocyte glucose-transport system cause cellular insulin-resistance in gestational diabetes—heterogeneity in the number and a novel abnormality in subcellular-localization of Glut4 glucose transporters. Diabetes. 43(12):1773–1785CrossRefGoogle Scholar
  49. 49.
    Jonas D, Dietz W, Simma B (2014) Hypoglycemia in newborn infants at risk. Klinische Padiatrie. 226(5):287–291PubMedCrossRefGoogle Scholar
  50. 50.
    Stanirowski PJ, Szukiewicz D, Pyzlak M, Abdalla N, Sawicki W, Cendrowski K (2017) Analysis of correlations between the placental expression of glucose transporters GLUT-1, GLUT-4 and GLUT-9 and selected maternal and fetal parameters in pregnancies complicated by diabetes mellitus. J Matern Fetal Neonatal Med. 32:650–659PubMedCrossRefGoogle Scholar
  51. 51.
    Sciullo E, Cardellini G, Baroni M, Torresi P, Mazziotti F, Pozzilli P, Fallucca F (1997) Glucose transporters (GLUT 1, GLUT 3) mRNA in human placenta of diabetic and non-diabetic pregnancies. Annali dell’Istituto Superiore di Sanita. 33(NO.3):361–365PubMedGoogle Scholar
  52. 52.
    Tumurbaatar B, Poole AT, Olson G, Makhlouf M, Sallam HS, Thukuntla S, Kankanala S, Ekhaese O, Gomez G, Chandalia M, Abate N (2017) Adipose tissue insulin resistance in gestational diabetes. Metab Syndr Relat Disorders 15(2):86–92CrossRefGoogle Scholar
  53. 53.
    Li W, Wei ZH, Jian LI (2014) Expression of Akt and GLUT-4 in adipose tissue of women with gestational diabetes mellitus and pregnant women with excessive weight gain. Med J Chin People’s Lib Army. 39(10):819–822Google Scholar
  54. 54.
    Colomiere M, Permezel M, Lappas M (2010) Diabetes and obesity during pregnancy alter insulin signalling and glucose transporter expression in maternal skeletal muscle and subcutaneous adipose tissue. J Mol Endocrinol. 44(No.4):213–223PubMedCrossRefGoogle Scholar
  55. 55.
    Govers R (2014) Molecular mechanisms of GLUT4 regulation in adipocytes. Diab Metab 40(6):400–410CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  1. 1.Department of Obstetrics and GynecologyShengjing Hospital Affiliated to China Medical UniversityShenyangChina

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