The purpose of this study was to examine the association between insulin sensitivity and a systemic marker of oxidative stress in a group of healthy women, and to determine if the relationship between oxidative stress and insulin sensitivity differed with ethnicity. The main findings were that: 1) protein carbonyls were associated with SID among AA women, while %fat and IAAT were associated with SID among EA women, 2) protein carbonyls were positively associated with FFA concentration among AA but not EA women and 3) women with higher glucose/FFA concentrations had a significantly greater concentration of circulating protein carbonyls compared to those with lower glucose/FFA concentrations. Our measure of insulin sensitivity was specific to glucose disposal, and thereby reflects primarily skeletal muscle glucose uptake. These observations suggest that oxidative stress may contribute to skeletal muscle insulin resistance among AA women, which may be mediated by circulating FFA and/or glucose.
Among potential factors that may contribute to the pathogenesis of type 2 diabetes, oxidative stress is thought to be an important underlying mechanism that leads to both insulin resistance and beta cell dysfunction 29
. While the majority of data regarding oxidative stress and insulin sensitivity have been performed in vitro
, several recent clinical trials have shown associations between oxidative stress and decreased insulin sensitivity 13, 14
. In this study oxidative stress was independently associated with SID
only among AA women. These findings suggest that oxidative stress may have a greater impact in the etiology of decreased insulin sensitivity in AA as compared to EA women.
The mechanism relating protein carbonyls to insulin sensitivity is not known, but may be related to the production of ROS within skeletal muscle. Previous investigations have shown associations between skeletal muscle mitochondrial dysfunction, ROS, and reduced insulin sensitivity 30-33
. The pathophysiology of ROS-induced insulin resistance involves a complex network of insulin signaling pathways. The primary stress pathways thought to be activated by ROS production are the nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways 34-36
. These stress activated pathways are thought to decrease insulin sensitivity by increasing serine phosphorylation while subsequently decreasing tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) 15, 36, 37
The reason why the association between protein carbonyls and SID
differed with ethnicity is not clear. However, we previously have shown that reduced muscle mitochondrial function among AA women may explain part of the ethnic differences in insulin sensitivity 38
. Additionally, Ballinger et al (personal communication) have assessed mitochondrial function in human endothelial cells (from cord blood of AA and EA donors) and found a significantly reduced mitochondrial reserve capacity among AA as compared to EA individuals. These experiments demonstrate a distinct difference in mitochondrial phenotype between AA and EA and suggest that increases in bioenergetic demand may reduce the bioenergetic reserve capacity to a greater extent in AA, rendering them more susceptible to production of ROS. Therefore, potential differences in mitochondrial phenotypes between AA and EA women may, in part, explain the ethnic differences for associations between oxidative stress and SID
. Future studies should incorporate skeletal muscle mitochondria measures, biomarkers of oxidative stress, and SID
in order to explore these potential ethnic physiological differences.
In addition to potential physiological phenotype differences between AA and EA, dietary and nutritional factors must also be considered. Clinical trials have shown that antioxidants (vitamins E, C, and glutathione) can improve insulin sensitivity in insulin resistant and/or diabetic patients 39-41
. Several studies have revealed that AA consume fewer daily fruits and vegetables and tend to have lower blood levels of antioxidant nutrients as compared to EA 42-44
. Given this information it seems plausible that a reduced dietary antioxidant intake in addition to a reduced mitochondrial functional capacity may render AA more vulnerable to oxidative stress associated diseases. Therefore, future studies should explore potential behavioral and dietary interventions that lead to improvements in both endogenous and exogenous antioxidant concentrations.
To further explore the relationship between glucose and FFA concentrations with levels of oxidative stress, we divided our subjects based on median levels of fasting glucose and FFA concentrations. We found that those with higher glucose/FFA concentrations had a significantly greater concentration of circulating protein carbonyls compared to those with lower glucose/FFA concentrations. Our findings are in agreement with several previous studies 4, 7, 15, 33
that have shown the ability of glucose and FFA to induce oxidative stress. Paolisso et al 4
demonstrated that infusion of FFA in healthy subjects caused an increase in oxidative stress. Additionally, they showed that type 2 diabetic patients demonstrated an inverse correlation between fasting plasma FFA concentration and the ratio of reduced/oxidized glutathione (one of the major endogenous antioxidants 4
. To our knowledge, this is the first in vivo
human study to demonstrate a relationship with elevated glucose/FFA concentrations and a systemic biomarker of oxidative stress in a non-diabetic population. This is an important finding since oxidative stress is triggered by elevations in both glucose and FFA, and has been linked to the activation of several stress pathways that lead to reduced insulin sensitivity 29
. Further study is warranted in order to better understand the mechanisms through which oxidative stress triggered by glucose/FFA in non-diabetic individuals contributes to the progression of type 2 diabetes.
Strengths of this study included robust measures of body composition, body fat distribution, a systemic biomarker of oxidative stress, and the use of a disposal-specific insulin sensitivity measure. Limitations included the relatively small sample size, the cross-sectional nature of the study, and measurement of only a single biomarker of oxidative stress. Additionally, our results are limited to a population of healthy women. Future research should include men and women of different ethnic background, and various stages of insulin resistance to better understand the contribution of oxidative stress to development of type 2 diabetes.
In conclusion, results from this study demonstrate an independent association between oxidative stress and insulin sensitivity in AA but not EA women, as well as an association between oxidative stress and circulating FFA that was specific to AA. Whether the higher prevalence of many metabolic diseases in AA vs EA (e.g., hypertension, type 2 diabetes) is related to aspects of greater oxidative damage within AA is an intriguing possibility that deserves further research.