The current study was intended to determine, if the flaxseed supplementation would have an effect on insulin resistance via regulation of oxidative stress in obese glucose intolerant people. The current study found that flaxseed supplementation decreased insulin resistance. Although the plasma insulin concentration did not change significantly, an HOMA-IR index significantly decreased, suggesting a decrease in insulin resistance or decreased glucose concentration following flaxseed supplementation. A highly significant positive relationship (r = 0.89) between HOMA-IR and insulin indicates that the decreased HOMA-IR is more closely related to insulin concentration than glucose concentration. Decreased HOMA-IR following flaxseed lignan or flaxseed supplementation without significant changes in insulin concentration has also been reported by others [28, 30]. No significant changes in plasma insulin concentration following flaxseed supplementation might be related to small sample sizes in the current study which warrant the need of future study with a larger sample size.
In the present study, flaxseed supplementation showed a beneficial effect on oxidative stress as determined by TBARS. Flaxseed supplementation significantly decreased TBARS concentration which suggests decreased lipid peroxidation in these participants and an antioxidant activity of flaxseed.
In the present study, TNF-α, IL-6, and CRP remained within normal ranges. The results suggest that these obese participants did not have low grade systemic inflammation, but these participants are classified as a high cardiovascular disease risk group . Studies show that CRP concentration remained the same following flaxseed or flaxseed lignan supplementation while CRP concentration in the control supplementation group increased [29, 30, 40, 41]. A similar result was found in the present study. While CRP concentration in flaxseed supplementation group remained the same as the baseline, it increased following wheat bran (control) supplementation. Although flaxseed oil has been reported to significantly decrease serum TNF-α or IL-6 in humans [25, 26], no significant changes were found in TNF-α or IL-6 following flaxseed or flaxseed lignan supplementation [28–30, 40] which is in agreement with the findings of the present study.
Increased glucose oxidation and NADPH oxidase activity secondary to hyperglycemia and obesity increase ROS generation [42, 43]. Participants in the present study were hyperglycemic and obese, and they had normal TNF-α and IL-6 concentrations which suggest that the participants might have had increased oxidative stress secondary to high plasma glucose concentrations and their obesity not secondary to inflammation. Increased oxidative stress may suppress insulin receptor activation or decrease the translocation of GLUT4 on the cell membrane . It was found that antioxidants increase glucose disposal via increased translocation of GLUT 4 on the cell membrane and increase basal glucose uptake via redistribution of GLUT 1 [44, 45]. Although GLUT expression or cellular glucose uptake was not measured in the present study, SDG treatment increased basal glucose uptake in human RBCs in our previous study .
Increased ROS, especially hydroxyl radicals increase TBARS concentration. TBARS is an indicator for lipid peroxidation, and it is measured in malondialdehyde (MDA) equivalents. Decreased TBARS concentration following flaxseed supplementation indicates decreased lipid peroxidation. SDG in flaxseed decreases lipid peroxidation by scavenging hydroxyl radical [47, 48]. Reduced lipid peroxidation may have maintained cell membrane integrity keeping insulin receptor intact, thus may have contributed to increased glucose disposal. The positive relationships seen between TBARS and insulin and TBARS and HOMA-IR in the present study are in agreement with other study findings that increased ROS triggers insulin resistance [49–52].
Weight loss improves insulin resistance by increasing insulin sensitivity . However, no significant weight changes in these participants suggest that decreased HOMA-IR index is not related to weight loss. Our results support that high glucose concentrations increase oxidative stress  as shown increased TBARS. As seen by others  the positive relationships between TBARS and HOMA-IR indicate that increased oxidative stress may have increased insulin resistance in these obese participants. Moreover, positive relationships between TBARS and TNF-α concentrations found in this study support that increased oxidative stress increases pro-inflammatory cytokines .
Soluble and insoluble fiber in flaxseed shown to improve glycemic control , and is inversely related to CRP concentrations . The current study did not evaluate the fiber effects on the insulin resistance and inflammation biomarkers. However, as discussed in elsewhere , the wheat bran supplementation provided higher concentration of dietary fiber (18.6 g/d) compared to flaxseed (13.1 g/d) in the current study. In addition, daily dietary fiber intake was not different between flaxseed and wheat bran groups . No significant changes in inflammation biomarkers or insulin resistance indicators (glucose or HOMA-IR) following wheat bran supplementation indicate that the antioxidant activity of flaxseed or other bioactive component of flaxseed such as α-liniolenic acid might have attributed to decreased insulin resistance rather than dietary fiber.
Decreased insulin resistance might be attributed to lignan via its antioxidant activity of flaxseed in these obese participants. However, the present study was not able to identify the direct role of lignan in insulin resistance due to a high α-linolenic acid content in whole flaxseed. Therefore, further study is needed to determine the effects of flaxseed lignan on insulin resistance and peripheral glucose uptake to identify the mechanism(s) of decreased insulin resistance. Although flaxseed decreased HOMA-IR and TBARS, but none of the changes in TBARS, insulin, and HOMA-IR between flaxseed and wheat bran supplementation groups was significantly different. No significant difference in HOMA-IR, insulin, and TBARS between flaxseed and wheat bran supplementation also supports the need of study using flaxseed lignan to further determine the mechanism(s) of decreased insulin resistance via antioxidant activity of flaxseed.
The present results indicate that obese participants were glucose intolerant without low grade systemic inflammation. Since these participants did not have an identified inflammatory condition, flaxseed supplementation may have not affected these inflammation biomarkers. If these participants had systemic inflammation secondary to obesity or impaired glucose tolerance, flaxseed effects on inflammation may have been seen. This also suggests the need of future study using either animal models with inflammation or people with systemic inflammation to determine flaxseed effects on inflammation.