Skip to main content

Advertisement

SpringerLink
Log in

Alpha-lipoic Acid Prevents Bone Loss in Type 2 Diabetes and Postmenopausal Osteoporosis Coexisting Conditions by Modulating the YAP/Glut4 Pathway

  • Original Paper
  • Published:
Cell Biochemistry and Biophysics Aims and scope Submit manuscript

Abstract

This study aims to characterize the bone-protecting effects of Alpha-lipoic acid (ALA), a potent antioxidant, against the detrimental effects of the coexistence of type 2 diabetes mellitus (T2DM) and postmenopausal osteoporosis (POP) and identify the possible mechanisms with particular reference to its modulation of YAP/Glut4 pathway. The T2DM and POP coexisting model was induced in mice by high fat diet (HFD) + Streptozocin (STZ) + ovariectomy (OVX). The mice in the treatment groups were given ALA for 10 weeks. In the in vitro study, MC3T3-E1 cells were induced with 500 μM methylglyoxal for 24 h with or without pretreatment with ALA for 24 h. The oxidative and antioxidative biomarkers, bone microarchitecture, histo-morphology, and related protein expression of apoptosis, osteogenic differentiation and the YAP/Glut4 pathway were detected. The results showed ALA could improve glucose tolerance, inhibit oxidative stress and apoptosis and alleviate bone loss. Further study by siRNA technology revealed that the YAP/Glut4 pathway was implicated in the pathogenesis of bone loss due to the coexistence of T2DM and POP. Taken together, the present study has demonstrated for the first time that ALA exerts potent protective effects against bone loss in T2DM and POP coexisting conditions by modulating the YAP/Glut4 pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9
Fig. 10
Fig. 11
Fig. 12

Similar content being viewed by others

Data availability

The data used to support the findings of this study are available from the corresponding authors upon request.

Abbreviations

ALA:

alpha-lipoic acid

T2DM:

type 2 diabetes mellitus

POP:

postmenopausal osteoporosis

HFD:

high fat diet

STZ:

streptozocin

OVX:

ovariectomy

OP:

osteoporosis

ER:

estrogen receptor

BMD:

bone mineral density

MG:

Methylglyoxal

FBS:

fetal bovine serum

FBG:

fasting blood glucose

PBG:

postprandial blood glucose

BV:

bone volume

BS:

bone surface

ROI:

region of interest

GP:

growth plate

HE:

hematoxylin and eosin

LDH:

lactate dehydrogenase

SOD:

superoxide dismutase

MDA:

malonaldehyde

GSH:

glutathione

DCFH-DA:

2,7-dichlorofluorescein diacetate

PVDF:

polyvinyl difluoride

EMD:

membranes

TBS:

tris-buffered saline

LSD:

least significant difference

OGTT:

oral glucose tolerance test

GP:

growth plate

References

  1. Xiao, L., et al. (2015). Changes of serum osteocalcin, calcium, and potassium in a rat model of type 2 diabetes. Cell Biochem Biophys, 71(1), 437–440.

    Article  CAS  PubMed  Google Scholar 

  2. Zhao, R. (2012). Immune regulation of osteoclast function in postmenopausal osteoporosis: a critical interdisciplinary perspective. International Journal of Medical Sciences, 9(9), 825–832.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Díaz, A., et al. (2019). Sex differences in age-associated type 2 diabetes in rats — Role of estrogens and oxidative stress. Oxidative Medicine and Cellular Longevity, 2019, 6734836.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Mastrandrea, L. D., et al. (2008). Young women with type 1 diabetes have lower bone mineral density that persists over time. Diabetes Care, 31(9), 1729–1735.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Zhou, R. K., Wang, Z. H., & Chao, M. (2014). Hispidulin exerts anti-osteoporotic activity in ovariectomized mice via activating AMPK signaling pathway. Cell Biochemistry and Biophysics, 69(2), 311–317.

    Article  CAS  PubMed  Google Scholar 

  6. Napoli, N., et al. (2017). Mechanisms of diabetes mellitus-induced bone fragility. Nature Reviews. Endocrinology, 13(4), 208–219.

    CAS  PubMed  Google Scholar 

  7. Li, Z., et al. (2016). Glucose transporter-4 facilitates insulin-stimulated glucose uptake in osteoblasts. Endocrinology, 157(11), 4094–4103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Packer, L., Witt, E. H., & Tritschler, H. J. (1995). Alpha-Lipoic acid as a biological Antioxidant. Free Radical Biology and Medicine, 19(2), 227–250.

    Article  CAS  PubMed  Google Scholar 

  9. Salehi, B., et al. (2019). Insights on the Use of α-Lipoic Acid for Therapeutic Purposes. Biomolecules, 9(8), 356.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Smith, A. R., et al. (2004). Lipoic acid as a potential therapy for chronic diseases associated with oxidative stress. Current Medicinal Chemistry, 11(9), 1135–1146.

    Article  CAS  PubMed  Google Scholar 

  11. Wollin, S. D., & Jones, P. J. (2003). Alpha-lipoic acid and cardiovascular disease. Jornal of Nutrition, 133(11), 3327–3330.

    Article  CAS  Google Scholar 

  12. Gomes, M. B., & Negrato, C. A. (2014). Alpha-lipoic acid as a pleiotropic compound with potential therapeutic use in diabetes and other chronic diseases. Diabetology & Metabolic Syndrome, 6(1), 80.

    Article  Google Scholar 

  13. Fu, C., et al. (2015). Alpha-lipoic acid promotes osteoblastic formation in H2O2-treated MC3T3-E1 cells and prevents bone loss in ovariectomized rats. Journal of Cellular Physiology, 230(9), 2184–2201.

    Article  CAS  PubMed  Google Scholar 

  14. Raehtz, S., et al. (2017). Estrogen Deficiency Exacerbates Type 1 Diabetes–Induced Bone TNF-α Expression and Osteoporosis in Female Mice. Endocrinology, 158(7), 2086–2101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kanazawa, I., & Sugimoto, T. (2018). Diabetes mellitus-induced bone fragility. Internal Medicine, 57(19), 2773–2785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lee, Y. S., et al. (2018). Effect of a bisphosphonate and selective estrogen receptor modulator on bone remodeling in streptozotocin-induced diabetes and ovariectomized rat model. Spine Journal, 18(10), 1877–1887.

    Article  Google Scholar 

  17. Li, Y., et al. (2018). Preventative effects of resveratrol and estradiol on streptozotocin-induced diabetes in ovariectomized mice and the related mechanisms. PLoS One, 13(10), e0204499.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Lu, S., et al. (2017). The osteogenesis-promoting effects of alpha-lipoic acid against glucocorticoid-induced osteoporosis through the NOX4, NF-kappaB, JNK and PI3K/AKT pathways. Scientific Reports, 7(1), 3331.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Mukaiyama, K., et al. (2015). Elevation of serum alkaline phosphatase (ALP) level in postmenopausal women is caused by high bone turnover. Aging Clinical and Experimental Research, 27(4), 413–418.

    Article  PubMed  Google Scholar 

  20. Oka, Y., et al. (2012). Tea polyphenols inhibit rat osteoclast formation and differentiation. Journal of Pharmacological Sciences, 118(1), 55–64.

    Article  CAS  PubMed  Google Scholar 

  21. Xie, H., et al. (2018). Possible therapeutic potential of berberine in the treatment of STZ plus HFD-induced diabeticosteoporosis. Biomedicien. Pharmacotherapy, 108, 280–287.

    Article  CAS  Google Scholar 

  22. Tüzün, Ş., et al. (2013). Impact of the training on the compliance and persistence of weekly bisphosphonate treatment in postmenopausal osteoporosis: a randomized controlled study. International Journal of Medical Sciences, 10(13), 1880–1887.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Wang, J., et al. (2016). Chondroprotective effects of alpha-lipoic acid in a rat model of osteoarthritis. Free Radical Research, 50(7), 767–780.

    Article  CAS  PubMed  Google Scholar 

  24. Desai, K., & Wu, L. (2007). Methylglyoxal and advanced glycation endproducts: new therapeutic horizons? Recent Patents on Cardiovascular Drug Discovery, 2(2), 88–89.

    Google Scholar 

  25. Vander Jagt, D. L. (2008). Methylglyoxal, diabetes mellitus and diabetic complications. Drug Metabolism and Drug Interactions, 23(1-2), 93–124.

    Article  Google Scholar 

  26. Dhar, A., et al. (2011). Chronic methylglyoxal infusion by minipump causes pancreatic beta-cell dysfunction and induces type 2 diabetes in Sprague-Dawley rats. Diabetes, 60(3), 899–908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chu, P., et al. (2017). Phosphocreatine protects endothelial cells from Methylglyoxal induced oxidative stress and apoptosis via the regulation of PI3K/Akt/eNOS and NF-κB pathway. Vascular Pharmacology, 91, 26–35.

    Article  CAS  PubMed  Google Scholar 

  28. Lian, I., et al. (2010). The role of YAP transcription coactivator in regulating stem cell self-renewal and differentiation. Genes Development, 24(11), 1106–1118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. He, C., et al. (2015). The Hippo/YAP pathway interacts with EGFR signaling and HPV oncoproteins to regulate cervical cancer progression. EMBO Molecular Medicine, 7(11), 1426–1449.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhao, B., Lei, Q., & Guan, K. (2008). The Hippo-YAP pathway: new connections between regulation of organ size and cancer. Current Opinion in Cell Biology, 20(6), 638–646.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Moroishi, T., et al. (2016). The Hippo Pathway Kinases LATS1/2 Suppress Cancer Immunity. Cell, 167(6), 1525–1539.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Collak, F. K., et al. (2017). Increased expression of YAP1 in prostate cancer correlates with extraprostatic extension. Cancer Biology & Medicine, 14(4), 405–413.

    Article  CAS  Google Scholar 

  33. Ma, R., et al. (2019). Activated YAP causes renal damage of type 2 diabetic nephropathy. European Review for Medical and Pharmacological Sciences, 23(2), 755–763.

    CAS  PubMed  Google Scholar 

  34. Larance, M., Ramm, G., & James, D. E. (2008). The GLUT4 code. Molecular Endocrinology, 22(2), 226–233.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lee, J. O., et al. (2012). Metformin regulates glucose transporter 4 (GLUT4) translocation through AMP-activated protein kinase (AMPK)-mediated Cbl/CAP signaling in 3T3-L1 preadipocyte cells. Journal of Biological Chemistry, 287(53), 44121–44129.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Castaneda, F., Layne, J. E., & Castaneda, C. (2006). Skeletal muscle sodium glucose co-transporters in older adults with type 2 diabetes undergoing resistance training. International Journal of Medical Sciences, 3(3), 84–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author contributions

All authors contributed to the study conception and design. H.S. and M.L. conceived and designed this study. L.X. and C.Z. performed the major experiments and data analysis and drafted the manuscript. C.W., J.B., G.H., Y.C. and G.X. provided technological support. All the authors have read and approved this manuscript.

Funding

The work was supported in part by grants from Important Science Fund of Science and Technology Bureau of Liaoning Province (2020JH2/10300056) and Fund of Department of Education of Liaoning Provincial (No. LZ2019016).

Author information

Author notes

  1. These authors contributed equally: Lei Xu, Chunfang Zhang

Authors and Affiliations

  1. Office of Ethics Committee, the First Affiliated Hospital, Dalian Medical University, Dalian, China

    Lei Xu

  2. Department of Pathology, the First Affiliated Hospital, Dalian Medical University, Dalian, China

    Chunfang Zhang

  3. Department of Clinical Pharmacology, College of Pharmacy, Dalian Medical University, Dalian, China

    Jiawu Bao, Guozhu Han, Changyuan Wang & Huijun Sun

  4. Department of Orthopaedics, the First Affiliated Hospital, Dalian Medical University, Dalian, China

    Yuanqing Cai, Gang Xu & Mozhen Liu

Authors
  1. Lei Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chunfang Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiawu Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guozhu Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Changyuan Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yuanqing Cai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Gang Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Huijun Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Mozhen Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Huijun Sun or Mozhen Liu.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Xu, L., Zhang, C., Bao, J. et al. Alpha-lipoic Acid Prevents Bone Loss in Type 2 Diabetes and Postmenopausal Osteoporosis Coexisting Conditions by Modulating the YAP/Glut4 Pathway. Cell Biochem Biophys (2024). https://doi.org/10.1007/s12013-024-01216-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12013-024-01216-w

Keywords

Search

Navigation