Potential Antidiabetic Activity of β-sitosterol from Modulation of Peroxisome Proliferator-activated Receptor Gamma (PPARγ)

Overview

Journal Comb Chem High Throughput Screen

Publisher Bentham Science Publishers

Specialty Chemistry

Date 2024 Feb 2

PMID 38305397

Authors

Muhammed Amanat

A F M Shahid Ud Daula

Randhir Singh

Affiliations

Soon will be listed here.

Abstract

Aim: To evaluate the antidiabetic potential of β-sitosterol from Zingiber roseum.

Background: Diabetes mellitus is a cluster of metabolic disorders, and 90% of diabetic patients are affected with Type II diabetes (DM2). For the treatment of DM2, thiazolidinedione drugs (TZDs) were proposed, but recent studies have shown that TZDs have several detrimental effects, such as weight gain, kidney enlargement (hypertrophy), fluid retention, increased risk of bone fractures, and potential harm to the liver (hepatotoxicity). That is why a new molecule is needed to treat DM2.

Objective: The current research aimed to assess the efficacy of β-Sitosterol from methanolic extract of Zingiber roseum in managing diabetes PPARγ modulation.

Methods: Zingiber roseum was extracted using methanol, and GC-MS was employed to analyze the extract. Through homology modeling, PPARγ structure was predicted. Molecular docking, MD simulation, free binding energies, QSAR, ADMET, and bioactivity and toxicity scores were all used during the in-depth computer-based research.

Results: Clinically, agonists of synthetic thiazolidinedione (TZDs) have been used therapeutically to treat DM2, but these TZDs are associated with significant risks. Hence, GC-MS identified phytochemicals to search for a new PPAR-γ agonist. Based on the investigation, β-sitosterol was found to have a higher binding affinity (-8.9 kcal/mol) than standard drugs. MD simulations and MMGBSA analysis also demonstrated that β-sitosterol bound to the PPAR-γ active site stably.

Conclusion: It can be concluded that β-sitosterol from attenuates Type-II diabetes by modulating PPARγ activity.

Citing Articles

and Studies of β-Sitosterol Nanoparticles as a Potential Therapy for Isoprenaline-Induced Cognitive Impairment in Myocardial Infarction, Targeting Myeloperoxidase.

Tallapalli P, Reddy Y, Yaraguppi D, Matangi S, Challa R, Vallamkonda B Pharmaceuticals (Basel). 2024; 17(8).

PMID: 39204198 PMC: 11359034. DOI: 10.3390/ph17081093.

References

Bosch X, Alfonso F, Bermejo J . [Diabetes and cardiovascular disease. A comprehensive insight to the new epidemic of the 21st century]. Rev Esp Cardiol. 2002; 55(5):525-7. DOI: 10.1016/s0300-8932(02)76645-1. View

Bermudez-Pirela V, Cano C, Medina M, Souki A, Lemus M, Leal E . Metformin plus low-dose glimeperide significantly improves Homeostasis Model Assessment for insulin resistance (HOMA(IR)) and beta-cell function (HOMA(beta-cell)) without hyperinsulinemia in patients with type 2 diabetes mellitus. Am J Ther. 2007; 14(2):194-202. DOI: 10.1097/01.pap.0000249909.54047.0e. View

Bermudez V, Finol F, Parra N, Parra M, Perez A, Penaranda L . PPAR-gamma agonists and their role in type 2 diabetes mellitus management. Am J Ther. 2010; 17(3):274-83. DOI: 10.1097/MJT.0b013e3181c08081. View

Copps K, White M . Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia. 2012; 55(10):2565-2582. PMC: 4011499. DOI: 10.1007/s00125-012-2644-8. View

Dong X, Park S, Lin X, Copps K, Yi X, White M . Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. J Clin Invest. 2005; 116(1):101-14. PMC: 1319221. DOI: 10.1172/JCI25735. View

Kim H, Noh J, Hong S, Hwang Y, Yang T, Lee M . Rosiglitazone stimulates the release and synthesis of insulin by enhancing GLUT-2, glucokinase and BETA2/NeuroD expression. Biochem Biophys Res Commun. 2008; 367(3):623-9. DOI: 10.1016/j.bbrc.2007.12.192. View

Chung M, Cho S, Bhuiyan M, Kim K, Lee S . Anti-diabetic effects of lemon balm ( Melissa officinalis) essential oil on glucose- and lipid-regulating enzymes in type 2 diabetic mice. Br J Nutr. 2010; 104(2):180-8. DOI: 10.1017/S0007114510001765. View

Hassani-Nezhad-Gashti F, Rysa J, Kummu O, Napankangas J, Buler M, Karpale M . Activation of nuclear receptor PXR impairs glucose tolerance and dysregulates GLUT2 expression and subcellular localization in liver. Biochem Pharmacol. 2018; 148:253-264. DOI: 10.1016/j.bcp.2018.01.001. View

Cho Y, Kim T, Lim S, Choi S, Shin H, Lee H . Type 2 diabetes-associated genetic variants discovered in the recent genome-wide association studies are related to gestational diabetes mellitus in the Korean population. Diabetologia. 2008; 52(2):253-61. DOI: 10.1007/s00125-008-1196-4. View

10.

Saadi H, Nagelkerke N, Carruthers S, Benedict S, Abdulkhalek S, Reed R . Association of TCF7L2 polymorphism with diabetes mellitus, metabolic syndrome, and markers of beta cell function and insulin resistance in a population-based sample of Emirati subjects. Diabetes Res Clin Pract. 2008; 80(3):392-8. DOI: 10.1016/j.diabres.2008.01.008. View

11.

Christodoulides C, Vidal-Puig A . PPARs and adipocyte function. Mol Cell Endocrinol. 2009; 318(1-2):61-8. DOI: 10.1016/j.mce.2009.09.014. View

12.

Wafer R, Tandon P, Minchin J . The Role of Peroxisome Proliferator-Activated Receptor Gamma () in Adipogenesis: Applying Knowledge from the Fish Aquaculture Industry to Biomedical Research. Front Endocrinol (Lausanne). 2017; 8:102. PMC: 5438977. DOI: 10.3389/fendo.2017.00102. View

13.

Moller D, Berger J . Role of PPARs in the regulation of obesity-related insulin sensitivity and inflammation. Int J Obes Relat Metab Disord. 2004; 27 Suppl 3:S17-21. DOI: 10.1038/sj.ijo.0802494. View

14.

Ferre P . The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes. 2004; 53 Suppl 1:S43-50. DOI: 10.2337/diabetes.53.2007.s43. View

15.

Malodobra-Mazur M, Cierzniak A, Ryba M, Sozanski T, Piorecki N, Kucharska A . L. Increases Glucose Uptake and the Expression of in Insulin-Resistant Adipocytes. Nutrients. 2022; 14(11). PMC: 9183168. DOI: 10.3390/nu14112307. View

16.

Nathan D, Buse J, Davidson M, Ferrannini E, Holman R, Sherwin R . Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care. 2008; 32(1):193-203. PMC: 2606813. DOI: 10.2337/dc08-9025. View

17.

Encinar J, Fernandez-Ballester G, Galiano-Ibarra V, Micol V . In silico approach for the discovery of new PPARγ modulators among plant-derived polyphenols. Drug Des Devel Ther. 2015; 9:5877-95. PMC: 4639521. DOI: 10.2147/DDDT.S93449. View

18.

Reddy J, Hashimoto T . Peroxisomal beta-oxidation and peroxisome proliferator-activated receptor alpha: an adaptive metabolic system. Annu Rev Nutr. 2001; 21:193-230. DOI: 10.1146/annurev.nutr.21.1.193. View

19.

Brun R, Tontonoz P, Forman B, Ellis R, Chen J, Evans R . Differential activation of adipogenesis by multiple PPAR isoforms. Genes Dev. 1996; 10(8):974-84. DOI: 10.1101/gad.10.8.974. View

20.

Fox C, Pencina M, Meigs J, Vasan R, Levitzky Y, DAgostino Sr R . Trends in the incidence of type 2 diabetes mellitus from the 1970s to the 1990s: the Framingham Heart Study. Circulation. 2006; 113(25):2914-8. DOI: 10.1161/CIRCULATIONAHA.106.613828. View