Nimbin analogs stimulate glucose uptake and glycogen storage in the insulin signalling cascade by enhancing the IRTK, PI3K and Glut-4 mechanism in myotubes.

Autor: Sudhakaran G; Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Chengalpattu District, Kattankulathur 603203, Tamil Nadu, India., Rajesh R; Department of Chemistry, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Chengalpattu District, Kattankulathur 603203, Tamil Nadu, India., Almutairi BO; Department of Zoology, College of Science, King Saud University, P.O. Box 2455, 11451 Riyadh, Saudi Arabia., Arokiyaraj S; Department of Food Science & Biotechnology, Sejong University, Seoul 05006, South Korea., Gopinath P; Department of Chemistry, Faculty of Engineering and Technology, SRM Institute of Science and Technology, Chengalpattu District, Kattankulathur 603203, Tamil Nadu, India. Electronic address: gopinatp1@srmist.edu.in., Arockiaraj J; Toxicology and Pharmacology Laboratory, Department of Biotechnology, Faculty of Science and Humanities, SRM Institute of Science and Technology, Chengalpattu District, Kattankulathur 603203, Tamil Nadu, India. Electronic address: jesuaroa@srmist.edu.in.
Jazyk: angličtina
Zdroj: Tissue & cell [Tissue Cell] 2023 Jun; Vol. 82, pp. 102104. Date of Electronic Publication: 2023 May 06.
DOI: 10.1016/j.tice.2023.102104
Abstrakt: Background: Diabetes Mellitus is a metabolic disorder characterized by insulin dysfunction or failure of the pancreatic β-cells to produce insulin resulting in hyperglycemia. Adverse effects of hyperglycemic conditions continue to be common, reducing treatment adherence. Intensified therapies are required for the constant loss of endogenous islet reserve.
Aim: This study aimed to evaluate the effect of Nimbin semi-natural analogs (N2, N5, N7, and N8) from A. indica on high glucose-induced ROS and apoptosis with insulin resistance in L6 myotubes evaluated along with Wortmannin and Genistein inhibitors and the expression of key genes in the insulin signalling pathway.
Materials and Methods: The analogs were screened for anti-oxidant and anti-diabetic activity using cell-free assays; The ability of analogs to suppress ROS and prevent apoptosis induced by High glucose and uptake glucose and glycogen storage in L6 myotubes was evaluated using DCFH-DA, AO-PI and 2NBDG staining. Further, the glucose uptake was performed in the presence of Insulin Receptor Tyrosine Kinase (IRTK) inhibitors, and the expression of key genes PI3K, Glut-4, GS and IRTK in the insulin signalling pathway were evaluated.
Key Findings: The Nimbin analogs were not toxic to the L6 cells, and the analogs could scavenge ROS and suppress cellular damage induced due to high glucose. Enhanced glucose uptake was observed in N2, N5 and N7 compared to N8. The maximum activity of optimum concentration was found to be 100 μM. The N2, N5 and N7 showed an increase in IRTK, which is equivalent to insulin at a concentration of 100 µM. The IRTK inhibitor with Genistein (50 µM) confirmed the presence of IRTK-dependent glucose transport activation; it also supports the expression of key genes PI3K, Glut-4, GS and IRTK. As a result of PI3K activation, N2, N5, and N7 exhibited the insulin-mimetic effect by enhancing glucose uptake and glycogen conversion regulating glucose metabolism.
Significance: N2, N5 and N7 could therapeutically benefit against insulin resistance by glucose metabolism modulation, insulin secretion, β-cell stimulation, inhibition of gluconeogenic enzymes and ROS protection.
Competing Interests: Conflict of Interest The authors declare no conflict of interest regarding this work.
(Copyright © 2023 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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