In the present study, we examined the associations of VFT and SFT with carotid atherosclerosis in patients with T2DM, and demonstrated that SFT was inversely associated with CIMT after adjustments for BMI and other traditional or non-traditional CVD risk factors only in men and not in women. We found that there was a significant gender effect on the relationship between SFT and CIMT. Also, this study showed that VFT and VFT/SFT ratio were not significantly correlated with CIMT in both men and women.
Recent studies have shown that regional adiposity of the body is more closely associated with atherosclerosis than the magnitude of generalized obesity[1, 3, 23]. In particular, VAT confers risks of metabolic and CV complications[4, 24, 25]. The possibility of an active metabolic role for VAT in the etiology of MS and CVD may be explained by the fact that the VAT has higher lipolytic activity and directly releases free fatty acids into the portal circulation, and this considerably contributes to insulin resistance. Khashper et al. reported that VAT thickness measured by CT scans were correlated with the presence and extent of coronary atheroma in asymptomatic subjects with DM. Wang et al. showed that subjects with visceral fat areas ≥80 cm2 on MRI had significantly higher CIMT than those without abdominal obesity regardless of BMI in a sample of middle-aged Chinese men. Kawamoto et al. found that maximal preperitoneal fat thickness assessed by US was an important risk factor for CIMT in patients aged ≥50 years with BMI ≥23 kgm-2. One study performed in a sample of 368 men with T2DM demonstrated that subjects with VFT ≥47.6 mm by US, regardless of normal waist circumference (WC), had higher CIMT compared with those with increased WC, but had less visceral fat. In another study by Dahlen et al., sagittal abdominal diameter evaluated by US was more important in predicting subclinical atherosclerosis, compared with WC, in middle aged patients with type 2 diabetes. However, the studies noted above did not evaluate the relationship between SAT and CIMT. In contrast with these studies, our findings indicate that VFT is not associated with CIMT in either male or female patients with T2DM. Although VFT was correlated with CIMT in men, this correlation disappeared after adjustment for BMI. Because the effects of VFT or SFT on carotid atherosclerosis vary according to categories of BMI representing general adiposity, we adjusted for BMI in our statistical analyses.
Profound endocrine and metabolic activity differences exist between visceral adipose tissue and subcutaneous adipose tissue. It is unclear whether subcutaneous fat tissue may be risk enhancing or, rather, protective for CVD. Some studies have revealed that the roles of subcutaneous abdominal fat in CVD risk factors or atherosclerosis are nearly identical to those for visceral abdominal fat, whereas other studies showed that subcutaneous abdominal fat may be “less pathogenic” or protective for CVD[6–9]. Subcutaneous adipose tissue displays less lipolytic activity, releases fewer inflammatory adipocytokines and has greater adiponectin gene expression than visceral adipose tissue. Subcutaneous adipose tissue is a preferential storage site of energy and, therefore, subcutaneous adipose tissue has been regarded as protective fat. Subcutaneous adipose tissue identified as “protective” fat depots in previous studies were mainly in non-abdominal adipose tissue regions, such as gluteal, thigh, or leg region SAT[5, 30, 31]. Snijder et al. suggested a protective role for peripheral subcutaneous adipose tissue, observing that increased thigh fat mass is associated with lower glucose, and lipid levels, independent of abdominal fat. In study by Park et al., thigh circumference was inversely associated with CIMT in both men and women and calf circumference was negatively correlated with CIMT in women with type 2 diabetes. However, one study found that subcutaneous fat accumulation, as assessed by increased hip circumference, was associated with an increased risk of T2DM and to a degree that generally similar to an increase BMI and WC. This result indicates that subcutaneous fat does not always “protect” against metabolic diseases. It is possible that, if positive caloric balance results in an increase in fat weight gain, the absolute direction of adipose tissue expansion may not differ between visceral adipose tissue versus subcutaneous adipose tissue.
In addition, some reports suggest that the effects of SAT on CVD risk may depend on accompanying amounts of VAT[30, 32, 33]. Few studies have assessed potential interactions between SAT and VAT. Some authors have reported that VAT may contribute to or exacerbate the pathogenic potential of SAT, such as an increase in insulin resistance, especially in obese individuals[30, 32]. On the other hand, others suggest that when there are low amounts of both VAT and SAT, the effects of lipolytic and adipokine activity by SAT on cardiometabolic risk factors are more evident. As a result, the adverse effects of SAT lessen with increasing amounts of VAT. Wildman et al. examined whether VAT modifies the effects of SAT assessed by CT on CIMT in 500 European- and African-Americans. They found that when there were low amounts of VAT, more SAT was associated with a higher CIMT, whereas when there were high amounts of VAT, more SAT was associated with a lower CIMT. These discrepant findings regarding the role of SAT on subclinical atherosclerosis or CVD risk factors in the literature may be due to differences in VAT amounts between participants in the previous studies. However, the mechanism underlying the potential beneficial effects of SAT in the presence of high amounts of VAT is not yet clear. Our results showed that SFT was negatively associated with CIMT in men despite adjustments for VFT and BMI. To our knowledge, few studies have focused on the measurement of SFT by US in patients with T2DM. Furthermore, no published studies have evaluated the role of SAT by US for carotid atherosclerosis in patients with T2DM.
Recently, a few studies have reported that the ratio between these two abdominal fat types (VAT:SAT) is an important tool for expressing the fat distribution in the abdomen. The ratio is strongly related to atherosclerotic risk factor and CIMT in non-obese men after adjustment of various risk factors. However, the respective relationships of VFT and SFT with CIMT were not significant. In disagreement with those results, our results showed that the VFT/SFT ratio was not correlated with CIMT. Our results are in agreement with those of Yamamoto et al., who reported that in 98 non-obese men, the ratio of maximum thickness of the preperitioneal fat and the minimum thickness of the subcutaneous fat, was not correlated with CIMT.
The standard method of measurement of abdominal fat is CT or MRI. However, growing evidence reveals that US is a noninvasive and reliable method to estimate these two fat compartments. Its validity compared to CT or MRI has been tested in diverse groups including older individuals, obese adults and patients with T2DM[11–13, 25]. To the best of our knowledge, only two studies have investigated the differential associations of VFT and SFT measured by US with subclinical atherosclerosis in T2DM, until now[13, 19]. In agreement with other studies, we found that VFT was correlated with several CVD risk factors such as BP, TC, and TG. However, these correlations disappeared after adjustment for BMI. In the present study, VFT was not correlated with HOMA-IR representing insulin resistance.
Regional fat distribution differs by gender. Previous studies reported that there are significant gender differences in abdominal adipose tissue distributions for a given waist circumference[36, 37]. Consistent with other studies, we found that men have greater VFT than women and that women have thicker SFT than men, although the mean BMIs in both men and women were similar. Therefore, gender must be considered when predicting abdominal fat distributions and associated subclinical atherosclerosis. We performed multiple regression analyses for men and women after adjusting for BMI, age, and other traditional and non-traditional CVD risk factors. We found that SFT was associated with CIMT only in men, irrespective of BMI.
A large proportion of patients in our study were taking antihypertensive drugs, statin, and antidiabetic drug such as thiazolidinedione, which alter the abdominal fat thickness as well as CIMT. Several antihypertensive drugs have been shown to significantly decrease CIMT. Thiazolidinediones have also been shown to decrease CIMT. Moreover, the data for statins have been the most impressive in regard to their effect on CIMT. Therefore, we adjusted these factors in multiple linear regression analysis. However, we could not find any significant associations between presence of therapeutic medications and CIMT.
Previous data regarding the differential contributions of VAT and SAT to carodiometabolic risk factors and atherosclerosis have been conflicting. Previous studies varied in design, sample, and methods applied for the assessment of adipose tissue such as CT, MRI and US.
However, this study has several limitations. First, as this was a cross-sectional study, causal relationships between SFT and CIMT cannot be determined. Second, because our study sample included individuals who received carotid US examination for evaluation of diabetic complications, some characteristics of our sample may be substantially different from those of other samples. In addition, relatively young patients without other cardiovascular risk factors except diabetes are tend to not to be ordered carotid US, while elderly patients or those with CV risk factors are tend to be ordered US. These factors can be selection bias in this study. Third, since some of the study population had several CVD risk factors such as hypertension and dyslipidemia, we could not completely eliminate the possible effects of underlying disease or medications. Fourth, this study lacked a non-T2DM control. Therefore, the generalizability of our study may be limited. Futher prospective population-based studies are required to address this important question. Fifth, the sample size was relatively small. However, previous studies have included only about 300 subjects. A larger number of patients should be analyzed for the confirmation of our results. Sixth, we used US for the measurement of fat thickness because it was considered the best cost-effective method at this time. Although CT and MRI are more accurate methods for the measurement of fat thickness, exposure to ionizing radiation of the former and the high cost of the later limit their usage.