We investigated resistin concentration and its potential associations with CVD risk factors, as well as with inflammation and endothelial dysfunction markers in a group of outpatient obese post-menopausal women.
We found that circulating levels of resistin were similar in T2DM and non-diabetic women, whereas they were significantly higher in T2DM women with CHD.
CHD is a multifactorial disease, but the relative impact of risk factors may differ according to gender (5, 6, 30, 37).
Among these factors, obesity has been demonstrated to confer a higher cardiovascular and mortality risk in T2DM women than in men (6, 9, 10). Adipose tissue is an active endocrine organ releasing several adipokines and inflammatory factors, including adiponectin, leptin, resistin, chemotactic protein 1 (MCP-1), TNF-α, IL-6, IL-1β, IL-10, and transforming growth factor (TGF)-β, which may contribute to the differential impact of obesity in the two genders.
Thus, serum leptin levels correlates positively with body fat content in either sex, but its levels are two times higher and its secretion rate is one third higher in women than in men (38). Similarly, also hsCRP levels are usually higher in women than in men, whereas men have higher levels of IL-6, Il-8, and TNF-α (39).
To date, data on potential gender differences in resistin levels, and specifically in T2DM women are sparse. It has been reported that the association between resistin and obesity is stronger in women than in men (40), although opposite results were reported in other studies (41). Thus, a recent study on 92 T2DM subjects reported no significant difference in resistin levels according to gender and BMI, while gender- and BMI-related differences emerged for leptin, adiponectin and visfatin levels (24).
In our study, women with CHD were older than those without it, but the association of resistin levels with CHD risk remained significant after adjustment for age and other potential major confounders, including renal function.
Post-menopausal women with and without T2DM participating to the study were comparable for renal function, which is an important factor potentially influencing resistin concentrations (42, 43).Thus, also in our series resistin levels were strongly associated with renal function, and creatinine levels were significant predictors of resistin concentration after multiple adjustment at regression analysis. Accordingly, Moreno et al. reported that renal function strongly influenced resistin levels in a large cohort of T2DM subjects, although the association was stronger in men than in women (44).
Conversely, resistin levels were not associated to BMI in our study. Similar to our data, resistin levels have been reported to be not significantly different accoding to BMI in a recent study (24). Similarly, Hansen et al. (25) did not find any difference in resistin level in obese and non-obese T2DM subjects. As in our series, other Authors failed to find any difference in resistin levels according to the presence of T2DM and/or obesity (26, 27, 45), whereas other recent studies only found minor differences (46).
On the contrary, Mabrouk et al. showed significantly higher resistin concentration in obese diabetics vs. obese non-diabetic subjects, as well as increased resistin level in obese diabetics and non-diabetics vs. slim healthy persons (47). Observed discrepancies may depend upon several factors, including whether or not adipose tissue is dysfunctional. Beyond the role of renal function as a major determinant of resistin levels in our as well as in other studies, our hypothesis is that in our cohort, resistin levels are similar in women with and without T2DM, because of a similar degree of dysfunctional obesity, which is not captured by BMI values. In women with CHD, the higher degree of chronic inflammation and endothelial dysfunction is likely linked to the higher resistin levels.
Moreover, our data showed that resistin levels correlated with inflammatory and endothelial dysfunction markers in T2DM women, suggesting that the association of resistin with CHD risk may be mediated by the inflammatory process. A huge amount of literature has established the link of systemic inflammation, T2DM and CVD risk, although these evidences failed to be translated in clinical recommendation so far.
Our data are in accordance with several studies showing that resistin plays a major regulatory role in the inflammatory response (48, 49). Resistin has also been reported to upregulate the expression of proinflammatory cytokines such as TNF-α, IL-6, IL-12, and monocyte chemoattractant protein in PBMCs, macrophages, and hepatic stellate cells via the nuclear factor-κB pathway (47, 50); the correlation of resistin levels with inflammatory and fibrinolytic markers has been reported both in the general population and in individuals with T2DM, coronary atherosclerosis, chronic kidney disease, rheumatoid arthritis, and/or sepsis (48, 49, 51).
A recent study conducted in subjects with and without ventricular dysfunction showed resistin levels were overall comparable to that of our study, and correlated with IL-6 and HDL/TG, but not with renal function as in our study. The youger mean age of participants (50) may partly explain the observed differences with our study
Subclinical inflammation is one of the underlying pathophysiological mechanisms linking obesity to insulin resistance, and in our study, resistin levels also correlated with the degree of insulin resistance, as assessed by HOMAIR, and with all the components of the metabolic syndrome (waist circumference, hypertension, HDL-C/Ttriglycerides levels), although the association remained significant only for TG at multivariate analysis. Chedraui et al. demonstrated that post-menopausal women with metabolic syndrome displayed significantly higher levels of resistin, together with higher leptin and insulin levels, differences mainly observed among women with abdominal obesity, as in our cohort (52). A recent systematic literature review and meta-analysis, including fifteen studies found that resistin levels were weakly correlated with insulin resistance in T2DM and obesity, but this association was stronger in subjects with hyperresistinemia (≥ 14.8 ng/ml) (53). In our study, resistin mean values were below that cut-off, and the association with HOMA IR was weak and disappeared at multivariate analysis.
Furthermore, significant associations were shown between resistin and tHcy and sVCAM levels, that were all comparable in T2DM women and controls, but increased in T2DM women with CHD. Human resistin may play an important regulatory role in the modulation of the interaction between endothelial cells, monocytes/macrophages, and VSMC in the pathogenesis and progression of atherosclerosis, as demonstrated in several experimental (54, 55), and clinical studies (56).
In our study, resistin was also independently associated with a higher CHD risk in T2DM women, after taking into account a large set of covariates.
A causal- effect relationship cannot be ascertained from our data, and for other inflammatory and not conventional CVD risk factors, it is overall difficult to establish whether these molecules are directly responsible for the atherosclerotic damage or their circulating levels are only markers of the underlining pathophysiological process.
In a cohort of 284 T2D patients (48% females), followed-up for 5.4 years, higher resistin levels were associated with reduced survival, and resistin concentration ≥ 11 ng/mL was an indicator of unfavorable outcomes (57), a cut-off exceeded in CHD women in our cohort. Several other studies reported high levels of resisitin in patients with established CVD, including myocardial infarction, recurrent ischemic events, and overall with CVD complications (48, 55). These data are in line with our results and point to a potential pathophysiological relationship of resistin with CVD risk in obese T2DM women.
Several limitations should be acknowledged when interpreting our results. The first deals with the cross –sectional study design and the relatively small number of subjects included in this analysis. However, several important confounding factors including lipid profile and major inflammatory and endothelial dysfunction markers were considered in our analysis.
The lack of data on genetic variants on human Retn gene, that have been correlated with Retn expression and resistin levels in metabolic disorders, including T2DM and obesity (58) is another potential limitation.