Skip to main content

Advertisement

SpringerLink
Log in

Anti-inflammatory potential of delta-9-tetrahydrocannabinol in hyperinsulinemia: an experimental study

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Background

Hyperinsulinemia (HI) means that the amount of insulin in the blood is higher than normal and is often associated with type 2 diabetes. It is known that delta-9-tetrahydrocannabinol (THC) obtained from a medicinal plant, Cannabis sativa, has therapeutic effects on many diseases.

Objective

This study aimed to investigate the effects of THC on inflammatory and oxidant status in rat pancreas with HI.

Methods

Rats were divided into groups; Control, HI, THC and HI + THC. Each group consists of 8 animals. HI and HI + THC groups were given 10% fructose in the drinking water for 12 weeks. In the last four weeks of the experiment, 1.5 mg kg−1 THC was injected intraperitoneally daily into THC and HI + THC groups. The expression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nuclear factor-kappa B (NF-κB) were detected. JNK/SAPK and Grap2/p38 levels, total antioxidant and oxidant capacities (TAC and TOC) were analyzed in the pancreas.

Results

Levels of IL-6, NF-κβ, and TNF-α mRNA expression were higher in the pancreas with HI than in the control (p < 0.001 for all). THC treatment reduced the expression of IL-6, NF-κβ, and TNF-α mRNAs in the HI + THC group compared to the HI group (p < 0.001 for all). TOC increased in the HI group compared to the control group (p < 0.001). However, THC treatment reduced TOC levels in the HI + THC group compared to the HI group (p < 0.001).

Conclusion

According to the results, the THC treatment may regulate inflammation and TOC in rats with hyperinsulinemia. Thus, we can say that THC may have anti-inflammatory and antioxidant potential in metabolic disorders.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Similar content being viewed by others

Abbreviations

AEC:

3-Amino-9ethyl carbazole

CBD:

Cannabidiol

CBDA:

Cannabinolic acid

CBG:

Cannabigerol

CBGA:

Cannabigerolic acid

CBN:

Cannabinol

Δ9 THCA:

Delta-9-tetrahydrocannabinolic acid

ERK:

Extracellular signal-regulated kinase

Grb2:

Growth factor receptor-bound protein 2

Grap2/p38:

Grb2-related adapter protein/p38

HI:

Hyperinsulinemia

Il-6:

Interleukin-6

JNK/SAPK:

Jun N-terminal kinase/stress-activated protein kinase

MAPK:

Mitogen-activated protein kinase

NF-κB:

Nuclear factor-kappa B

qRT-PCR:

Quantitative real-time polymerase chain reaction

TAC:

Total antioxidant capacity

THC:

Delta-9-tetrahydrocannabinol

TNF-α:

Tumor necrosis factor-alpha

TNFR-1:

Tumor necrosis factor receptor-1

TOC:

Total oxidant capacity

References

  1. Andersen DK, Korc M, Petersen GM et al (2017) Diabetes, pancreatogenic diabetes, and pancreatic cancer. Diabetes 66(5):1103–1110

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Young BE, Padilla J, Finsen SH et al (2022) Role of endothelin-1 receptors in limiting leg blood flow and glucose uptake during hyperinsulinemia in type 2 diabetes. Endocrinology 163(3):bqac008

    Article  PubMed  Google Scholar 

  3. Gupta AP, Syed AA, Garg R et al (2019) Pancreastatin inhibitor PSTi8 attenuates hyperinsulinemia induced obesity and inflammation mediated insulin resistance via MAPK/NOX3-JNK pathway. Eur J Pharmacol 864:172723

    Article  CAS  PubMed  Google Scholar 

  4. Thomas DD, Corkey BE, Istfan NW et al (2019) Hyperinsulinemia: an early indicator of metabolic dysfunction. J Endocr Soc 3(9):1727–1747

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mohamed MA, Ahmed MA, El Sayed RA (2019) Molecular effects of Moringa leaf extract on insulin resistance and reproductive function in hyperinsulinemic male rats. J Diabetes Metab Disord 18(2):487–494

    Article  PubMed  PubMed Central  Google Scholar 

  6. Weber KS, Simon MC, Strassburger K et al (2018) Habitual fructose intake relates to insulin sensitivity and fatty liver index in recent-onset type 2 diabetes patients and individuals without diabetes. Nutrients 10(6):E774

    Article  Google Scholar 

  7. Bartley C, Brun T, Oberhauser L et al (2019) Chronic fructose renders pancreatic β-cells hyper-responsive to glucose-stimulated insulin secretion through extracellular ATP signaling. Am J Physiol Endocrinol Metab 317(1):E25–E41

    Article  CAS  PubMed  Google Scholar 

  8. Singh S, Sharma A, Guru B et al (2022) Fructose-mediated NLRP3 activation induces inflammation and lipogenesis in adipose tissue. J Nutr Biochem 107:109080

    Article  CAS  PubMed  Google Scholar 

  9. Rohm TV, Meier DT, Olefsky JM et al (2022) Inflammation in obesity, diabetes, and related disorders. Immunity 55(1):31–55

    Article  CAS  PubMed  Google Scholar 

  10. Yamashita AS, Belchior T, Lira FS et al (2018) Regulation of metabolic disease-associated inflammation by nutrient sensors. Mediators Inflamm 2018:8261432

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kumar D, Shankar K, Patel S et al (2018) Chronic hyperinsulinemia promotes meta-inflammation and extracellular matrix deposition in adipose tissue: implications of nitric oxide. Mol Cell Endocrinol 477:15–28

    Article  CAS  PubMed  Google Scholar 

  12. Kim EK, Choi EJ (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta 1802(4):396–405

    Article  CAS  PubMed  Google Scholar 

  13. Zuo G, Ren X, Qian X et al (2019) Inhibition of JNK and p38 MAPK-mediated inflammation and apoptosis by ivabradine improves cardiac function in streptozotocin-induced diabetic cardiomyopathy. J Cell Physiol 234(2):1925–1936

    Article  CAS  PubMed  Google Scholar 

  14. Hussain T, Tan B, Yin Y et al (2016) Oxidative stress and ınflammation: What polyphenols can do for us? Oxid Med Cell Longev 2016:7432797

    Article  PubMed  PubMed Central  Google Scholar 

  15. Dinu AR, Rogobete AF, Bratu T et al (2020) Cannabis sativa revisited-crosstalk between microrna expression, ınflammation, oxidative stress, and endocannabinoid response system in critically ıll patients with sepsis. Cells 9(2):E307

    Article  Google Scholar 

  16. Maayah ZH, Takahara S, Ferdaoussi M et al (2020) The molecular mechanisms that underpin the biological benefit of full spectrum cannabis extract in the treatment of neuropathic pain and inflammation. Biochim Biophys Acta Mol Basis Dis 1866(7):165771

    Article  CAS  PubMed  Google Scholar 

  17. Britch S, Goodman A, Wiley J et al (2020) Antinociceptive and immune effects of delta-9-tetrahydrocannabinol or cannabidiol in male versus female rats with persistent inflammatory pain. J Pharmacol Exp Ther 373(3):416–428

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Khanal P, Patil BM (2022) Reversal of insulin resistance by Ficus benghalensis bark in fructose-induced insulin-resistant rats. J Ethnopharmacol 284:114761

    Article  CAS  PubMed  Google Scholar 

  19. Abdelrahman AM, Al Suleimani YM, Ashique M et al (2018) Effect of infliximab and tocilizumab on fructose-induced hyperinsulinemia and hypertension in rats. Biomed Pharmacother 105:182–186

    Article  CAS  PubMed  Google Scholar 

  20. Pfaffl MW (2001) A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 29(9):e45

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Breijyeh Z, Jubeh B, Bufo SA et al (2021) Cannabis: a toxin-producing plant with potential therapeutic uses. Toxins 13(2):117

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bielawiec P, Harasim-Symbor E, Chabowski A (2020) Phytocannabinoids: useful drugs for the treatment of obesity? Special Focus Cannabidiol Front Endocrinol 11:114

    Google Scholar 

  23. Vella RK, Jackson DJ, Fenning AS (2017) Δ9-tetrahydrocannabinol prevents cardiovascular dysfunction in STZ-diabetic Wistar-Kyoto rats. Biomed Res Int 2017:7974149

    Article  PubMed  PubMed Central  Google Scholar 

  24. Banaszkiewicz M, Tarwacka P, Krzywonos-Zawadzka A et al (2022) Δ9-tetrahydrocannabinol (Δ9-THC) improves ischemia/reperfusion heart dysfunction and might serve as a cardioprotective agent in the future treatment. Front Biosci 27(4):114

    Article  CAS  Google Scholar 

  25. Li C, Ford ES, McGuire LC et al (2006) Trends in hyperinsulinemia among nondiabetic adults in the U.S. Diabetes Care 29(11):2396–2402

    Article  PubMed  Google Scholar 

  26. Arias-Chávez DJ, Mailloux-Salinas P, Altamirano J et al (2022) Consumption of combined fructose and sucrose diet exacerbates oxidative stress, hypertrophy and CaMKIIδ oxidation in hearts from rats with metabolic syndrome. Mol Cell Biochem 477(4):1309–1320

    Article  PubMed  Google Scholar 

  27. Beydogan AB, Coskun ZM, Bolkent S (2019) The protective effects of Δ9-tetrahydrocannabinol against inflammation and oxidative stress in rat liver with fructose-induced hyperinsulinemia. J Pharm Pharmacol 71(3):408–416

    Article  CAS  PubMed  Google Scholar 

  28. Chandel S, Sathis A, Dhar M et al (2020) Hyperinsulinemia promotes endothelial inflammation via increased expression and release of Angiopoietin-2. Atherosclerosis 307:1–10

    Article  CAS  PubMed  Google Scholar 

  29. Ruge T, Lockton JA, Renstrom F et al (2009) Acute hyperinsulinemia raises plasma interleukin-6 in both nondiabetic and type 2 diabetes mellitus subjects, and this effect is inversely associated with body mass index. Metabolism 58(6):860–866

    Article  CAS  PubMed  Google Scholar 

  30. Popko K, Gorska E, Stelmaszczyk-Emmel A et al (2010) Proinflammatory cytokines Il-6 and TNF-α and the development of inflammation in obese subjects. Eur J Med Res 15(2):120–122

    Article  PubMed  PubMed Central  Google Scholar 

  31. Liu T, Zhang L, Joo D et al (2017) NF-κB signaling in inflammation. Signal Transduct Target Ther 2:17023

    Article  PubMed  PubMed Central  Google Scholar 

  32. Turcotte C, Blanchet MR, Laviolette M et al (2016) The CB2 receptor and its role as a regulator of inflammation. Cell Mol Life Sci 73(23):4449–4470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yang L, Li FF, Han YC et al (2015) Cannabinoid receptor CB2 is involved in tetrahydrocannabinol-induced anti-inflammation against lipopolysaccharide in MG-63 cells. Mediators Inflamm 2015:362126

    Article  PubMed  PubMed Central  Google Scholar 

  34. Dybala MP, Gebien LR, Reyna ME et al (2020) Implications of integrated pancreatic microcirculation: crosstalk between endocrine and exocrine compartments. Diabetes 69(12):2566–2574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Linnemann AK, Blumer J, Marasco MR et al (2017) Interleukin 6 protects pancreatic β cells from apoptosis by stimulation of autophagy. FASEB J 31(9):4140–4152

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wu S, Dong K, Wang J et al (2018) Tumor necrosis factor alpha improves glucose homeostasis in diabetic mice independent with tumor necrosis factor receptor 1 and tumor necrosis factor receptor 2. Endocr J 65(6):601–609

    Article  CAS  PubMed  Google Scholar 

  37. Garg R, Kumariya S, Katekar R et al (2021) JNK signaling pathway in metabolic disorders: an emerging therapeutic target. Eur J Pharmacol 901:174079

    Article  CAS  PubMed  Google Scholar 

  38. Pereira S, Yu WQ, Moore J et al (2016) Effect of a p38 MAPK 260 inhibitor on FFA-induced hepatic insulin resistance in vivo. Nutr Diabetes 6:e210

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Wang Y, Hai B, Niu X et al (2017) Chronic intermittent hypoxia disturbs insulin secretion and causes pancreatic injury via the MAPK signaling pathway. Biochem Cell Biol 95(3):415–420

    Article  CAS  PubMed  Google Scholar 

  40. Yadav UC, Rani V, Deep G et al (2016) Oxidative stress and metabolic disorders: pathogenesis and therapeutic strategies. Life Sci 148:183–193

    Article  PubMed  Google Scholar 

  41. Leenders F, Groen N, de Graaf N et al (2021) Oxidative stress leads to β-cell dysfunction through loss of β-cell identity. Front Immunol 12:690379

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Dawidowicz AL, Olszowy-Tomczyk M, Typek R (2021) CBG, CBD, Δ9-THC, CBN, CBGA, CBDA and Δ9-THCA as antioxidant agents and their intervention abilities in antioxidant action. Fitoterapia 152:104915

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

No specific funding has been received for the present study.

Author information

Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Demiroglu Bilim University, Istanbul, Turkey

    Zeynep Mine Coskun Yazici

  2. Department of Medical Biology, Faculty of Cerrahpasa Medicine, Istanbul University-Cerrahpasa, 34098, Cerrahpasa, Istanbul, Turkey

    Bilgenur Bilge & Sema Bolkent

Authors
  1. Zeynep Mine Coskun Yazici
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bilgenur Bilge
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sema Bolkent
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ZMCY and SB contributed to the conception and design of this study. ZMCY, BB and SB performed the experiments and analyzed the data. All authors approved the final version of the manuscript submitted for publication.

Corresponding author

Correspondence to Sema Bolkent.

Ethics declarations

Competing interest

There are no conflicts of interest to declare.

Ethical approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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 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

Yazici, Z.M.C., Bilge, B. & Bolkent, S. Anti-inflammatory potential of delta-9-tetrahydrocannabinol in hyperinsulinemia: an experimental study. Mol Biol Rep 49, 11891–11899 (2022). https://doi.org/10.1007/s11033-022-07996-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-022-07996-9

Keywords

Search

Navigation