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Underlying biochemical effects of intermittent fasting, exercise and honey on streptozotocin-induced liver damage in rats

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Abstract

Purpose

Derangements of liver transcriptional factors and enzymes have important implications in diabetes-induced related complications. Hence, this study which consists of two experimental phases was aimed at evaluating the possible underlying molecular mechanisms of intermittent fasting (IF), exercise starvation and honey in streptozotocin (STZ)-mediated liver damage in diabetic rats.

Methods

The diabetic rats were treated orally with distilled water (0.5 ml/kg), IF, starvation and honey at 1 g/kg body weight in the non-diabetic phase for four (4) weeks. After STZ injections, four (4) weeks of IF, exercise, starvation, and honey therapy were used as interventions prior to a biochemical evaluation of the liver.

Results

IF and exercise greatly decreased liver transcription factor (resistin, SREBP-1c), inflammatory cytokines/enzyme (TNF-α, IL-6, IL-1ß, MPO) as well as oxidative and nitrergic stress with correspondence increased liver PPAR-γ, IL-10, SOD, CAT and GSH in diabetic rats unlike starvation and honey regimen relative to diabetic controls. Furthermore, IF and exercise significantly improved hepatic glycogen synthase and decreased glycogen phosphorylase in diabetic rats compared to the diabetic control group, but starvation and honey therapy had no such influence. IF and exercise strategically reduces STZ-induced liver metabolic disorder via through modulation of liver transcriptional factors and inhibition of pro-inflammatory cytokines, oxido-nitrergic and adipokine signaling pathway.

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Data availability

The corresponding author can provide all of the data used in this article upon request.

Code availability

Not applicable.

Abbreviations

STZ:

Streptozotocin,

IF:

Intermittent fasting

TNF-α:

Tumor necrotic factor-alpha,

IL-6::

Interleukin-6

IL-1β:

Interleukin-1 beta

IL-10:

Interleukin-10

GSH:

Glutathione reductase

SOD:

Superoxide dismutase

CAT:

Catalase

MDA:

Malonaldehyde

LPO:

Lipid peroxidation

NO:

Nitric oxide,

MPO:

Myeloperoxidase

SREBP1c:

Sterol regulatory element binding protein 1c

PPAR- γ:

Peroxisome proliferator-activated receptor-y

References

  1. Hudish LI, Reusch JEB, Sussel L. β Cell dysfunction during progression of metabolic syndrome to type 2 diabetes. J Clin Investig. 2019;129(10):4001–8.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Erejuwa O, Nwobodo N, Akpan J, Okorie U, Ezeonu C, Ezeokpo B, Nwadike K, Erhiano E, Abdul Wahab M, Sulaiman S. Nigerian honey ameliorates hyperglycemia and dyslipidemia in Alloxan-induced diabetic rats. Nutrients. 2016;8(3):95.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Petersen MC, Shulman GI. Mechanisms of insulin action and insulin resistance. Physiol Rev. 2018;98(4):2133–223.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Xu N, Zhang Y, Doycheva DM, Ding Y, Zhang Y, Tang J, Guo H, Zhang JH. Adiponectin attenuates neuronal apoptosis induced by hypoxia-ischemia via the activation of AdipoR1/APPL1/LKB1/AMPKpathway in neonatal rats. Neuropharmacology. 2018;133:415–28.

    Article  CAS  PubMed  Google Scholar 

  5. Henson J, Yates T, Edwardson CL, Khunti K, Talbot D, Gray LJ, Davies MJ. Sedentary time and markers of chronic low-grade inflammation in a high risk population. PLoS ONE. 2013;8(10):78350–007835.

    Article  Google Scholar 

  6. Esser N, Legrand-Poels S, Piette J, Scheen AJ, Paquot N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res Clin Pract. 2014;105:141–50.

    Article  CAS  PubMed  Google Scholar 

  7. Harvie M, Howell A. Potential benefits and harms of intermittent energy restriction and intermittent fasting amongst obese, overweight and normal weight subjects-a narrative review of human and animal evidence. Behav Sci (Basel, Switzerland). 2017;7(1).

  8. Anton SD, Moehl K, Donahoo WT, Marosi K, Lee SA. Flipping the metabolic switch: understanding and applying the health benefits of fasting. Obesity. 2018;26(2):254–68.

    Article  PubMed  Google Scholar 

  9. Almasaudi SB, El-Shitany NA, Abbas, AT, Abdel-dayem UA, Ali SS, al Jaouni SK, Harakeh S. Antioxidant, anti-inflammatory, and antiulcer potential of Manuka Honey against gastric ulcer in rats. Oxidative Med Cell Longev. 2016;3643824.

  10. Akanmu M, Olowookere T, Atunwa S, Ibrahim B, Lamidi O, Adams P, Ajimuda B, Adeyemo L. Neuropharmacological effects of Nigerian honey in mice. Afr J Trad Compl Alt Med. 2011;8(3).

  11. Al Aamri ZM, Ali BH. Does honey have any salutary effect against streptozotocin - induced diabetes in rats. J Diabetes Metab Disord. 2017;16(1).

  12. Szalai Z, Szász A, Nagy I, Puskás LG, Kupai K, Király A, ... , Varga C. Anti-inflammatory effect of recreational exercise in TNBS-induced colitis in rats: role of NOS/HO/MPO system. Oxidative Med Cell Longev. 2014.

  13. Bradley PP, Priebat DA, Christensen RD, Rothstein G. Measurement of cutaneous inflammation: Estimation of neutrophil content with an enzyme marker. J Investig Dermatol. 1982;78(3):206–9.

    Article  CAS  PubMed  Google Scholar 

  14. Hillegass L, Griswold D, Brickson B, Albrightson-Winslow C. Assessment of myeloperoxidase activity in whole rat kidney. J Pharmacol Methods. 1990;24(4):285–95.

    Article  CAS  PubMed  Google Scholar 

  15. Van Doorn R, Leijdekkers CM, Henderson PT. Synergistic effects of phorone on the hepatotoxicity of bromobenzene and paracetamol in mice. Toxicology. 1978;11:225–33.

    Article  PubMed  Google Scholar 

  16. Miranda KM, Espey MG, Wink DA. A rapid, simple spectrophotometric method for simultaneous detection of nitrate and nitrite. Nitric Oxide. 2001;5(1):62–71.

    Article  CAS  PubMed  Google Scholar 

  17. Evans JL, Maddux B, Goldfine ID. The molecular basis for oxidative stress-induced insulin resistance. Antioxid Redox Signal. 2005;7(7–8):1040–52.

    Article  CAS  PubMed  Google Scholar 

  18. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11(2):98–107.

    Article  CAS  PubMed  Google Scholar 

  19. Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to insulin resistance and type 2 diabetes. Nature. 2006;444(7121):840–6.

    Article  CAS  PubMed  Google Scholar 

  20. Whitton PD, Hems DA. Glycogen synthesis in the perfused liver of streptozotocin-diabetic rats. Biochem J. 1975;150(2):153–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Rao PV, Pugazhenthi S, Khandelwal RL. The effects of streptozotocin-induced diabetes and insulin supplementation on expression of the glycogen phosphorylase gene in rat liver. J Biol Chem. 1995;270(42):24955–60.

    Article  CAS  PubMed  Google Scholar 

  22. Solini A, Di Virgilio F, Chiozzi P, Fioretto P, Passaro A, Fellin R. A defect in glycogen synthesis characterizes insulin resistance in hypertensive patients with type2 diabetes. Hypertension. 2001;37(6):1492–6.

    Article  CAS  PubMed  Google Scholar 

  23. Richardson SJ, Willcox A, Bone AJ, Foulis AK, Morgan NG. Islet-associated macrophages in type 2 diabetes. Diabetologia. 2009;52(8):1686–8.

    Article  CAS  PubMed  Google Scholar 

  24. Parker GJ, Lund KC, Taylor RP, McClain DA. Insulin resistance of glycogen synthase mediated by O-linked N-acetylglucosamine. J Biol Chem. 2003;278:10022–7.

    Article  CAS  PubMed  Google Scholar 

  25. Bollen M, Keppens S, Stalmans W. Specific features of glycogen metabolism in the liver. Biochem J. 1988;336(1):19–31.

    Article  Google Scholar 

  26. Abdulwahab DA, El-Missiry MA, Shabana S, Othman AI, Amer ME. Melatonin protects the heart and pancreas by improving glucose homeostasis, oxidative stress, inflammation and apoptosis in T2DM-induced rats. Heliyon. 2021;7(3):06474.

    Article  Google Scholar 

  27. Griendling KK, FitzGerald GA. Oxidative Stress and Cardiovascular Injury. Circulation. 2003;108(16):1912–6.

    Article  PubMed  Google Scholar 

  28. Yubero-Serrano, EM, Delgado-Lista J, Peña-Orihuela P, Perez-Martinez P, Fuentes F, Marin C, Tunez I, Jose Tinahones F, Perez-Jimenez F, Roche HM, Lopez-Miranda J. Oxidative stress is associated with the number of components of. 2013

  29. El-Missiry MA, Amer MA, Hemieda FA, Othman AI, Sakr DA, Abdulhadi HL. Cardioameliorative effect of punicalagin against streptozotocin-induced apoptosis, redox imbalance, metabolic changes and inflammation. Egypt J Basic Appl Sci. 2015;2(4):247–60.

    Google Scholar 

  30. Mahmoud AM, Ashour MB, Abdel-Moneim A, Ahmed OM. Hesperidin and naringin attenuate hyperglycemia-mediated oxidative stress and proinflammatory cytokine production in high fat fed/streptozotocin-induced type 2 diabetic rats. J Diabetes Complicat. 2012;26(6):483–90.

    Article  Google Scholar 

  31. Kogel V, Trinh S, Gasterich N, Beyer C, Seitz J. Long-term glucose starvation induces inflammatory responses and phenotype switch in primary cortical rat astrocytes. J Mol Neurosci. 2021;71(11):2368–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nishida K, Otsu K. Inflammation and metabolic cardiomyopathy. Cardiovasc Res. 2017;113(4):389–98.

    Article  CAS  PubMed  Google Scholar 

  33. Zhang B, Shen Q, Chen Y, Pan R, Kuang S, Liu G, Sun G, Sun X. Myricitrin alleviates oxidative stress-induced inflammation and apoptosis and protects mice against diabetic cardiomyopathy. Sci Rep. 2017;7(1).

  34. ALmohaimeed HM, Mohammedsaleh ZM, Batawi AH, Balgoon MJ, Ramadan OI, Baz HA, al Jaouni S, Ayuob NN. Synergistic anti-inflammatory and neuroprotective effects of Cinnamomum cassia and Zingiber officinale Alleviate diabetes-induced hippocampal changes in male Albino rats: structural and molecular evidence. Front Cell Dev Biol. 2021;9.

  35. Bastard JP, Maachi M, van Nhieu JT, Jardel C, Bruckert E, Grimaldi A, Robert JJ, Capeau J, Hainque B. Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. J Clin Endocrinol Metab. 2002;87(5):2084–9.

    Article  CAS  PubMed  Google Scholar 

  36. Dinarello CA. Blocking interleukin-1β in acute and chronic autoinflammatory diseases. J Intern Med. 2010;269(1):16–28.

    Article  Google Scholar 

  37. Akash MS, Rehman K, Chen S. Role of inflammatory mechanisms in pathogenesis of type 2 diabetes mellitus. J Cell Biochem. 2013;114(3):525–31.

    Article  CAS  PubMed  Google Scholar 

  38. Jayaraman S, Devarajan N, Rajagopal P, Babu S, Ganesan SK, Veeraraghavan VP, Palanisamy CP, Cui B, Periyasamy V, Chandrasekar K. Sitosterol circumvents obesity induced inflammation and insulin resistance by down-regulating IKK_/NF-_B and JNK signaling pathway in adipocytes of Type 2 diabetic rats. Molecules. 2021;26:2101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kheiripour N, Karimi J, Khodadadi I, Tavilani H, Goodarzi MT, Hashemnia M. Silymarin prevents lipid accumulation in the liver of rats with type 2 diabetes via sirtuin1 and SREBP-1c. J Basic Clin Physiol Pharmacol. 2018;29(3):301–8.

    Article  CAS  PubMed  Google Scholar 

  40. Jumli MN,  Nadeem MI. The Mechanistic and Pathophysiological Role of Adiponectin and Resistin towards Regulation of Food Intake and Appetite in Cardiovascular Associated Risk Factor of Metabolic Syndrome, Type 2 Diabetes - From Pathophysiology to Cyber Systems. Anca Pantea Stoian, IntechOpen, 2021.

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Acknowledgements

The authors thank the technical staff at the Department of Physiology at Delta State University in Abraka, Nigeria.

Author information

Authors and Affiliations

  1. Department of Physiology, Faculty of Basic Medical Science, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria

    Ejime Agbonifo-Chijiokwu, Kingsley E. Nwangwa, Mega O. Oyovwi, Alexander O. Naiho, Ejiro Peggy Ohwin, Azuka Prosper Ehiwarior & Shalom Udoka Nwabuoku

  2. Department of Hunan Physiology, Achievers University, Owo, Ondo State, Nigeria

    Mega O. Oyovwi

  3. Department of Pharmacology, Faculty of Basic Medical Science, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria

    Benneth Ben-Azu & Emuesiri Goodies Moke

  4. Department of Physiology, University of Medical Sciences, Ondo, Ondo State, Nigeria

    Victor Emojevwe

  5. Department of Medical Biochemistry, Faculty of Basic Medical Science, College of Health Sciences, Delta State University, Abraka, Delta State, Nigeria

    Evelyn Tarela Ojugbeli

  6. Department of Physiology, Faculty of Basic Medical Science, Babcock University, Illisan-Romo, Ogun State, Nigeria

    Bright O. Oghenetega

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  1. Ejime Agbonifo-Chijiokwu
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Contributions

Conceptualization E.A.C., N.E.K; data curation, writing original draft preparation. E.A.E., O.M.O., BBA B.O.O., EGM; review and editing BBA, O.M.O., E.G.M., N.E.K and E.V.; supervision.N.E.K.; validation N.E.K.; funding acquisition E.A.C., B.O.O and O.M.O. All authors have read and agreed to the publishing of the manuscript.

Corresponding author

Correspondence to Benneth Ben-Azu.

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Ethical approval

The Ethical Review Committee of Delta State University gave their approval to perform this study on 09/11/2021, with the reference number REC/FBMS/DELSU/21/121.

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Agbonifo-Chijiokwu, E., Nwangwa, K.E., Oyovwi, M.O. et al. Underlying biochemical effects of intermittent fasting, exercise and honey on streptozotocin-induced liver damage in rats. J Diabetes Metab Disord 22, 515–527 (2023). https://doi.org/10.1007/s40200-022-01173-2

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