In this study we identified subclinical atherosclerosis in T1DM patients and obese subjects as indicated by their significantly higher cIMT (mainly in boys) compared to that of healthy controls. Our results suggest that the common pathogenetic factor involved in endothelial damage in obese and T1DM children and adolescents seems to be a reduced insulin function (insulin deficiency in diabetics and insulin resistance in obese patients, respectively). Insulin acts by modulating the release of vasodilator substances, such as nitric oxide and prostaglandins, from vascular endothelium, by both stimulating and inhibiting the sympathetic nervous system and by protecting smooth muscle cells in blood vessel from apoptosis induced by oxidative stress 29
. Thus the vasodilatory and antioxidant effects of insulin are depressed in case of insulin deficiency (i.e. type 1 diabetes) and insulin resistance (i.e. obesity) conditions.
It is well documented that cIMT correlates with coronary atherosclerosis 4
, and that it represents an independent predictor of future cardiovascular events 9
. It also well correlates with parameters of invasive examination tools, such as coronary angiography and intravascular ultrasound 4, 30
Studies on increased cIMT in children and adolescents affected with obesity, T1DM, dyslipidemia, hypertension and chronic renal failure, compared to healthy controls, have yielded conflicting results 31, 32
. The different conclusions may be explained by the non-homogenous populations studied and by the variety of ultrasound methods used. Although in our study obese individuals showed only slightly elevated mean cIMT compared to subjects with T1DM, a significant high number of diabetic and obese patients had cIMT above the normal range, indicating that these patients showed early signs of atherosclerosis development compared with healthy controls.
The degree and duration of hyperglycemia has been associated with macrovascular complications and increased cardiovascular risk in adults and preadolescent children with T1DM 5, 33-36
. In the present study no association between cIMT and HbA1C at the time of visit (a marker of glycemic control) was observed in diabetic subjects. However, the positive correlation between cIMT (especially of the left common carotid intima) and fasting blood glucose suggests that accumulation of glycation end products, as a consequence of not optimal insulin therapy, increases oxidative stress and the subsequent cell damage. This hypothesis is also confirmed by the negative correlation, even if not statistically significant, between the values of cIMT and the units of insulin daily administered. In obese individuals, the positive correlation between basal and after oral glucose load insulin levels and cIMT shows that insulin resistance causes an imbalance of vascular homeostasis mechanisms responsible for the endothelial damage and dysfunction 29, 37
Previous studies have shown that cIMT is negatively correlated with HDL cholesterol levels and positively related with LDL levels, confirming that dyslipidemia has a prominent role in the pathogenesis of endothelial dysfunction with progression to atherosclerosis 6, 38, 39
. In line with data reported in literature, HDL cholesterol values represent a protective factor for cIMT in our obese population. On the other hand, although increased cIMT has been documented in children with daytime hypertension, as well as in those with nocturnal hypertension and T1DM 25, 40
, in our study population no association between conventional cardiovascular risk factors, such as blood pressure or LDL cholesterol and cIMT was found. This could be explained by the short duration of the disease at the time of examination, and the young age of the study population.
The gender-related difference in cIMT measurements observed in our study (higher prevalence of atherosclerosis and cardiovascular disease among males compared to females) is in line with data reported in literature on the general population of children and adolescents 33, 34
. Furthermore, our obese subjects showed a higher value of cIMT during puberty than that recorded in those at the prepubertal age. This could be explained by the change of insulin sensitivity for increased activity of the growth hormone axis (GH)-IGF1, which worsens the condition of insulin resistance during puberty. Furthermore, recently Skilton and colleagues have positively correlated cIMT with height in non-diabetic children aged 8-years 41
, while in this study we have observed that diabetic children with high risk for increased cIMT are likely males at pubertal age less than 150 cm tall (Figure ). Additional study in selected groups of children should be carried-out to get more conclusive results.
In conclusion, we found that diabetic and obese children present (as adults) an endothelial damage, confirmed by increased cIMT values. Our results point out the importance of identifying children with the highest risk for cardiovascular heart disease using noninvasive studies, even if more studies on wider populations are warranted to confirm the findings. We also observed that there is a positive correlation between high levels of basal and after oral loading glucose insulin levels (a sign of insulin resistance) and increased cIMT in obese, as well as between high fasting blood glucose levels (a sign of relative insulin deficiency) and cIMT in T1DM patients. Thus it is necessary to normalize blood glucose values by optimizing insulin therapy in diabetic subjects, and to reduce hyperinsulinism by weight loss and physical activity in obese subjects, in order to prevent future cardiovascular risks.