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Despite rigorous endeavors, existing attempts to handle type 2 diabetes (T2DM) are still a long way off, as a substantial number of patients do not meet therapeutic targets. Insulin resistance in skeletal muscle is discerned as a forerunner in the pathogenesis of T2DM and can be detected years before its progress. Studies have revealed the antidiabetic properties of Carica papaya (C. papaya), but its molecular mechanism on insulin receptor substrate-1 (IRS-1)/Akt signaling mechanisms is not yet known. The present study aimed to evaluate the role of C. papaya on IRS1 and Akt in high-fat-diet–streptozotocin-induced type 2 diabetic rats and also to analyze the bioactive compounds of C. papaya against IRS-1 and Akt via in silico analysis. Ethanolic extract of the leaves of C. papaya (600 mg/kg of body weight) was given daily for 45 days postinduction of T2DM up to the end of the study. Gluconeogenic enzymes, glycolytic enzymes, gene expression, and immunohistochemical analysis of IRS-1 and Akt in skeletal muscle were evaluated. C. papaya treatment regulated the levels of gluconeogenic and glycolytic enzymes and the levels of IRS-1 and Akt in skeletal muscle of type 2 diabetic animals. In silico studies showed that trans-ferulic acid had the greatest hit rate against the protein targets IRS-1 and Akt. C. papaya restored the normoglycemic effect in diabetic skeletal muscle by accelerating the expression of IRS-1 and Akt. [ABSTRACT FROM AUTHOR]

In the management of type 2 diabetes, oral antidiabetic drugs have several side effects, which in turn have led the pharmaceutical industry to search for good therapeutic, non-toxic and reliable drugs. Carica papaya (C. papaya) is one of several plants in nature that have been found to possess anti-diabetic properties. Despite studies being focused on the antidiabetic activity of C. papaya, the molecular mechanism against high fat diet induced insulin resistance is yet to be identified. The role of C. papaya was evaluated on insulin signaling molecules, such as the insulin receptor (IR) and glucose transporter-4 (GLUT4) in high fat, diet-streptozotocin induced type 2 diabetic rats, and analyzed the bioactive compounds of C. papaya against IR and GLUT4 via molecular docking and dynamics. The ethanolic extract of C. papaya leaves (600 mg/kg of body weight) was given daily to male wistar rats for 45 days and we observed the various biochemical parameters, gene expression analysis and histopathology of skeletal muscle. Molecular docking and dynamics were undertaken to understand the bioactive compounds with the greatest hit rate. C. papaya treatment was able to control blood glucose levels, the lipid profile and serum insulin, but it facilitated tissue antioxidant enzymes and IR and GLUT4 levels. The in-silico study showed that kaempferol, quercitin and transferulic acid were the top three ligands with the greatest hit rate against the protein targets. Our preliminary findings, for the first time, showed that C. papaya reinstates the glycemic effect in the diabetic skeletal muscle by accelerating the expression of IR and GLUT4. [ABSTRACT FROM AUTHOR]