Disruption Of Glucose Tolerance Caused By Glucocorticoid Excess In Rats Is Partially Prevented, But Not Attenuated, By Arjunolic Acid

Abstract

Arjunolic acid (AA) obtained from plants of the Combretaceae family has shown anti-diabetic effects. Here, we analyzed whether the diabetogenic effects of dexamethasone (DEX) treatment on glucose homeostasis may be prevented or attenuated by the concomitant administration of AA. Adult Wistar rats were assigned to the following groups: vehicle-treated (Ctl), DEX-treated (1 mg/kg body weight intraperitoneally for 5 days) (Dex), AA-treated (30 mg/kg body weight by oral gavage twice per day) (Aa), AA treatment previous to and concomitant to DEX treatment (AaDex), and AA treatment after initiation of DEX treatment (DexAa). AA administration significantly ameliorated (AaDex) (P>0.05), but did not attenuate (DexAa), the glucose intolerance induced by DEX treatment. AA did not prevent or attenuate the elevation in hepatic glycogen and triacylglycerol content caused by DEX treatment. All DEX-treated rats exhibited hepatic steatosis that seemed to be more pronounced when associated with AA treatment given for a prolonged period (AaDex). Markers of liver function and oxidative stress were not significantly altered among the groups. Therefore, AA administered for a prolonged period partially prevents the glucose intolerance induced by DEX treatment, but it fails to produce this beneficial effect when given after initiation of GC treatment. Since AA may promote further hepatic steatosis when co-administered with GCs, care is required when considering this phytochemical as a hypoglycemiant and/or insulin-sensitizing agent.5210972982Ortsäter, H., Sjöholm, A., Rafacho, A., Regulation of glucocorticoid receptor signaling and the diabetogenic effects of glucocorticoid excess (2012) State of the art of therapeutic endocrinology, p. 1. , InTech, RijekaRhen, T., Cidlowski, J.A., Antiinflammatory action of glucocorticoids: New mechanisms for old drugs (2005) N Engl J Med, 353, p. 1711Schäcke, H., Döcke, W.D., Asadullah, K., Mechanims involved in the side effects of glucocorticoids (2002) Pharmacol Ther, 96, p. 23Wajngot, A., Giacca, A., Grill, V., Vranic, M., Efendic, S., The diabetogenic effects of glucocorticoids are more pronounced in low- than in high-insulin responders (1992) Proc Natl Acad Sci USA, 89, p. 6035Schneiter, P., Tappy, L., Kinetics of dexamethasone-induced alterations of glucose metabolism in healthy humans (1998) Am J Physiol, 275, p. E806Nicod, N., Giusti, V., Besse, C., Tappy, L., Metabolic adaptations to dexamethasone-induced insulin resistance in healthy volunteers (2003) Obes Res, 11, p. 625Rafacho, A., Quallio, S., Ribeiro, D.L., Taboga, S.R., Paula, F.M., Boschero, A.C., Bosqueiro, J.R., The adaptive compensations in endocrine pancreas from glucocorticoid-treated rats are reversible after the interruption of treatment (2010) Acta Physiol, 200, p. 223Rafacho, A., Abrantes, J.L., Ribeiro, D.L., Paula, F.M., Pinto, M.E., Boschero, A.C., Bosqueiro, J.R., Morphofunctional alterations in endocrine pancreas of short- and long-term dexamethasone-treated rats (2011) Horm Metab Res, 43, p. 275Rafacho, A., Boschero, A.C., Ortsäter, H., Functional and molecular aspects of glucocorticoid in the endocrine pancreas and glucose homeostasis (2012) State of the art of therapeutic endocrinology, p. 121. , InTech, RijekaVan Raalte, D.H., Nofrate, V., Bunck, M.C., Van Iersel, T., Elassaiss Schaap, J., Nässander, U.K., Heine, R.J., Diamant, M., Acute and 2-week exposure to prednisolone impair different aspects of beta-cell function in healthy men (2010) Eur J Endocrinol, 162, p. 729Willi, S.M., Kennedy, A., Wallace, P., Ganaway, E., Rogers, N.L., Garvey, W.T., Troglitazone antagonizes metabolic effects of glucocorticoids in humans: Effects on glucose tolerance, insulin sensitivity, suppression of free fatty acids, and leptin (2002) Diabetes, 51, p. 2895Thomas, C.R., Turner, S.L., Jefferson, W.H., Bailey, C.J., Prevention of dexamethasone-induced insulin resistance by metformin (1998) Biochem Pharmacol, 56, p. 1145Ragavan, B., Krishnakumari, S., Effect of terminalia arjuna stem bark extract on the activities of marker enzymes in alloxan induced diabetic rats (2005) AncSci Life, 25, p. 8Ragavan, B., Krishnakumari, S., Antidiabetic effect of T. arjuna bark extract in alloxan induced diabetic rats (2006) Indian J Clin Biochem, 21, p. 123Manna, P., Sinha, M., Sil, P.C., Protective role of arjunolic acid in response to streptozotocin-induced type-I diabetes via the mitochondrial dependent and independent pathways (2009) Toxicology, 257, p. 53Biswas, M., Kar, B., Bhattacharya, S., Kumar, R.B., Ghosh, A.K., Haldar, P.K., Antihyperglycemic activity and antioxidant role of Terminalia arjuna leaf in streptozotocin-induced diabetic rats (2011) Pharm Biol, 49, p. 335Manna, P., Das, J., Ghosh, J., Sil, P.C., Contribution of type 1 diabetes to rat liver dysfunction and cellular damage via activation of NOS, PARP, IkappaBalpha/NF- kappaB, MAPKs, and mitochondria-dependent pathways: Prophylatic role of arjunolic acid (2010) Free RadicBiol Med, 48, p. 1465Facundo, V., Rios, K.A., Medeiros, C.M., Militão, J.S.L.T., Miranda, A.L., Epifanio, R.A., Carvalho, M.P., Rezende, C.M., Arjunolic acid ethanolic extract of Combretum leprosum root and its use as a potential multi-functional phytomedicine and drug for neurodegenerative disorders: Anti-inflammatory and anticholinesterasic activities (2005) J Braz Chem Soc, 16, p. 1309Rafacho, A., Marroquí, L., Taboga, S.R., Abrantes, J.L., Silveira, L.R., Boschero, A.C., Carneiro, E.M., Quesada, I., Glucocorticoids in vivo induce both insulin hypersecretion and enhanced glucose sensitivity of stimulus- secretion coupling in isolated rat islets (2010) Endocrinology, 151, p. 85Paula, F.M., Boschero, A.C., Carneiro, E.M., Bosqueiro, J.R., Rafacho, A., Insulin signaling proteins in pancreatic islets of insulin-resistant rats induced by glucocorticoid (2011) Biol Res, 44, p. 251Matthews, D.R., Hosker, J.P., Rudenski, A.S., Naylor, B.A., Treacher, D.F., Turner, R.C., Homeostatic model assessment: Insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man (1985) Diabetologia, 28, p. 412Guerrero-Romero, F., Simental-Mendia, L.E., Gonzalez-Ortiz, M., Martínez-Abundis, E., Ramos-Zavala, M.G., Hernández-Gonzales, S.O., Jacques-Camarena, O., Rodríguez-Morán, M., The product of triglycerides and glucose, a simple measure of insulin sensitivity. Comparison with the euglycemic- hyperinsulinemic clamp (2010) J Clin Endocrinol Metab, 95, p. 3347Lo, S., Russell, J.C., Taylor, A.W., Determination of glycogen in small tissue samples (1970) J Appl Physiol, 28, p. 234Giozzet, V.A., Rafacho, A., Boschero, A.C., Carneiro, E.M., Bosqueiro, J.R., Dexamethasone treatment in vivo counteracts the functional pancreatic islet alterations caused by malnourishment in rats (2008) Metabolism, 57, p. 617Tietze, F., Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: Applications to mammalian blood and other tissues (1969) Anal Biochem, 27, p. 502Draper, H.H., Hadley, M., Malondialdehyde determination as index of lipid peroxidation (1990) Methods Enzymol, 186, p. 421Reznick, A.Z., Packer, L., Oxidative damage to proteins: Spectrophotometric method for carbonyl assay (1994) Methods Enzymol, 233, p. 357Weir, G.C., Bonner-Weir, S., Five stages evolving beta-cell dysfunction during progression to diabetes Diabetes, 53 (2004) suppl, 3, p. S16Burén, J., Lai, Y.C., Lungdren, M., Eriksson, J.W., Jensen, J., Insulin action and insulin signaling in fat and muscle from dexamethasone-treated rats (2008) Arch Biochem Biophys, 474, p. 91Mokuda, O., Sakamoto, Y., Ikeda, T., Mashiba, H., Sensitivity and responsiveness of glucose output to insulin in isolated perfused liver from dexamethasone-treated rats (1991) Horm Metab Res, 23, p. 53Longano, C.A., Fletcher, H.P., Insulin release after acute hydrocortisone treatment in mice (1983) Metabolism, 32, p. 603Manna, P., Sil, P.C., Impaired redox signaling and mitochondrial uncoupling contributes vascular inflammation and cardiac dysfunction in type 1 diabetes (2012) Protective role of arjunolic acid, Biochimie, 94, p. 786Muoio, D.M., Newgard, C.B., Obesity-related derangements in metabolic regulation (2006) Annu Rev Biochem, 75, p. 36

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