One of the key findings in this study was that plasma RBP4 was not associated with indices of metabolic syndrome, such as waist circumference, HDL cholesterol, ApoB/ApoAI ratio, and the HOMA index. However, there was a significant correlation of RBP4 with serum triglycerides.
RBP4 has been identified as an adipocytokine that is increased in circulation in mouse models of obesity and insulin resistance.18
Furthermore, transgenic expression and administration of RBP4 into mice induced insulin resistance in this previous report.19
However, some studies have reported contradictory findings regarding the association of RBP4 with IR.13-14
So, the assessment of the importance of RBP4 is needed in diverse groups. Our findings of this study are in accordance with findings reported by Takashima, et al.19
, which showed that serum RBP4 did not correlate with fasting blood glucose, HDL cholesterol, waist-hip ratio, BMI, and fasting insulin, but significantly correlated with triglycerides.
There are some possible explanations for the lack of association of RBP4 with indices of IR. First, HOMA-IR may not be an ideal measurement of insulin sensitivity, especially in subjects with impaired fasting glucose (IFG) or impaired glucose tolerance (IGT).20
Although HOMA-IR has been shown to have a strong correlation with insulin resistance in diabetic and non-diabetic subjects, the correlation was not demonstrated in subjects with IFG or IGT. Perhaps this may partially explain the lack of correlation between RBP4 and HOMA IR in this study. However, Stefan, et al.21
has reported that RBP4 is associated with an elevation of liver fat but not visceral fat in humans. Since liver fat is associated with hepatic insulin sensitivity and HOMA IR shows good correlation with hepatic insulin sensitivity, there may be some other factors responsible for the contradictory results. Perhaps the difference in results may be attributed to a difference in ethnicity, degree of obesity, and subset of the patients analyzed. This study was performed on an Asian population with BMI and HOMA indices that are relatively low compared to studies performed on Caucasians. The study was also performed on treated hypertensives with 38.6% of patients defined as having metabolic syndrome, which may have influenced the results. Second, the lack of association of RBP4 with adiponectin, HMW adiponectin, BMI, waist-hip ratio, and HDL cholesterol may be explained by the fact that RBP4 may not be associated with visceral and intramyocellular fat. Since insulin increases the rate of depletion of vitamin A from the liver, the association of RBP4 reported in previous studies may be the consequence of hepatic IR rather than the cause.22,23
Further studies are needed to clarify the mechanism for the cross-sectional association of RBP4 with metabolic indices.
Contrary to previous reports,11,12
HMW adiponectin did not demonstrate a superior predictive value for IR compared to total adiponectin with the predictive value for IR being slightly better for HMW adiponectin (AUC = 0.680) compared to adiponectin (AUC = 0.648). HMW adiponectin demonstrated a slightly stronger independent association with the HOMA index and ApoB/ApoAI ratio compared to total adiponectin. However, the HMW adiponectin/total adiponectin ratio did not demonstrate a stronger association with the HOMA index and metabolic indices. The reason for the lack of stronger association of HMW adiponectin with IR and metabolic indices is not clear. Several studies have demonstrated the superiority of HMW adiponectin compared to total adiponectin.11,12,24
However, a recent study by Blüher, et al.25
demonstrated a lack of superiority of HMW adiponectin over total adiponectin in predicting metabolic variables at baseline and in response to exercise. A possible explanation for the discrepancy may be that the relationship between metabolic variables and HMW adiponectin may be different in diabetics and non-diabetics. Studies have shown that selective reduction of posttranslational modification of the lysine residue of adiponectin results in the lowering of HMW adiponectin in diabetes, which increases in response to insulin sensitizers.25,26
The absence of diabetics in this study population may account for the lack of superior association of HMW adiponectin with metabolic variables.
The limitations of this study need to be addressed. First, the antihypertensive and lipid-lowering medications might have partially influenced the results from the data. Statins are known to increase the levels of heme oxygenase which is regarded as the primary cellular defense mechanism against increased levels of reactive oxygen species.27
Heme oxygenase and adiponectin levels move in conjunction with animal models of obesity, hypertension, diabetes, and metabolic syndrome.28,29
It was possible that the level of adipocytokines and metabolic parameters were influenced by the medications, especially statins, but the proportions of patients taking medications were not different between the groups. Second was the difference in gender distribution between the groups. To minimize the confusion, we demonstrated and compared the level of adipocytokines according to gender in the two groups. Third, the study sample only included Asians, and it is possible that results from the present study may not be applicable to other ethnic and racial groups.
In conclusion, RBP4 was not associated with IR or metabolic indices and the predictive value for IR was minimal in hypertensive subjects. HMW adiponectin did not have a superior predictive value for IR compared to adiponectin.