Molecular basis of the anti-hyperglycemic activity of RA-3 in hyperlipidemic and streptozotocin-induced type 2 diabetes in rats

Abstract

Background Insulin resistance is a hallmark of type 2 diabetes mellitus (T2DM) and the underlying cause of various metabolic changes observed in type 2 diabetic patients. This study investigated the molecular basis of the anti-hyperglycemic activity of the lanosteryl triterpene (RA-3), from Protorhus longifolia stem bark, in hyperlipidemic and streptozotocin (STZ)-induced T2DM in rats. Methods The high-fat diet fed (HFD) and STZ-induced T2DM in rat model was used to evaluate the anti-hyperglycemic activity of RA-3. The hyperlipidemic rats received a single intraperitoneal injection of STZ (35 mg/kg body weight) to induce T2DM. The experimental animals received a daily oral single dose of RA-3 (100 mg/kg body) for a period of 28 days, whiles the control group received distilled water only. The animals were euthanized, and skeletal muscle was collected for protein (IRS-1, AKT, GSK and GLUT 4) expression analysis. Western blot confirmed expression of the proteins. Results Treatment of the diabetic animals with the RA-3 showed marked reduction in fasting plasma glucose levels in comparison to the untreated diabetic group animals. A significant decrease in p-GSK-3β and p-AKT expression was observed, whereas the expression of IRS-1 ser307 were increased when compared to the diabetic control group. This effect was ablated upon treatment with RA-3 and this was concomitant to an observed increase in GLUT 4 expression. Conclusions The results obtained in the present study strongly suggested that the anti-hyperglycemic effect of RA-3 could partly be associated with its ability to improve cellular glucose uptake in muscle tissue from T2DM.

6,8-(1,3-Diaminoguanidine) luteolin and its Cr complex show hypoglycemic activities and alter intestinal microbiota composition in type 2 diabetes mice

“…37 Furthermore, in the glucose metabolism pathway, AKT-1 can regulate GSK-3β/GLUT-4 and mTOR/S6K1/ IRS-1. 38,39 In this study, DAGL and DAGL•Cr upregulated the relative transcription and protein expression levels of six genes (PI3K, AKT-1, mTOR, GLUT-4, S6K1, and IRS-1) in T2DM mice and downregulated mRNA transcription and protein expression levels of GSK-3β. When PI3K is activated, it produces a second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3) on the plasma membrane, which binds to the pleckstrin homology domain of protein kinase B (PKB/AKT-1), allowing PDK1 to phosphorylate Ser308 of the AKT-1 protein.…”

<p>Potential Impact of the Multi-Target Drug Approach in the Treatment of Some Complex Diseases</p>

“…Several plant-derived pure compounds have been reported to exhibit glycemic control with different mechanisms of action, suitable for the multi-target approach. 11,12 In vitro and in vivo models of diabetes studies have shown some of the plant-derived compounds such as ginsenoside Rb1, [13][14][15]88 methyl-3β-hydroxylanosta-9,24dien-21-oate (RA-3) [89][90][91][92] and mangiferin 93,94 (Figure 4) to have a promising potential multi-target effect against diabetes (Table 1). Even though natural products' level of bioavailability, efficacy and specificity on binding to targets is still debatable, with the help of some computational chemistry, these potential hindering challenges could be overcome.…”

Computational and Biological Evaluation of Benzothiazole Derivatives in Streptozotocin Induced Diabetes Rats

“…All the animals became diabetic after three days of beta cells degeneration. Nicotinamide-adenine dinucleotide (NAD) in pancreas islet beta cells and causes histopathological effects in beta cells which probably intermediates induction of diabetes (Engel et al, 2019;Mabhida et al, 2019;Premilovac et al, 2017).…”