In this study we demonstrated the unique cytokine/adipokine profile associated with diabetes in a randomly selected cohort of Mexican Americans. Dissection of levels of cytokine and adipokine expression indicated elevated levels of IL-6, TNF-α and paradoxically, adiponectin to be associated with diabetes. The elevation of IL-6 and TNF-α remained statistically significant after controlling for age and BMI. In contrast, IL-8 was elevated only in older participants with diabetes, and leptin levels were low in diabetes at all ages. Consistent with our observations, Ho et al (14
) also reported elevated levels of TNF-α in non-diabetic Mexican Americans. Given the fact that Mexican Americans are more susceptible to metabolic syndrome and its associated co-morbidities, the pre-existing levels might suggest a predisposition of this population to certain chronic conditions.
Elevated levels of IL-6 in both poorly controlled diabetes and well-controlled diabetes are well studied in other ethnic groups (11
). When stratified on the basis of AIc values we found that IL-6, TNF-α and IL-8 were most significantly elevated in the group with A1c values >6.5%. In a correlation analysis we were then able to confirm that the quality of glucose control does correlate with levels of pro-inflammatory cytokines in a linear fashion. These findings were similar to what we have observed with in our comparison by diabetes status. One likely explanation for this could be that most of our diabetes is poorly controlled and therefore the two analysis showed similar results
Elevated levels of IL-8 were significantly associated with TNF-α, and both of these with diabetes. Elevation of IL-8 may be in response to high levels of TNF-α as TNF-α regulates epithelial tissue-derived IL-8 (1
). The associations between IL-8 and TNF-α have not been previously reported in any other ethnic/racial groups and therefore warrants further investigation. Interestingly we found IL-8 to be down regulated in obese participants. This strengthens our hypothesis that the IL-8 in diabetes is mainly derived from the epithelium rather than adipose tissue. Additionally possibility of existence of other pathways of IL-8 synthesis cannot be excluded. It has been shown recently that B cell-derived IL-8 is elevated in individuals with diabetes through activation of Toll like receptor 2 (TLR2) on B cells (18
), where metabolic end products of hyperglycemia have been shown to activate TLR2 in poorly controlled diabetes (6
We also found CRP to be significantly elevated in individuals with diabetes and to be moderately associated with elevated levels of IL-6. A sensitive marker of low-grade inflammation, CRP is the most commonly measured marker of inflammation. We also observed negative association of leptin in diabetes participants again suggesting chronic inflammation. Leptin is known to be regulated by immune responses (1
), inasmuch that the acute immune response and release of TNF-α and IL-1β results in a prompt short term release and increase in plasma levels of leptin. However, chronic inflammation and its resultant constitutive up-regulation of pro-inflammatory cytokines will cause suppression of leptin, and this is presumably what we have observed (24
). In contrast to our findings leptin levels have been reported to be higher in Hispanic women (21
). This could be partially explained by the fact that the observation made by Kings et al was in Hispanics as whole whereas we are reporting our observations in a homogenous group of Mexican Americans. Additionally our measurements were made mainly in diabetics whereas King et al studied these relationships in terms of adiposity, which could result in observed differences in findings between two studies. Moreover, our findings are further strengthen by the observations made by King et al suggesting ethnic diversity in levels of adiponectin and its association with several chronic diseases.
Inversely it also possible that obese individuals who have high levels of leptin may be in the acute phase of inflammation and therefore still have high levels of leptin. Given this relationship of leptin with acute and chronic inflammation, leptin could serve as a valuable marker for predicting acute inflammation in individuals with both obesity and diabetes.
Even though the association was attenuated after controlling for BMI we observed high levels of adiponectin and resistin in diabetes. Previous reports have suggested low levels of adiponectin to be markers of metabolic syndrome, type-2 diabetes and cardiovascular disease in both non-Hispanic whites and African Americans (22
). Therefore higher levels of adiponectin observed in diabetes in our population suggests, that this might be a compensatory mechanism to overcome the downstream detrimental effects of inflammation such as cardiovascular disease. Although not statistically significant, the trend for higher adiponectin in participants with higher HbA1c may have a protective role. It is of note that this cannot be the result of medications such as rosiglitazone, which are known to increase adiponectin and TNF-α as none of the participants in this study were on rosiglitazone.
There are limitations to our study. The sample size is small, and this may be have led to weaker associations among some of the cytokines. Most of the adiponectin we measured was low molecular weight adiponectin; nevertheless our findings provide a foundation for understanding how adiponectin may be affected by diabetes in this population of mainly Mexican Americans. Our population was homogenously Mexican American and therefore it would be difficult to generalize our findings to all Hispanics, which are genetically disparate. Additionally the cross-sectional nature of the study also allow for measurement of associations between pro-inflammatory markers and diabetes. In order to fully understand the association and the biological role they might play in development of co-morbidities in diabetes we need a prospective study with a significantly larger sample size.
In conclusion we show that the cytokine/adipokine profile of Mexican Americans with diabetes is one of low-grade inflammation. Since the levels of pro-inflammatory cytokines strongly correlated with AIc values indicates that quality of glucose control plays a role in initiation of the acute phase response. The increase in circulating levels of IL-6, IL-8 and TNF-α is similar to that previously reported for African Americans and non-Hispanic whites with diabetes (5
). What is unique in our population is that, the increase in circulating levels of pro-inflammatory markers is accompanied by lower levels of leptin.