Abstract
Background: The present study was conducted to evaluate the mitigating effects of Asiatic Acid (AA), on the changes in carbohydrate metabolism, insulin signaling molecules and renal function markers in Streptozotocin (STZ)-Nicotinamide (NAD) induced diabetic rats.
Methods: AA (20 mg/kg BW) was supplemented orally to the diabetic rats for 42 days. The levels of plasma glucose, Hemoglobin (Hb), glycosylated hemoglobin (HbA1c) insulin and renal function markers, carbohydrate metabolic enzymes in the kidney and insulin signaling molecules in skeletal muscle were measured.
Results: The administration of AA elicited a significant decrease in the levels of plasma glucose, insulin resistance, HbA1c, urea, uric acid, creatinine, glycogen, glycogen synthase, glucose-6- phosphatase, and fructose-1,6-bisphosphatase and a significant increase of body weight development, insulin, Hb, hexokinase, and glycogen phosphorylase and mRNA expressions of insulin signaling molecule like insulin receptor 1, insulin receptor 2 and glucose transporter-4 in the STZ-NAD induced diabetic rats. Further, the protective effect of AA was evidenced by its histological annotation of the kidney tissues.
Conclusion: Hence, this study concluded that AA can protect against renal dysfunction by attenuating carbohydrate metabolic disorder and subsequently enhances glucose utilization and renal function in STZ-NAD-induced diabetic rats.
Keywords: Asiatic acid, diabetes mellitus, natural products, renal dysfunction, insulin, HbA1c.
Graphical Abstract
[1]
International Diabetes Federation. IDF Diabetes Atlas - 8th edition.
Available from:. http://www.diabetesatlas.org Accessed on: June 13, 2018
[2]
Brahmanaidu, P.; Uddandrao, V.V.S.; Sasikumar, V.; Naik, R.R.; Pothani, S.; Begum, M.S.; Rajeshkumar, M.P.; Varatharaju, C.; Meriga, B.; Rameshreddy, P.; Kalaivani, A.; Saravanan, G. Reversal of endothelial dysfunction in aorta of streptozotocin-nicotinamide-induced type-2 diabetic rats by S-Allylcysteine. Mol. Cell. Biochem., 2017, 432(1-2), 25-32.
[http://dx.doi.org/10.1007/s11010-017-2994-0] [PMID: 28258439]
[http://dx.doi.org/10.1007/s11010-017-2994-0] [PMID: 28258439]
[3]
Kashihara, N.; Haruna, Y.; Kondeti, V.K.; Kanwar, Y.S. Oxidative stress in diabetic nephropathy. Curr. Med. Chem., 2010, 17(34), 4256-4269.
[http://dx.doi.org/10.2174/092986710793348581] [PMID: 20939814]
[http://dx.doi.org/10.2174/092986710793348581] [PMID: 20939814]
[4]
Colagiuri, S. Diabesity: Therapeutic options. Diabetes Obes. Metab., 2010, 12(6), 463-473.
[http://dx.doi.org/10.1111/j.1463-1326.2009.01182.x] [PMID: 20518802]
[http://dx.doi.org/10.1111/j.1463-1326.2009.01182.x] [PMID: 20518802]
[5]
Saravanan, G.; Ponmurugan, P.; Deepa, M.A.; Senthilkumar, B. Modulatory effects of diosgenin on attenuating the key enzymes activities of carbohydrate metabolism and glycogen content in streptozotocin-induced diabetic rats. Can. J. Diabetes, 2014, 38(6), 409-414.
[http://dx.doi.org/10.1016/j.jcjd.2014.02.004] [PMID: 24993510]
[http://dx.doi.org/10.1016/j.jcjd.2014.02.004] [PMID: 24993510]
[6]
Saravanan, G.; Ponmurugan, P.; Kumar, G.P.S.; Rajarajan, T. Antidiabetic effect of S-allylcysteine: Effect on plasma and tissue glycoproteins in experimental diabetes. Phytomedicine, 2010, 17(14), 1086-1089.
[http://dx.doi.org/10.1016/j.phymed.2010.04.008] [PMID: 20576413]
[http://dx.doi.org/10.1016/j.phymed.2010.04.008] [PMID: 20576413]
[7]
Uddandrao, V.V.S.; Brahmanaidu, P.; Ravindarnaik, R.; Suresh, P.; Vadivukkarasi, S.; Saravanan, G. Restorative potentiality of S-allylcysteine against diabetic nephropathy through attenuation of oxidative stress and inflammation in streptozotocin-nicotinamide-induced diabetic rats. Eur. J. Nutr., 2019, 58(6), 2425-2437.
[http://dx.doi.org/10.1007/s00394-018-1795-x] [PMID: 30062492]
[http://dx.doi.org/10.1007/s00394-018-1795-x] [PMID: 30062492]
[8]
Sathibabu Uddandrao, V.V.; Brahmanaidu, P.; Nivedha, P.R.; Vadivukkarasi, S.; Saravanan, G. Beneficial role of some natural products to attenuate the diabetic cardiomyopathy through nrf2 pathway in cell culture and animal models. Cardiovasc. Toxicol., 2018, 18(3), 199-205.
[http://dx.doi.org/10.1007/s12012-017-9430-2] [PMID: 29080123]
[http://dx.doi.org/10.1007/s12012-017-9430-2] [PMID: 29080123]
[9]
Rameshreddy, P.; Uddandrao, V.V.S.; Brahmanaidu, P.; Vadivukkarasi, S.; Ravindarnaik, R.; Suresh, P.; Swapna, K.; Kalaivani, A.; Parvathi, P.; Tamilmani, P.; Saravanan, G. Obesity-alleviating potential of asiatic acid and its effects on ACC1, UCP2, and CPT1 mRNA expression in high fat diet-induced obese Sprague-Dawley rats. Mol. Cell. Biochem., 2018, 442(1-2), 143-154.
[http://dx.doi.org/10.1007/s11010-017-3199-2] [PMID: 28993954]
[http://dx.doi.org/10.1007/s11010-017-3199-2] [PMID: 28993954]
[10]
Brandstrup, N.; Kirk, J.E.; Bruni, C. The hexokinase and phosphoglucoisomerase activities of aortic and pulmonary artery tissue in individuals of various ages. J. Gerontol., 1957, 12(2), 166-171.
[http://dx.doi.org/10.1093/geronj/12.2.166] [PMID: 13416554]
[http://dx.doi.org/10.1093/geronj/12.2.166] [PMID: 13416554]
[11]
Koide, H.; Oda, T. Pathological occurrence of glucose-6-phosphatase in serum in liver diseases. Clin. Chim. Acta, 1959, 4, 554-561.
[http://dx.doi.org/10.1016/0009-8981(59)90165-2] [PMID: 14410580]
[http://dx.doi.org/10.1016/0009-8981(59)90165-2] [PMID: 14410580]
[12]
Gancedo, J.M.; Gancedo, C. Fructose-1,6-diphosphatase, phosphofructokinase and glucose-6-phosphate dehydrogenase from fermenting and non fermenting yeasts. Arch. Mikrobiol., 1971, 76(2), 132-138.
[http://dx.doi.org/10.1007/BF00411787] [PMID: 4324161]
[http://dx.doi.org/10.1007/BF00411787] [PMID: 4324161]
[13]
Ong, K.C.; Khoo, H.E. Effects of myricetin on glycemia and glycogen metabolism in diabetic rats. Life Sci., 2000, 67(14), 1695-1705.
[http://dx.doi.org/10.1016/S0024-3205(00)00758-X] [PMID: 11021354]
[http://dx.doi.org/10.1016/S0024-3205(00)00758-X] [PMID: 11021354]
[14]
Golden, S.; Wals, P.A.; Katz, J. An improved procedure for the assay of glycogen synthase and phosphorylase in rat liver homogenates. Anal. Biochem., 1977, 77(2), 436-445.
[http://dx.doi.org/10.1016/0003-2697(77)90257-3] [PMID: 402866]
[http://dx.doi.org/10.1016/0003-2697(77)90257-3] [PMID: 402866]
[15]
Shull, K.H.; Ashmore, J.; Mayer, J. Hexokinase, glucose-6-phosphatase and phosphorylase levels in hereditarily obese-hyperglycemic mice. Arch. Biochem. Biophys., 1956, 62(1), 210-216.
[http://dx.doi.org/10.1016/0003-9861(56)90104-7] [PMID: 13353922]
[http://dx.doi.org/10.1016/0003-9861(56)90104-7] [PMID: 13353922]
[16]
Naidu, P.B.; Sathibabu Uddandrao, V.V.; Naik, R.R.; Pothani, S.; Munipally, P.K.; Meriga, B.; Begum, M.S.; Varatharaju, C.; Pandiyan, R.; Saravanan, G. Effects of S-allylcysteine on biomarkers of the polyol pathway in rats with type 2 diabetes. Can. J. Diabetes, 2016, 40(5), 442-448.
[http://dx.doi.org/10.1016/j.jcjd.2016.03.006] [PMID: 27373435]
[http://dx.doi.org/10.1016/j.jcjd.2016.03.006] [PMID: 27373435]
[17]
Uddandrao, V.S.; Brahmanaidu, P.; Saravanan, G. Therapeutical perspectives of S-allylcysteine: Effect on diabetes and other disorders in animal models. Cardiovasc. Hematol. Agents Med. Chem., 2017, 15, 71-77.
[18]
BrahmaNaidu, P.; Nemani, H.; Meriga, B.; Mehar, S.K.; Potana, S.; Ramgopalrao, S. Mitigating efficacy of piperine in the physiological derangements of high fat diet induced obesity in Sprague Dawley rats. Chem. Biol. Interact., 2014, 221, 42-51.
[http://dx.doi.org/10.1016/j.cbi.2014.07.008] [PMID: 25087745]
[http://dx.doi.org/10.1016/j.cbi.2014.07.008] [PMID: 25087745]
[19]
Edelman, D.; Olsen, M.K.; Dudley, T.K.; Harris, A.C.; Oddone, E.Z. Utility of hemoglobin A1c in predicting diabetes risk. J. Gen. Intern. Med., 2004, 19(12), 1175-1180.
[http://dx.doi.org/10.1111/j.1525-1497.2004.40178.x] [PMID: 15610327]
[http://dx.doi.org/10.1111/j.1525-1497.2004.40178.x] [PMID: 15610327]
[20]
Kandasamy, N.; Ashokkumar, N. Protective effect of bioflavonoid myricetin enhances carbohydrate metabolic enzymes and insulin signaling molecules in streptozotocin-cadmium induced diabetic nephrotoxic rats. Toxicol. Appl. Pharmacol., 2014, 279(2), 173-185.
[http://dx.doi.org/10.1016/j.taap.2014.05.014] [PMID: 24923654]
[http://dx.doi.org/10.1016/j.taap.2014.05.014] [PMID: 24923654]
[21]
Matschinsky, F.M. Assessing the potential of glucokinase activators in diabetes therapy. Nat. Rev. Drug Discov., 2009, 8(5), 399-416.
[http://dx.doi.org/10.1038/nrd2850] [PMID: 19373249]
[http://dx.doi.org/10.1038/nrd2850] [PMID: 19373249]
[22]
Ramachandran, V.; Saravanan, R. Efficacy of asiatic acid, a pentacyclic triterpene on attenuating the key enzymes activities of carbohydrate metabolism in streptozotocin-induced diabetic rats. Phytomedicine, 2013, 20(3-4), 230-236.
[http://dx.doi.org/10.1016/j.phymed.2012.09.023] [PMID: 23102509]
[http://dx.doi.org/10.1016/j.phymed.2012.09.023] [PMID: 23102509]
[23]
Brahma Naidu, P.; Uddandrao, V.V.; Ravindar Naik, R.; Suresh, P.; Meriga, B.; Begum, M.S.; Pandiyan, R.; Saravanan, G. Ameliorative potential of gingerol: Promising modulation of inflammatory factors and lipid marker enzymes expressions in HFD induced obesity in rats. Mol. Cell. Endocrinol., 2016, 419, 139-147.
[http://dx.doi.org/10.1016/j.mce.2015.10.007] [PMID: 26493465]
[http://dx.doi.org/10.1016/j.mce.2015.10.007] [PMID: 26493465]
[24]
Unger, R.H.; Grundy, S. Hyperglycaemia as an inducer as well as a consequence of impaired islet cell function and insulin resistance: implications for the management of diabetes. Diabetologia, 1985, 28(3), 119-121.
[PMID: 3888754]
[PMID: 3888754]
[25]
Braithwaite, S.S.; Palazuk, B.; Colca, J.R.; Edwards, C.W., III; Hofmann, C. Reduced expression of hexokinase II in insulin-resistant diabetes. Diabetes, 1995, 44(1), 43-48.
[http://dx.doi.org/10.2337/diab.44.1.43] [PMID: 7813813]
[http://dx.doi.org/10.2337/diab.44.1.43] [PMID: 7813813]
[26]
Skovsø, S. Modeling type 2 diabetes in rats using high fat diet and streptozotocin. J. Diabetes Investig., 2014, 5(4), 349-358.
[http://dx.doi.org/10.1111/jdi.12235] [PMID: 25411593]
[http://dx.doi.org/10.1111/jdi.12235] [PMID: 25411593]
[27]
Zhao, S.; Chu, Y.; Zhang, C.; Lin, Y.; Xu, K.; Yang, P.; Fan, J.; Liu, E. Diet-induced central obesity and insulin resistance in rabbits. J. Anim. Physiol. Anim. Nutr. (Berl.), 2008, 92(1), 105-111.
[PMID: 18184386]
[PMID: 18184386]
[28]
Kalaiarasi, P.; Pugalendi, K.V. Antihyperglycemic effect of 18 beta-glycyrrhetinic acid, aglycone of glycyrrhizin, on streptozotocin-diabetic rats. Eur. J. Pharmacol., 2009, 606(1-3), 269-273.
[http://dx.doi.org/10.1016/j.ejphar.2008.12.057] [PMID: 19374864]
[http://dx.doi.org/10.1016/j.ejphar.2008.12.057] [PMID: 19374864]
[29]
Rhodes, C.J.; White, M.F. Molecular insights into insulin action and secretion. Eur. J. Clin. Invest., 2002, 32(Suppl. 3), 3-13.
[http://dx.doi.org/10.1046/j.1365-2362.32.s3.2.x] [PMID: 12028370]
[http://dx.doi.org/10.1046/j.1365-2362.32.s3.2.x] [PMID: 12028370]
[30]
Camps, M.; Castelló, A.; Muñoz, P.; Monfar, M.; Testar, X.; Palacín, M.; Zorzano, A. Effect of diabetes and fasting on GLUT-4 (muscle/fat) glucose-transporter expression in insulin-sensitive tissues. Heterogeneous response in heart, red and white muscle. Biochem. J., 1992, 282(Pt 3), 765-772.
[http://dx.doi.org/10.1042/bj2820765] [PMID: 1554359]
[http://dx.doi.org/10.1042/bj2820765] [PMID: 1554359]
[31]
Garvey, W.T. Glucose transport and NIDDM. Diabetes Care, 1992, 15(3), 396-417.
[http://dx.doi.org/10.2337/diacare.15.3.396] [PMID: 1559408]
[http://dx.doi.org/10.2337/diacare.15.3.396] [PMID: 1559408]
[32]
Parim, B.; Uddandrao, V.V.S.; Saravanan, G. Diabetic cardiomyopathy: molecular mechanisms, detrimental effects of conventional treatment, and beneficial effects of natural therapy. Heart Fail. Rev., 2019, 24(2), 279-299.
[http://dx.doi.org/10.1007/s10741-018-9749-1] [PMID: 30349977]
[http://dx.doi.org/10.1007/s10741-018-9749-1] [PMID: 30349977]
Article Metrics
10