Insulin sensitization via partial agonism of PPARγ and glucose uptake through translocation and activation of GLUT4 in PI3K/p-Akt signaling pathway by embelin in type 2 diabetic rats

• Published in: Biochimica et biophysica acta Vol. 1830; no. 1; pp. 2243 - 2255
• Main Authors: Gandhi, Gopalsamy Rajiv, Stalin, Antony, Balakrishna, Kedike, Ignacimuthu, Savarimuthu, Paulraj, Michael Gabriel, Vishal, Rajagopal
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.01.2013
• Subjects: active sites; adipose tissue; Adipose Tissue - metabolism; Adipose Tissue - pathology; agonistic behavior; animal disease models; Animals; antioxidants; Benzoquinones - chemistry; Benzoquinones - pharmacology; binding capacity; blood glucose; body weight changes; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - pathology; Embelia - chemistry; Embelia ribes; Embelin; Fruit - chemistry; Gene Expression Regulation - drug effects; glucose; Glucose - metabolism; Glucose Transporter Type 4 - metabolism; glucose transporters; GLUT4; glycemic control; high fat diet; homeostasis; Homeostasis - drug effects; Hypoglycemic Agents - chemistry; Hypoglycemic Agents - pharmacology; insulin; Insulin Resistance; Insulin-Secreting Cells - metabolism; Insulin-Secreting Cells - pathology; islets of Langerhans; liver; Male; mechanism of action; Molecular-docking; noninsulin-dependent diabetes mellitus; obesity; Obesity - drug therapy; Obesity - metabolism; Obesity - pathology; phosphatidylinositol 3-kinase; Phosphatidylinositol 3-Kinases - metabolism; PI3K/p-Akt; PPAR gamma - agonists; PPAR gamma - metabolism; PPARγ; Protein Transport - drug effects; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Wistar; signal transduction; Signal Transduction - drug effects; skeletal muscle; Type 2 diabetes mellitus; weight gain; FFA; PBS; T2DM; Embelin; HFD; SOD; FBG; MW; Type 2 diabetes mellitus; GPx; PPARγ; TC; TZDs; Molecular-docking; TG; b wt; PI3K/p-Akt; CAT; STZ; OGTT; GLUT4
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.10.016

The present study was aimed at isolating an antidiabetic molecule from a herbal source and assessing its mechanism of action. Embelin, isolated from Embelia ribes Burm. (Myrsinaceae) fruit, was evaluated for its potential to regulate insulin resistance, alter β-cell dysfunction and modulate key markers involved in insulin sensitivity and glucose transport using high-fat diet (HFD) fed-streptozotocin (STZ) (40mg/kg)-induced type 2 diabetic rats. Molecular-dockings were performed to investigate the binding modes of embelin into PPARγ, PI3K, p-Akt and GLUT4 active sites. Embelin (50mg/kg b wt.) reduced body weight gain, blood glucose and plasma insulin in treated diabetic rats. It further modulated the altered lipid profiles and antioxidant enzymes with cytoprotective action on β-cell. Embelin significantly increased the PPARγ expression in epididymal adipose tissue compared to diabetic control group; it also inhibited adipogenic activity; it mildly activated PPARγ levels in the liver and skeletal muscle. It also regulated insulin mediated glucose uptake in epididymal adipose tissue through translocation and activation of GLUT4 in PI3K/p-Akt signaling cascade. Embelin bound to PPARγ; it disclosed stable binding affinities to the active sites of PI3K, p-Akt and GLUT4. These findings show that embelin could improve adipose tissue insulin sensitivity without increasing weight gain, enhance glycemic control, protect β-cell from damage and maintain glucose homeostasis in adipose tissue. Embelin can be used in the prevention and treatment of type 2 diabetes mellitus caused due to obesity. [Display omitted] ► Embelin was isolated from Embelia ribes Burm. fruit. ► Embelin suppressed the body weight gain in type 2 diabetic rats. ► Embelin increased the PPARγ expression in epididymal adipose tissue. ► Embelin regulated glucose uptake through GLUT4 in PI3K/ p-Akt signaling. ► Embelin docked with PPARγ, PI3K, p-Akt and GLUT4.