Extracts from Stevia rebaudiana Bertoni, a plant native to Central and South America, have been used as a sweetener since ancient times. Currently, Stevia extracts are largely used as a noncaloric high-potency biosweetener alternative to sugar, due to the growing incidence of type 2 diabetes mellitus, obesity, and metabolic disorders worldwide. Despite the large number of studies on Stevia and steviol glycosides in vivo, little is reported concerning the cellular and molecular mechanisms underpinning the beneficial effects on human health. The effect of four commercial Stevia extracts on glucose transport activity was evaluated in HL-60 human leukaemia and in SH-SY5Y human neuroblastoma cells. The extracts were able to enhance glucose uptake in both cellular lines, as efficiently as insulin. Our data suggest that steviol glycosides could act by modulating GLUT translocation through the PI3K/Akt pathway since treatments with both insulin and Stevia extracts increased the phosphorylation of PI3K and Akt. Furthermore, Stevia extracts were able to revert the effect of the reduction of glucose uptake caused by methylglyoxal, an inhibitor of the insulin receptor/PI3K/Akt pathway. These results corroborate the hypothesis that Stevia extracts could mimic insulin effects modulating PI3K/Akt pathway. 1. Introduction Stevia rebaudiana Bertoni is a weak perennial shrub belonging to Asteraceae (Compositae) family, native to subtropical regions of Brazil and Paraguay. Its leaves have been used as a sweetener since ancient times and for many other medicinal purposes in Latin America and the Orient for centuries [1, 2]. The “sweet herb” has gained increasing interest from nutritional researchers and commercial area in the last years, due to the growing need to find new natural calorie-free sweeteners alternative to sugar. Indeed, in both industrialized and developing countries, the incidence of type 2 diabetes mellitus and obesity is sharply increasing as a result of dietary behaviours, reduced physical activities, and ageing. These metabolic disorders have become major public health problems worldwide [3, 4]. Glycemic control is fundamental to the management of diabetes since it is associated with significantly decreased rates of retinopathy, nephropathy, neuropathy, and cardiovascular disease, the most common cause of death in diabetic patients. The effort to achieve near-normoglycemia through the key strategy of glycemic control includes recommendations for prevention and control of diabetes, for example, monitoring carbohydrate intake and limiting the consumption
References
[1]
J. R. Hanson and B. H. De Oliveira, “Stevioside and related sweet diterpenoid glycosides,” Natural Product Reports, vol. 10, no. 3, pp. 301–309, 1993.
[2]
A. D. Kinghorn and D. D. Soejarto, “Discovery of terpenoid and phenolic sweeteners from plants,” Pure and Applied Chemistry, vol. 74, no. 7, pp. 1169–1179, 2002.
[3]
P. Z. Zimmet, D. J. McCarty, and M. P. De Courten, “The global epidemiology of non-insulin-dependent diabetes mellitus and the metabolic syndrome,” Journal of Diabetes and its Complications, vol. 11, no. 2, pp. 60–68, 1997.
[4]
R. A. DeFronzo, “The triumvirate: β-cell, muscle, liver. A collusion responsible for NIDDM,” Diabetes, vol. 37, no. 6, pp. 667–687, 1988.
[5]
“American Diabetes Association: Standards of Medical Care in Diabetes-2013,” Diabetes Care, vol. 36, supplement 1, pp. S11–S66, 2013.
[6]
B. Crammer and R. Ikan, “Sweet glycosides from the Stevia plant,” Chemistry in Britain, vol. 22, no. 10, pp. 915–917, 1986.
[7]
V. Chatsudthipong and C. Muanprasat, “Stevioside and related compounds: therapeutic benefits beyond sweetness,” Pharmacology and Therapeutics, vol. 121, no. 1, pp. 41–54, 2009.
[8]
EFSA Panel on Food Additives and Nutrient Sources (ANS), “Scientific Opinion on safety of steviol glycosides for the proposeduses as a food additive,” EFSA Journal, vol. 8, no. 4, p. 1537, 2010.
[9]
European Food Safety Authority, “Revised exposure assessment for steviol glycosides for the proposed uses as a food additive,” EFSA Journal, vol. 9, no. 1, p. 1972, 2011.
[10]
JECFA (Joint FAO/WHO Expert Committee on Food Additives), Compendium of Food Additive Specifications, Monograph 5. Steviol glycosides, 2008, http://www.fao.org/ag/agn/jecfa-additives/details.html?id=898.
[11]
JECFA (Joint FAO/WHO Expert Committee on Food Additives), “Safety evaluation of certain food additives. Prepared by the 69th meeting of the Joint FAO/WHO Expert Committee on Food Additives,” WHO Food Additives Series, vol. 66, pp. 183–220, 2009.
[12]
S. K. Goyal, S. Samsher, and R. K. Goyal, “Stevia (Stevia rebaudiana) a bio-sweetener: a review,” International Journal of Food Sciences and Nutrition, vol. 61, no. 1, pp. 1–10, 2010.
[13]
G. Brahmachari, L. C. Mandal, R. Roy, S. Mondal, and A. K. Brahmachari, “Stevioside and related compounds—molecules of pharmaceutical promise: a critical overview,” Archiv der Pharmazie, vol. 344, no. 1, pp. 5–19, 2011.
[14]
M. Suttajit, U. Vinitketkaumnuen, U. Meevatee, and D. Buddhasukh, “Mutagenicity and human chromosomal effect of stevioside, a sweetener from Stevia rebaudiana Bertoni,” Environmental Health Perspectives, vol. 101, no. 3, pp. 53–56, 1993.
[15]
S. Tavarini and L. G. Angelini, “Stevia rebaudiana Bertoni as a source of bioactive compounds: the effect of harvest time, experimental site and crop age on steviol glycoside content and antioxidant properties,” Journal of the Science of Food and Agriculture, vol. 93, no. 9, pp. 2121–2212, 2013.
[16]
N. Shivanna, M. Naika, F. Khanum, and V. K. Kaul, “Antioxidant, anti-diabetic and renal protective properties of Stevia rebaudiana,” Journal of Diabetes and Its Complications, vol. 27, no. 2, pp. 103–113, 2013.
[17]
P. B. Jeppesen, S. Gregersen, C. R. Poulsen, and K. Hermansen, “Stevioside acts directly on pancreatic β cells to secrete insulin: actions independent of cyclic adenosine monophosphate and adenosine triphosphate-sensitive K+-channel activity,” Metabolism, vol. 49, no. 2, pp. 208–214, 2000.
[18]
N. Lailerd, V. Saengsirisuwan, J. A. Sloniger, C. Toskulkao, and E. J. Henriksen, “Effects of stevioside on glucose transport activity in insulin-sensitive and insulin-resistant rat skeletal muscle,” Metabolism, vol. 53, no. 1, pp. 101–107, 2004.
[19]
P. Chan, K.-L. Wong, I.-M. Liu, T.-F. Tzeng, T.-L. Yang, and J.-T. Cheng, “Antihyperglycemic action of angiotensin II receptor antagonist, valsartan, in streptozotocin-induced diabetic rats,” Journal of Hypertension, vol. 21, no. 4, pp. 761–769, 2003.
[20]
T.-H. Chen, S.-C. Chen, P. Chan, Y.-L. Chu, H.-Y. Yang, and J.-T. Cheng, “Mechanism of the hypoglycemic effect of stevioside, a glycoside of Stevia rebaudiana,” Planta Medica, vol. 71, no. 2, pp. 108–113, 2005.
[21]
P. B. Jeppesen, S. Gregersen, K. K. Alstrup, and K. Hermansen, “Stevioside induces antihyperglycaemic, insulinotropic and glucagonostatic effects in vivo: studies in the diabetic Goto-Kakizaki (GK) rats,” Phytomedicine, vol. 9, no. 1, pp. 9–14, 2002.
[22]
R. Abudula, V. V. Matchkov, P. B. Jeppesen, H. Nilsson, C. Aalkj？r, and K. Hermansen, “Rebaudioside A directly stimulates insulin secretion from pancreatic beta cells: a glucose-dependent action via inhibition of ATP-sensitive K+-channels,” Diabetes, Obesity and Metabolism, vol. 10, no. 11, pp. 1074–1085, 2008.
[23]
R. A. Medina and G. I. Owen, “Glucose transporters: expression, regulation and cancer,” Biological Research, vol. 35, no. 1, pp. 9–26, 2002.
[24]
R. Augustin, “The protein family of glucose transport facilitators: it's not only about glucose after all,” IUBMB Life, vol. 62, no. 5, pp. 315–333, 2010.
[25]
C. Leloup, M. Arluison, N. Kassis et al., “Discrete brain areas express the insulin-responsive glucose transporter GLUT4,” Molecular Brain Research, vol. 38, no. 1, pp. 45–53, 1996.
[26]
C. Choeiri, W. Staines, and C. Messier, “Immunohistochemical localization and quantification of glucose transporters in the mouse brain,” Neuroscience, vol. 111, no. 1, pp. 19–34, 2002.
[27]
V. C. Russo, K. Kobayashi, S. Najdovska, N. L. Baker, and G. A. Werther, “Neuronal protection from glucose deprivation via modulation of glucose transport and inhibition of apoptosis: a role for the insulin-like growth factor system,” Brain Research, vol. 1009, no. 1-2, pp. 40–53, 2004.
[28]
Y. Benomar, N. Naour, A. Aubourg et al., “Insulin and leptin induce Glut4 plasma membrane translocation and glucose uptake in a human neuronal cell line by a phosphatidylinositol 3-kinase-dependent mechanism,” Endocrinology, vol. 147, no. 5, pp. 2550–2556, 2006.
[29]
T. Maraldi, D. Fiorentini, C. Prata, L. Landi, and G. Hakim, “Stem cell factor and H2O2 induce GLUT1 translocation in M07e cells,” BioFactors, vol. 20, no. 2, pp. 97–108, 2004.
[30]
T. Maraldi, D. Fiorentini, C. Prata, L. Landi, and G. Hakim, “Glucose-transport regulation in leukemic cells: how can H2O2 mimic stem cell factor effects?” Antioxidants and Redox Signaling, vol. 9, no. 2, pp. 271–279, 2007.
[31]
F. Ismail-Beigi, “Metabolic regulation of glucose transport,” Journal of Membrane Biology, vol. 135, no. 1, pp. 1–10, 1993.
[32]
A. R. Saltiel and C. R. Kahn, “Insulin signalling and the regulation of glucose and lipid metabolism,” Nature, vol. 414, no. 6865, pp. 799–806, 2001.
[33]
A. E. W. Hendrickson, P. Haluska, P. A. Schneider et al., “Expression of insulin receptor isoform A and insulin-like growth factor-1 receptor in human acute myelogenous leukaemia: effect of the dual-receptor inhibitor BMS-536924 in vitro,” Cancer Research, vol. 69, no. 19, pp. 7635–7643, 2009.
[34]
A. Tarozzi, F. Morroni, A. Merlicco et al., “Sulforaphane as an inducer of glutathione prevents oxidative stress-induced cell death in a dopaminergic-like neuroblastoma cell line,” Journal of Neurochemistry, vol. 111, no. 5, pp. 1161–1171, 2009.
[35]
A. Minarini, A. Milelli, V. Tumiatti et al., “Cystamine-tacrine dimer: a new multi-target-directed ligand as potential therapeutic agent for Alzheimer's disease treatment,” Neuropharmacology, vol. 62, no. 2, pp. 997–1003, 2012.
[36]
C. Angeloni, E. Motori, D. Fabbri et al., “H2O2 preconditioning modulates phase II enzymes through p38 MAPK and PI3K/Akt activation,” American Journal of Physiology, vol. 300, no. 6, pp. H2196–H2205, 2011.
[37]
S. Hrelia, D. Fiorentini, T. Maraldi et al., “Doxorubicin induces early lipid peroxidation associated with changes in glucose transport in cultured cardiomyocytes,” Biochimica et Biophysica Acta, vol. 1567, pp. 150–156, 2002.
[38]
D. Fiorentini, C. Prata, T. Maraldi et al., “Contribution of reactive oxygen species to the regulation of Glut1 in two hemopoietic cell lines differing in cytokine sensitivity,” Free Radical Biology and Medicine, vol. 37, no. 9, pp. 1402–1411, 2004.
[39]
D. D. Clarke and L. Sokoloff, “Circulation and energy metabolism of the brain,” in Basic Neurochemistry, G. J. Siegel, B. W. Agranoff, R. W. Albers, S. K. Molinoff, P. B. Fisher, and M. D. Uhler, Eds., pp. 637–669, Lippincott-Ratven, Philadelphia, Pa, USA, 1999.
[40]
F. Pasquier, A. Boulogne, D. Leys, and P. Fontaine, “Diabetes mellitus and dementia,” Diabetes and Metabolism, vol. 32, no. 5, pp. 403–414, 2006.
[41]
K. F. Neumann, L. Rojo, L. P. Navarrete, G. Farías, P. Reyes, and R. B. Maccioni, “Insulin resistance and Alzheimer's disease: molecular links amp; clinical implications,” Current Alzheimer Research, vol. 5, no. 5, pp. 438–447, 2008.
[42]
E. Adeghate, T. Donath, and A. Adem, “Alzheimer disease and diabetes mellitus: do they have anything in common?” Current Alzheimer Research, vol. 10, no. 6, pp. 609–617, 2013.
[43]
E. Eruslanov and S. Kusmartsev, “Identification of ROS using oxidized DCFDA and flow-cytometry,” Methods in Molecular Biology, vol. 594, pp. 57–72, 2010.
[44]
S. Egert, N. Nguyen, and M. Schwaiger, “Myocardial glucose transporter GLUT1: translocation induced by insulin and ischemia,” Journal of Molecular and Cellular Cardiology, vol. 31, no. 7, pp. 1337–1344, 1999.
[45]
V. Gazit, R. Ben-Abraham, O. Vofsi, and Y. Katz, “L-cysteine increases glucose uptake in mouse soleus muscle and SH-SY5Y cells,” Metabolic Brain Disease, vol. 18, no. 3, pp. 221–231, 2003.
[46]
T. Maraldi, C. Prata, D. Fiorentini, L. Zambonin, L. Landi, and G. Hakim, “Signal processes and ROS production in glucose transport regulation by thrombopoietin and granulocyte macrophage-colony stimulation factor in a human leukaemic cell line,” Free Radical Research, vol. 41, no. 12, pp. 1348–1357, 2007.
[47]
C. Prata, T. Maraldi, L. Zambonin, D. Fiorentini, G. Hakim, and L. Landi, “ROS production and Glut1 activity in two human megakaryocytic cell lines,” BioFactors, vol. 20, no. 4, pp. 223–233, 2004.
[48]
C. Prata, T. Maraldi, D. Fiorentini, L. Zambonin, G. Hakim, and L. Landi, “Nox-generated ROS modulate glucose uptake in a leukaemic cell line,” Free Radical Research, vol. 42, no. 5, pp. 405–414, 2008.
[49]
C. Caliceti, L. Zambonin, C. Prata et al., “Effect of plasma membrane cholesterol depletion on glucose transport regulation in leukaemia cells,” PLoS ONE, vol. 7, no. 7, Article ID e41246, 2012.
[50]
L. P. van der Heide, G. M. J. Ramakers, and M. P. Smidt, “Insulin signaling in the central nervous system: learning to survive,” Progress in Neurobiology, vol. 79, no. 4, pp. 205–221, 2006.
[51]
R. R. Girgis, J. A. Javitch, and J. A. Lieberman, “Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway,” Molecular Psychiatry, vol. 13, no. 10, pp. 918–929, 2008.
[52]
C. Wu, S. Butz, Y.-S. Ying, and R. G. W. Anderson, “Tyrosine kinase receptors concentrated in caveolae-like domains from neuronal plasma membrane,” Journal of Biological Chemistry, vol. 272, no. 6, pp. 3554–3559, 1997.
[53]
J. Sánchez-Wandelmer, A. Dávalos, G. de la Pe？a et al., “Haloperidol disrupts lipid rafts and impairs insulin signaling in SH-SY5Y cells,” Neuroscience, vol. 167, no. 1, pp. 143–153, 2010.
[54]
T. J. Chaplinski, T. E. Bennett, and J. F. Caro, “Alteration in insulin receptor expression accompanying differentiation of HL-60 leukaemia cells,” Cancer Research, vol. 46, no. 3, pp. 1203–1207, 1986.
[55]
J. M. Lord, C. M. Bunce, R. J. Duncan et al., “Changes in insulin receptor expression in HL60 cells induced to differentiate towards neutrophils or monocytes,” Journal of Molecular Endocrinology, vol. 1, no. 3, pp. 197–201, 1988.
[56]
J. P. Abita, C. Gauville, and F. Saal, “Characterization of insulin receptors in human promyelocytic leukaemia cell HL60,” Biochemical and Biophysical Research Communications, vol. 106, no. 2, pp. 574–581, 1982.
[57]
M. Sousa Silva, R. A. Gomes, A. E. Ferreira, A. Ponces Freire, and C. Cordeiro, “The glyoxalase pathway: the first hundred years… and beyond,” Biochemical Journal, vol. 453, no. 1, pp. 1–15, 2013.
[58]
P. Matafome, C. Sena, and R. Sei？a, “Methylglyoxal, obesity, and diabetes,” Endocrine, vol. 43, no. 3, pp. 472–484, 2013.
