We show that non-obese young adults with type 1 diabetes have early signs of atherosclerosis, as reflected by a significantly increased cIMT concomitant with lower insulin sensitivity, compared with matched non-diabetic individuals. In addition, insulin sensitivity correlated inversely with cIMT, regardless of glycemic control, blood pressure, lipids and BMI.
Young adults with an increased burden of components of the metabolic syndrome have increased cIMT, in whom hypertension and low HDL-cholesterol levels seem to be powerful predictors . Importantly the young type 1 diabetes individuals in the present study were insulin resistant despite any clinical characteristics of the metabolic syndrome and, therefore, enabled us to investigate the correlation between insulin sensitivity per se and cIMT. Recently, in attempt to examine the influence of insulin sensitivity on cIMT, young adults were investigated with the clamp technique but no relationship was observed between these factors . This is in contrast to other studies [28–32], as well as the present study. We have no good explanation for this observation, although differences in population, variations in cardiometabolic risk profile and extent of insulin resistance make these studies not easily comparable . At the same time development of factors in the metabolic syndrome seems to be fairly similar in different populations of children and adolescents . Notwithstanding this, our finding is consistent with some previous studies suggesting that insulin resistance is a major component of the metabolic syndrome, beyond glycemic control and clinical characteristics for the metabolic syndrome, in young type 1 diabetes [35–37].
Despite no differences in blood pressure, waist circumference, BMI, plasma lipid levels or smoking habits, cIMT was significantly increased in type 1 diabetic subjects compared to healthy individuals. Clustering of metabolic factors, such as hyperglycemia and insulin resistance, are risk factors suggested to be involved in the progression of cIMT [16, 38]. Interestingly, after adjustment of the components in the metabolic syndrome i.e. blood pressure, BMI, waist circumference, triglycerides, HDL cholesterol and HbA1c, only Si, affected group differences. This finding suggests that insulin resistance is the most powerful factor associated to cIMT in the current study. The correlation coefficient, and in particular the r2 value, suggests that 16% of changes in cIMT can be accounted for by changes in Si. In contrast, this correlation was smaller for each group tested suggested being due to the small sample size. There was also no interaction between groups, cIMT and Si, supporting the idea that insulin resistance is a single important factor for CVD in a general population [10, 39, 40].
HbA1c did not correlate with cIMT in the present study. Previous studies suggest that increased cIMT in type 1 diabetes patients is due to diabetes itself, concomitant with an increase in LDL cholesterol . In contrast, long-term follow up studies clearly demonstrate that the progression of cIMT is largely explained by differences in HbA1c, and that diabetes duration, sBP and BMI could influence the increment in cIMT in childhood and adolescent diabetes . However, neither intensive diabetes treatment, nor levels of HbA1c, had any influences on early cIMT changes . This might be explained by the involvement of formation of long-lived advanced glycation end products, highly reactive to the vessel wall, which usually takes several years to develop. Nevertheless, early and intensive insulin treatment in individuals with type 1 diabetes seems to be important to slow cIMT progression independent of other traditional CVD risk factors . This is in contrast with a recent study demonstrating that a high cumulative dose of insulin associates with an increase in cIMT in type 1 diabetes. In an attempt to minimize the effect of insulin resistance as a potential confounder, these researchers investigated type 1 diabetes individuals . We now clearly show that in our currently studied adolescent and young adult type 1 diabetes individuals, who, despite being devoid of any characteristics of the metabolic syndrome, are insulin resistant. The dysregulation of carbohydrate and lipid metabolism ensuing insulin resistance may serve to exacerbate the atherosclerotic progression. In the insulin resistant state, the normal suppression by insulin of free fatty acid release from adipose tissue is impaired so that the characteristic diabetic dyslipidemia occurs, i.e. hypertriglyceridemia, low HDL-cholesterol concentrations and elevation of free fatty acids. Defective insulin mediated fatty acid suppression also is suggested to induce insulin resistance in type 1 diabetes individuals . Although our participants had no features of the metabolic syndrome, we cannot entirely exclude that high levels of free fatty acids might explain the association between insulin resistance and cIMT observed. Pro-coagulability and low grade inflammation, often seen in chronic hyperglycemia, can induce insulin resistance . However, as there was no sign of low-grade inflammation in the present study, it is unlikely that heightened inflammatory activity was involved in the cIMT thickening in the diabetic subjects.
The special strengths of the present study are worth emphasizing: only individuals without any clinical features of the metabolic syndrome took part in the study, which therefore allows us to investigate the role of insulin sensitivity per se on cIMT. However, certain weaknesses have to be mentioned as well: since this was a cross-sectional study, we cannot draw any conclusions as to causal relationships between insulin resistance and cIMT. We also cannot exclude parameters other than the classical metabolic factors causing linkage between our findings such as non-esterified fatty acids.