Ethanolic Extract of Allium cepa Stimulates Glucose Transporter Typ 4-Mediated Glucose Uptake by the Activation of Insulin Signaling

Abstract

The present work was undertaken to investigate the effects and the molecular mechanism of the standardized ethanolic extract of Allium cepa (onion) on the glucose transport for controlling diabetes mellitus. A. cepa stimulates glucose uptake by the rat skeletal muscle cells (L6 myotubes) in both time- and dose-dependent manners. This effect was shown to be mediated by the increased translocation of glucose transporter typ 4 protein from the cytoplasm to the plasma membrane as well as the synthesis of glucose transporter typ 4 protein. The effect of A. cepa extract on glucose transport was stymied by wortmannin, genistein, and AI½. In vitro phosphorylation analysis revealed that, like insulin, A. cepa extract also enhances the tyrosine phosphorylation of the insulin receptor-β, insulin receptor substrate-1, and the serine phosphorylation of Akt under both basal and insulin-stimulated conditions without affecting the total amount of these proteins. Furthermore, it is also shown that the activation of Akt is indispensable for the A. cepa-induced glucose uptake in L6 myotubes. Taken together, these findings provide ample evidence that the ethanolic extract of A. cepa stimulates glucose transporter typ 4 translocation-mediated glucose uptake by the activation of the phosphatidylinositol-4,5-bisphosphate 3-kinase/Akt dependent pathway.

Key words

Allium cepa - Amaryllidaceae - Allioideae - L6 myotubes - insulin - glucose uptake

• References

• 1 Koistinen HA, Galuska D, Chibalin AV, Yang J, Zierath JR, Holman GD, Henriksson HW. 5-Amino-imidazole carboxamide riboside increases glucose transport and cell-surface GLUT4 content in skeletal muscle from subjects with type 2 diabetes. Diabetes 2003; 52: 1066-1072
• 2 Koistinen HA, Chibalin AV, Zierath JR. Aberrant p 38 mitogen-activated protein kinase signaling in skeletal muscle from Type 2 diabetic patients. Diabetologia 2003; 46: 1324-1328
• 3 Petersen KF, Shulman GI. Etiology of insulin resistance. Am J Med 2006; 119 (5 Suppl. 1) S10-S16
• 4 Zierath JR, He L, Gumà A, Wahlström EO, Klip A, Henriksson HW. Insulin action on glucose transport and plasma membrane GLUT4 content in skeletal muscle from patients with NIDDM. Diabetologia 1996; 39: 1180-1189
• 5 Hotamisligil GS. Inflammation and metabolic disorders. Nature 2006; 444: 860-867
• 6 Tominaga M, Matsumoto M, Igarashi M, Eguchi H, Sekikawa H, Sasaki H. Insulin antibody does not cause insulin resistance during glucose clamping in rats. Diabetes Res Clin Pract 1992; 18: 143-150
• 7 Goodyear LJ, Giorgino F, Sherman LA, Carey J, Smith RJ, Dohm DL. Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects. J Clin Invest 1995; 95: 2195-2204
• 8 Ahmad F, Levedo J, Cortright R, Dohm GL, Goldstein BJ. Alterations in skeletal muscle protein-tyrosine phosphatase activity and expression in insulin-resistant human obesity and diabetes. J Clin Invest 1997; 100: 449-458
• 9 Ramachandran C, Aebersold R, Tonks NK, Pot DA. Sequential dephosphorylation of a multiply phosphorylated insulin receptor peptide by protein tyrosine phosphatases. Biochemistry 1992; 31: 4232-4238
• 10 Ozougwu JC. Anti-diabetic effects of Allium cepa (onions) aqueous extracts on alloxan-induced diabetic Rattus novergicus . Pharmacologyonline 2011; 1: 270-281
• 11 Kumari K, Augusti KT. Antidiabetic and antioxidant effects of S-methyl cysteine sulfoxide isolated from onions (Allium cepa Linn) as compared to standard drugs in alloxan diabetic rats. Indian J Exp Biol 2002; 40: 1005-1009
• 12 Kumari K, Mathew BC, Augusti KT. Antidiabetic and hypolipidemic effects of S-methyl cysteine sulfoxide isolated from Allium cepa Linn. Indian J Biochem Biophys 1995; 32: 49-54
• 13 Kumari K, Augusti KT. Lipid lowering effect of S-methyl cysteine sulfoxide from Allium cepa Linn in high cholesterol diet fed rats. J Ethnopharmacol 2007; 109: 367-371
• 14 Yoshinari O, Shiojima Y, Igarashi K. Anti-obesity effects of onion extract in zucker diabetic fatty rats. Nutrients 2012; 4: 1518-1526
• 15 Fang XK, Gao J, Zhu DN. Kaempferol and quercetin isolated from Euonymus alatus improve glucose uptake of 3 T3-L1 cells without adipogenesis activity. Life Sci 2008; 82: 615-622
• 16 Aguirre L, Arias N, Macarulla MT, Gracia A, Portillo MP. Beneficial effects of quercetin on obesity and diabetes. Open Nutraceuticals 2011; 4: 189-198
• 17 Jadhav R, Puchchakayala G. Hypoglycemic and antidiabetic activity of flavonoids: boswellic acid, ellagic acid, quercetin, rutin on streptozotocin-nicotinamide induced type 2 diabetic rats. Int J Pharm Pharm Sci 2012; 4: 251-256
• 18 Kamalakkannan N, Prince PS. Antihyperglycaemic and antioxidant effect of rutin, a polyphenolic flavonoid, in streptozotocin-induced diabetic wistar rats. Basic Clin Pharmacol Toxicol 2006; 98: 97-103
• 19 Anhe GF, Okamoto MM, Kinote A, Sollon C, Lellis-Santos C, Anhe FF, Lima GA, Hirabara SM, Velloso LA, Bordin S, Machado UF. Quercetin decreases inflammatory response and increases insulin action in skeletal muscle of ob/ob mice and in L6 myotubes. Eur J Pharmacol 2012; 689: 285-293
• 20 Kappel VD, Cazarolli LH, Pereira DF, Postal BG, Zamoner A, Reginatto FH, Silva FR. Involvement of GLUT4 in the stimulatory effect of rutin on glucose uptake in rat soleus muscle. J Pharm Pharmacol 2013; 65: 1179-1186
• 21 Watson RT, Kanzaki M, Pessin JE. Regulated membrane trafficking of the insulin-responsive glucose transporter 4 in adipocytes. Endocr Rev 2004; 25: 177-204
• 22 Chan JC, Malik VJW, Kodowaki T, Yajnik CS, Yoon KH, Hu FB. Diabetes in Asia: epidemiology, risk factors, and pathophysiology. JAMA 2009; 301: 2129-2140
• 23 Downward J. PI 3-kinase. Akt and cell survival. Semin Cell Dev Biol 2004; 2: 177-182
• 24 Wang L, Chen Y, Sternberg P, Cai J. Essential roles of the PI3 kinase/Akt pathway in regulating Nrf2-dependent antioxidant functions in the RPE. Invest Ophthalmol Vis Sci 2008; 16: 1671-1680
• 25 Rahuja N, Mishra A, Gautam S, Tamrakar AK, Maurya R, Jain SK, Srivastava AK. Antidiabetic activity in flowers of Nymphaea rubra . Int J Pharm Sci Rev Res 2013; 22: 121-133
• 26 Mishra A, Srivastava R, Srivastava SP, Gautam S, Tamrakar AK, Maurya R, Srivastava AK. Antidiabetic activity of heart wood of Pterocarpus marsupium Roxb. and analysis of phytoconstituents. Indian J Exp Biol 2013; 51: 363-374