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Vitamin D Combined with Pioglitazone Mitigates Type-2 Diabetes-induced Hepatic Injury Through Targeting Inflammation, Apoptosis, and Oxidative Stress

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Abstract—

Inflammation is a major pathophysiological factor in development of type-2 diabetes mellitus (T2DM). Vitamin D (VITD) plays an imperative role in modulation of several inflammatory responses. The current study aimed to investigate the possible beneficial effects of coadministration of VITD with pioglitazone (PIO), a PPAR-γ agonist, in fructose/streptozotocin (F/STZ) T2DM model in male Wistar rats. T2DM was induced by maintaining rats on 10% (w/v) fructose in drinking water for 9 weeks with an intraperitoneal injection of sub-diabetogenic dose of STZ (35 mg/kg) by the end of the fourth week. One week after STZ injection, PIO (10 mg/kg/day) alone or with VITD (500 IU/kg/day) was administered orally to diabetic rats till the end of the experiment. Blood samples were collected, livers were homogenized to determine biochemical parameters, and samples of livers were fixed in 10% formalin in saline for histological examination. Administration of PIO alone improved diabetes-induced inflammatory and oxidative states besides controlling hyperglycemia and decreasing apoptosis. Coadministration of VIT D with PIO promoted additional improvement in glycemic and lipid profiles, provided further control on diabetic-induced hepatic inflammation evident by downregulating TLR2, TLR4, and IKK-β while upregulating IκB-α expression and reducing inflammatory cytokines namely; NF-κB, TNF-α, IL-6, and IL-1β, decreasing apoptosis and oxidative stress by hampering caspase-3 and MDA contents, respectively, and improved liver histology than PIO alone. These beneficial effects of VIT D may expand its use by diabetics combined with antidiabetic drugs due to its anti-inflammatory, antioxidant, and antiapoptotic properties.

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ACKNOWLEDGEMENTS

We kindly thank Dr. Mohamed Abdelraziq (Department of Pathology, Faculty of Veterinary Medicine, Cairo University) for performing the histopathological studies. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    Hend A. Hamouda, Suzan M. Mansour & Mohammed F. Elyamany

  2. Department of Pharmacology, Toxicology and Biochemistry, Faculty of Pharmacy, Future University in Egypt, Cairo, Egypt

    Suzan M. Mansour

  3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    Hend A. Hamouda

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  1. Hend A. Hamouda
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  2. Suzan M. Mansour
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  3. Mohammed F. Elyamany
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection, and analysis were performed by Hend A. Hamouda. The first draft of the manuscript was written by Hend A. Hamouda, revised, and modified by Suzan M. Mansour. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Hend A. Hamouda.

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Animal use and care procedures were approved by the Ethical Committee for Animal Experimentation at Faculty of Pharmacy, Cairo University (Permission number: PT 1049) and concur with the US National Institutes of Health guide for the Care and Use of Laboratory Animals. The article does not include human participants. This part is presented in the “Animals” section in the “MATERIALS AND METHODS”.

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Hamouda, H.A., Mansour, S.M. & Elyamany, M.F. Vitamin D Combined with Pioglitazone Mitigates Type-2 Diabetes-induced Hepatic Injury Through Targeting Inflammation, Apoptosis, and Oxidative Stress. Inflammation 45, 156–171 (2022). https://doi.org/10.1007/s10753-021-01535-7

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