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Modulation of PPAR-γ, SREBP-1c and inflammatory mediators by luteolin ameliorates β-cell dysfunction and renal damage in a rat model of type-2 diabetes mellitus

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Abstract

Background

Natural products have been recommended as a complementary therapy for type 2 diabetes mellitus (T2DM) due to constraints of safety and tolerability of existing anti-diabetic agents. Luteolin exhibits anti-diabetic and anti-inflammatory effects. Hence, the impact of luteolin on glucose homoeostasis and organ damage was investigated in high-fat diet (HFD) and streptozotocin (STZ) induced T2DM in rats.

Methods and results

Male Wistar rats were maintained on HFD (provided 55% energy as fat) for 10 days. Subsequently, a single dose of 40 mg/kg STZ was injected intraperitoneally on the 11th day. Seventy-two hours after STZ administration, diabetic rats with established hyperglycemia (fasting serum glucose > 200 mg/dL) were randomized into different groups having six rats each and orally administered either 0.5% hydroxy propyl cellulose or pioglitazone (10 mg/kg) or luteolin (50 mg/kg or 100 mg/kg) once daily for 28 days, while continuing HFD for respective groups. Luteolin significantly reduced hyperglycaemia, homoeostasis model assessment (HOMA) of insulin resistance (HOMA-IR) levels, and improved hypoinsulinemia and HOMA of b-cell function (HOMA-B) in a dose-dependent manner. Increased TNF-α, IL-6 and NFκB levels in diabetic rats were significantly regulated. Additionally, luteolin significantly augmented PPAR-γ expression while attenuating sterol regulatory element binding protein-1c (SREBP-1c) expression. Histopathological scrutiny validated that luteolin effectively attenuated HFD-STZ-induced injury in pancreatic β-cells and kidneys to near normalcy.

Conclusion

Our study showed that luteolin ameliorated hyperglycemia and improved hypoinsulinemia, β-cell dysfunction, and renal impairment in HFD-STZ-induced diabetic rats by attenuating inflammation and dysregulated cytokine secretion through modulation of PPAR-γ, TNF-α, IL-6 and NF-kB expression and down-regulation of SREBP-1c.

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Data availability

The data generated during the current study are available from the corresponding author upon reasonable request.

Abbreviations

T2DM:

Type 2 diabetes mellitus

HFD:

High-fat diet

STZ:

Streptozotocin

HOMA:

Homoeostasis model assessment

HOMA-IR:

Homoeostasis model assessment of insulin resistance

HOMA-B:

Homoeostasis model assessment of β-cell function

IR:

Insulin resistance

TNF-α:

Tumor necrosis factor-α

IL-6:

Interleukin-6

NFκB:

Nuclear factor-κB

PPAR-γ:

Peroxisome proliferator-activated receptor-γ

SREBP-1c:

Sterol regulatory element binding protein-1c

HPC:

Hydroxy propyl cellulose

QUICKI:

Quantitative Insulin Sensitivity Check Index

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Acknowledgements

The authors acknowledge the technical support rendered by Mr. P. Praveen Kumar, Laboratory assistant of the Department of Research and Development, Saveetha Institute of Medical and Technical Sciences, Chennai, India during the study.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

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Authors and Affiliations

  1. Department of Pharmacology, Saveetha Medical College and Hospital, Saveetha Institute of Medical and Technical Sciences, Saveetha Nagar, Thandalam, Chennai, Tamil Nadu, 602105, India

    Syed Ilyas Shehnaz

  2. Department of Pharmacology, Center for Transdisciplinary Research, Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, 600077, India

    Anitha Roy

  3. Department of Research and Development, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, 602105, India

    Rajagopalan Vijayaraghavan & Senthilkumar Sivanesan

  4. Department of Biosciences, Institute of Biotechnology, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, 602105, India

    Senthilkumar Sivanesan

  5. Department of Veterinary Pathology, Madras Veterinary College, Chennai, Tamil Nadu, 600 007, India

    Natesan Pazhanivel

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  1. Syed Ilyas Shehnaz
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Contributions

SIS conceived and designed the experiments, guided by AR. SIS performed the experiments, guided by RV and SS. NP and SIS contributed to the analysis and interpretation of histopathological data. SIS and RV performed the statistical analysis. The first draft of the manuscript was written by SIS with contributions to the methodology section by RV, SS and NP. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. The authors declare that all data was generated in-house and that no paper mill was used.

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Correspondence to Syed Ilyas Shehnaz.

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The authors have no relevant financial or non-financial interests to disclose.

Ethical approval

The experiments were designed in accordance with the Committee for Control and Supervision of Experiments on Animals; Ministry of Forests, Environment and Climate Change, Government of India, and were approved by the Institutional Animal Ethics Committee (Approval No. SU/CLAR/RD/007/ 2019, dated: 21.12.2019).

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Shehnaz, S.I., Roy, A., Vijayaraghavan, R. et al. Modulation of PPAR-γ, SREBP-1c and inflammatory mediators by luteolin ameliorates β-cell dysfunction and renal damage in a rat model of type-2 diabetes mellitus. Mol Biol Rep 50, 9129–9142 (2023). https://doi.org/10.1007/s11033-023-08804-8

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