Dietary sulforaphane reduces oxidative stress in diabetes

Type 2 diabetes is characterized by increased oxidative stress, which may result in vascular pathologies (Bekyarova, Ivanova, and Madjova, 2007). Certain dietary phytochemicals may ameliorate oxidative stress and restore a more normal metabolic milieu. As reviewed by Angeloni, Leoncini, Malaguti, Angelini, Hrelia, and Hrelia (2009), one such phytochemical found in cruciferous vegetables such as broccoli sprouts, sulforaphane (SFN), induces phase-II enzymes and increases endogenous antioxidant activity, as confirmed in vitro (Piao et al., 2005; Xue et al., 2008; Zhu et al., 2008), in rodents (Wu et al., 2004; Cho et al., 2006; Piao et al., 2005), and in healthy humans (Murashima et al., 2004; Riedl et al., 2009). To verify that these effects extend to diabetic populations, Bahadoran, Mirmiran, Hosseinpanah, Hedayati, Hosseinpour-Niazi, and Azizi (2011) tested broccoli sprouts powder (BSP) on biomarkers of oxidative stress in diabetics.

A total of 81 type 2 diabetes patients were randomized in a double-blind fashion into three groups: 27 with BSP (standardized for ~22.5 µmol/g SFN) at 10 grams per day (BSP10), 29 with BSP at 5 grams per day (BSP5), and 25 with placebo (PLC). Subjects consumed one packet per day of their treatment for 28 days. A 3-day dietary recall, weight, height (for BMI), and blood samples for evaluating fasting blood glucose (mg/dL) and biomarkers of oxidative stress were collected at baseline and at the end of the four week intervention. Total oxidant status (TOS; µmol Trolox H2O2/L), total antioxidant capacity (TAC; µmol Trolox Equiv/L), and oxidative stress index (OSI; arbitrary unit) were assayed, as well as serum malondialdehyde (MDA; µmol/L) and oxidized-low density lipoprotein (OX-LDL; mU/L) which reflect lipid peroxidation.

Attrition was 22% (18 subjects), of which seven were omitted because of mild gastrointestinal events or flushing. After 28 days, TAC in BSP5 (0.28 ± 0.004) and BSP10 (0.29 ± 0.005) were significantly higher than PLC (0.25 ± 0.005) showing an increase in antioxidant status. Significance was maintained when compared to baseline as well: TAC in BSP5 (10.3 ± 12.9) and BSP10 (15.9 ± 9.9) were significantly higher. Serum MDA in BSP5 (4.32 ± 0.2) and BSP10 (4.07 ± 0.2) were significantly lower than PLC (5.1 ± 0.2), and OX-LDL of BSP10 (6.94 ± 0.2) but not BSP5 (7.43 ± 0.2) was significantly lower than PLC (7.90 ± 0.2). Baseline comparison showed a similar pattern, with serum MDA in BSP5 (-8.9 ± 28.0) and OX-LDL (-4.9 ± 23.0) in BSP10 were also both significantly reduced. These measures suggest a reduction in lipid peroxidation that is consistent at the higher BSP dose. Compared to baseline, the OSI in BSP5 (-8.3 ± 13.4) and BSP10 (-13.7 ± 7.6) were significantly lower. The OSI is calculated as TOS/TAC, so the reduction indicates a more favorable shift in antioxidant:oxidant status. Fasting blood glucose was significantly decreased in BSP5 (12 ± 18.3%) and BSP10 (19.6 ± 16.4%) relative to baseline. This may reflect an improvement in glucose metabolism through the reduction of oxidative stress, or vice versa. A recent meta-analysis of vitamin-antioxidants C and E on plasma glucose found no effect (Akbar, Bellary, and Griffiths, 2011) which may suggest against the former. It is well documented that hyperglycemia increases oxidative stress (Brownlee, 2005), but it cannot be determined from the study design of Bahadoran et al. (2011) if the reduction in blood glucose preceded the changes in oxidative stress.

Because there were no significant differences at baseline for 3-day dietary recall, medications, or lifestyle (though details on this self-reported data were not given), there is a reasonable confidence that the BSP mediated the effects. The relative contribution of SFN to the changes cannot be determined in this study, as the presence of other phytochemicals in the BSP is propriety information. However, in rats, broccoli sprouts low in the SFN precursor glucoraphanin compared to a control group did not reduce oxidative stress, while broccoli sprouts high in glucoraphanin did (Wu et al., 2004). It is likely SFN per se is responsible for the reduction in oxidative stress in the experiment by Bahadoran et al. (2011). However, it remains to be determined if daily dosing is necessary or for how long the changes remain after discontinuation of BSP consumption. Serum total oxidant status was not significantly changed by either treatment compared to PLC or baseline. This could be because the dose was insufficient to have an effect, the length of treatment was too short, or the treatment does not alter oxidants in the assay. Another human trial (Riedl et al., 2009) established a dose-response effect from SFN on phase-II enzyme expression at a minimum dose of 51 µmol per day. Bahadoran et al. (2011) used doses of 112 µmol and 225 µmol SFN per day. Other research (Murashima et al. (2004) used fresh broccoli sprouts at 100 grams per day. Because of this variability, the ideal dose of SFN or broccoli sprouts is not yet understood.

Broccoli sprout powder standardized for sulforaphane increased serum antioxidant capacity in type 2 diabetes patients and reduced serum MDA and OX-LDL, markers of lipid peroxidation. These results suggest that BSP may be an effective therapy to reduce the risk of vascular complications caused by oxidative stress in this population and warrant additional research. In particular, establishing dose thresholds, elucidating the relationship of glycemic changes and oxidative stress, and linking the reduction of oxidative stress with relevant vascular outcomes is essential.

References

Akbar, S., Bellary, S., & Griffiths, H. (2011). Dietary antioxidant interventions in type 2 diabetes patients: a meta-analysis The British Journal of Diabetes & Vascular Disease, 11 (2), 62-68 DOI: 10.1177/1474651411407558

Angeloni, C., Leoncini, E., Malaguti, M., Angelini, S., Hrelia, P., & Hrelia, S. (2009). Modulation of phase II enzymes by sulforaphane: implications for its cardioprotective potential. Journal of Agricultural and Food Chemistry, 57(12), 5615-5622. doi: 10.1021/jf900549c

Bahadoran, Z., Mirmiran, P., Hosseinpanah, F., Hedayati, M., Hosseinpour-Niazi, S., & Azizi, F. (2011). Broccoli sprouts reduce oxidative stress in type 2 diabetes: a randomized double-blind clinical trial. European Journal of Clinical Nutrition, 65(8), 972-977. doi: 10.1038/ejcn.2011.59

Bekyarova, G. Y., Ivanova, D. G., & Madjova, V. H. (2007). Molecular mechanisms associating oxidative stress with endothelial dysfunction in the development of various vascular complications in diabetes mellitus. Folia Medica, 49(3-4), 13-19. www.ncbi.nlm.nih.gov/pubmed/18504928

Brownlee, M. (2005). The Pathobiology of Diabetic Complications: A Unifying Mechanism. Diabetes, 54(6), 1615-1625. doi:10.2337/diabetes.54.6.1615

Cho, E. J., Lee, Y. A., Yoo, H. H., & Yokozawa, T. (2006). Protective Effects of Broccoli (Brassica oleracea) against Oxidative Damage in Vitro and in Vivo. Journal of Nutritional Science and Vitaminology, 52(6), 437-444. doi: 10.3177/jnsv.52.437

Murashima, M., Watanabe, S., Zhuo, X.-G., Uehara, M., & Kurashige, A. (2004). Phase 1 study of multiple biomarkers for metabolism and oxidative stress after one-week intake of broccoli sprouts. BioFactors, 22(1-4), 271-5. www.ncbi.nlm.nih.gov/pubmed/15630296

Piao, X. L., Kim, H. Y., Yokozawa, T., Lee, Y. A., Piao, X. S., & Cho, E. J. (2005). Protective effects of broccoli (Brassica oleracea) and its active components against radical- induced oxidative damage. Journal of Nutritional Science and Vitaminology, 51(3), 142- 7. www.ncbi.nlm.nih.gov/pubmed/16161763

Riedl, M. A., Saxon, A., & Diaz-Sanchez, D. (2009). Oral sulforaphane increases Phase II antioxidant enzymes in the human upper airway. Clinical immunology, 130(3), 244-51. doi: 10.1016/j.clim.2008.10.007

Xue, M., Qian, Q., Adaikalakoteswari, A., Rabbani, N., Babaei-Jadidi, R., & Thornalley, P. J. (2008). Activation of NF-E2-related factor-2 reverses biochemical dysfunction of endothelial cells induced by hyperglycemia linked to vascular disease. Diabetes, 57(10), 2809-17. doi: 10.2337/db06-1003

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Zhu, H., Jia, Z., Strobl, J. S., Ehrich, M., Misra, H. P., & Li, Y. (2008). Potent induction of total cellular and mitochondrial antioxidants and phase 2 enzymes by cruciferous sulforaphane in rat aortic smooth muscle cells: cytoprotection against oxidative and electrophilic stress. Cardiovascular Toxicology, 8(3), 115-25. doi: 10.1007/s12012-008- 9020-4

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