In this study, we conducted a cross-sectional analysis to determine whether the relationship between individual FA and markers of IR varied in an ethnic- and/or sex-specific manner in a population of healthy young Canadian adults. Previous investigations have examined the relationships between FA and markers of IR in older adults, as well as in unhealthy men and women from geographically distinct populations[18, 27]; however, we believe that this is the first study to investigate these relationships in a population of healthy young men and women differing in ethnicity but living in the same geographical region. This enabled us to observe ethnic-specific associations between FA and markers of IR while avoiding the recognized confounder of geographical location. Indeed, we observed that numerous associations between FA and markers of IR were only seen in certain ethnicities. We hypothesize that this could be due to underlying genetic differences that could influence FA composition in an ethnic-specific manner[28, 29]. Moreover, we also examined whether sex could influence the relationships between FA and markers of IR within each ethnicity. We noted that although men and women showed similar relationships between FA and markers of IR, the correlations in men were typically stronger compared to women. This aligns with previous work by Frias et al., who demonstrated that elevations of plasma free FA concentrations impaired insulin sensitivity in the tissues of men, but not women. This suggests that underlying sex-specific characteristics (e.g. hormone levels, adiposity, lifestyle habits, and quantity of muscle mass) are influencing this relationship[30, 31]. In short, our study has identified numerous ethnic-specific associations between FA and markers of IR, and the majority of these associations appeared to be more robust in men.
Of additional interest, we noted that South Asian subjects had significantly higher levels of fasting insulin and glucose concentrations compared to Caucasian subjects despite having a similar BMI (22.8 ± 0.3 kg/m2 versus 22.7 ± 0.1 kg/m2). This finding seems to agree with past work in which differences in glucose metabolism between South Asian and European individuals residing near San Francisco (CA, USA) or southeast England were reported[18, 27].
Saturated fatty acids (SFA)
Of the SFA examined, 14:0 (myristic acid) was positively associated with fasting insulin and HOMA-IR in the Caucasian population, and with fasting insulin in the East Asian population. Furthermore, these associations remained significant when examining men and women separately within each ethnicity. This agrees with past work by Lovejoy et al., which examined the associations between relative FA levels in the cholesterol ester (CE) and phospholipid (PL) fractions of red blood cells (RBC) and markers of IR (i.e. fasting insulin and glucose, and HOMA-IR) in 38 young men and women. Lovejoy and colleagues reported that of the FA examined, relative abundance of CE 14:0 demonstrated the greatest number of positive associations with markers of IR and that these associations were similarly reflected in the PL fraction. Together, our findings and those of Lovejoy et al. suggest that, across multiple ethnicities and within both genders, 14:0 appears to be strongly correlated with markers of IR.
We also found that 18:0 (stearic acid) was positively associated with fasting glucose and HOMA-IR in men and women in our Caucasian population. Similar results were reported by Ebbesson et al. who demonstrated that the relative abundance of 18:0 in RBC was positively associated with fasting glucose. Additionally, Wang et al. found that 18:0 in CE and PL fractions were positively associated with the development of diabetes in middle-aged adults. Although we observed associations with 18:0 in the Caucasian population, we did not detect associations in East Asian or South Asian subjects. Again, this emphasizes the importance of examining associations between FA and markers of IR in an ethnic-specific fashion.
Monounsaturated fatty acids (MUFA)
Previous work by Mozaffarian et al. demonstrated that the relative abundance (expressed as % FA) of 16:1n9 (palmitoleic acid) in the PL fraction of plasma was positively associated with markers of IR in men (i.e. fasting insulin and glucose, and HOMA-IR), but not women, in a European-majority multi-ethnic population. We could not confirm this trend between 16:1n9 and markers of IR in our population; however, this may be explained by differences in study design. Specifically, we examined total plasma FA whereas this previous study examined FA in plasma PL. Despite this, analyzing total plasma FA has uncovered additional associations with longer-chain MUFA that will ultimately contribute to our understanding of how MUFA may influence markers of IR.
We observed a positive association between 18:1c9 (oleic acid) and fasting glucose in both Caucasian and East Asian populations; however, this association appeared to be stronger in Caucasians. Interestingly, previous studies examining the relationship between 18:1c9 and IR have generated inconsistent results. For example, Ryan et al. demonstrated that diets rich in 18:1c9 can reduce IR in T2D adult males, while Mayer-Davis et al. revealed a positive association between dietary 18:1c9 and IR. Even further uncertainty was provided by Lovejoy et al. and Hekmatdoost et al., who both reported no evidence of a relationship between 18:1c9 and markers of IR[34, 35]. A novel aspect of our study was that we analyzed the relationships between 18:1c9 and markers of IR in a sex-specific manner, which may provide a partial explanation of the discrepancy existing in the literature. We found that the relationship between 18:1c9 and fasting glucose was driven by Caucasian men, not women. We do not believe that this association has been recognized before and underlines potential sex-specific differences regarding the relationship between 18:1c9 and markers of IR.
Interestingly, we observed associations between 18:1t6-8 (sum of 18:1t6, t7, t8) and HOMA-IR in the Caucasian population, which to our knowledge has not been previously reported. Furthermore, this association appeared to be stronger in men compared to women. Although we adjusted our regression models to account for total fat intake, we acknowledge that FFQ can introduce inaccuracies in self-reporting. Therefore, we cannot exclude that this sex difference in 18:1t6-8 may be related to differences in dietary habits (e.g. ruminant milk and meat consumption) that were inaccurately reported by participants.
We also found that 18:1t11 (trans-vaccenic acid) was positively associated with HOMA-IR in Caucasians, but not in East or South Asian populations. This finding is in agreement with a previous study reporting that vaccenic acid levels isolated from serum triglycerides were positively associated with fasting insulin and HOMA-IR in Caucasian males classified as either normoinsulinaemic/normoglycaemic or hyperinsulinaemic/hyperglycaemic. Conversely, Takeuchi et al. recently reported that healthy young Japanese men and women (22.8 ± 3.0 yrs) supplemented with 0.6% trans-FA for 4-weeks demonstrated no effect on fasting measures of insulin and glucose. While the findings of these two previous studies may initially appear to conflict, the results of our current research may shed some light on this issue. Indeed, our data suggests that trans-FA are more strongly associated with adverse effects on glucose metabolism in Caucasians, and less so in East and South Asian populations.
Polyunsaturated fatty acids (PUFA)
In the PUFA class, we found that 18:2n6 (linoleic acid) was positively associated with fasting glucose in our Caucasian population, but not in the East Asian or South Asian groups. Previous studies investigating the relationships between 18:2n6 and markers of IR have often generated inconsistent results. For example, several previous studies have found no evidence of an association between 18:2n6 and markers of IR in diabetic Japanese adults or overweight French adolescents. In contrast, Salomaa et al. observed that 18:2n6 in serum CE was lower in diabetic patients compared to healthy controls. Our data therefore adds to the current literature as we have uncovered a novel association with 18:2n6 in a healthy young population; however, it is clear that further investigation of the relationship between 18:2n6 and markers of IR is required.
We also found that 18:2c9t11 (cis-9, trans-11 conjugated linoleic acid) was positively associated with HOMA-IR in Caucasians. These results appear to conflict with previous findings demonstrating a beneficial effect of 18:2c9t11 on insulin sensitivity in middle-aged healthy adults; however, the different ages between these two populations makes it difficult to directly compare the studies. The majority of research examining CLA has been conducted in rodents and has either not focused on specific CLA isoforms or has generated inconsistent results[41, 42]. Since findings from rodent models cannot always be extrapolated to humans, this reinforces the need for further examination of the effects of 18:2c9t11 on IR in humans. To our knowledge, this is the first study to demonstrate that the 18:2c9t11 isoform in plasma is positively associated with markers of IR in Caucasians, but that this association does not exist in East Asian and South Asian populations. Closer investigation revealed that 18:2c9t11 was positively associated with HOMA-IR in both Caucasian men and women. However, this relationship was more significant in Caucasian men compared to women, which further points towards a role of sex-specific characteristics on associations between FA and markers of IR.
Challenges and limitations
We acknowledge that there are several limitations to consider with the present study. Firstly, we did not separate total FA into individual lipid classes, which would provide further insight into dietary habits (i.e. namely FA consumption) in relation to ethnicity and sex. Thus, we were unable to determine whether a FA in a specific lipid fraction was driving the associations with markers of IR. Future investigations examining FA and markers of IR should consider separating total FA into distinct lipid classes, as well as considering different biological materials (e.g. serum or erythrocytes) in order to better understand the relationships between FA and IR. Secondly, the smaller sample size for the South Asian population may have limited our ability to detect potential associations in this ethnic group, and further studies in larger populations are still required. Thirdly, it is important to note that the current study was performed in young healthy adults. As such, it remains to be seen whether these relationships also exist in at-risk (e.g. obese and T2D) populations. Finally, our cross-sectional analysis did not allow us to draw conclusions on cause and effect. To address this, prospective studies are required to examine whether the plasma FA profile in young adults can predict risk for developing T2D later in life.