In the current study in T2DM patients, indices of vascular function were found to be inter-related suggesting that they probably reflect overlapping pathophysiological aspects of the vascular atherosclerotic damage in T2DM patients. Further to this finding, markers of endothelial function (FMD), smooth muscle cell function (NMD) and large artery stiffness (PWV) were shown to share common correlates. Older age, longer duration of diabetes and treatment with insulin were associated with all markers of vascular dysfunction, although each marker appeared to be independently associated with specific distinct parameters.
Previous studies comparing patients with T2DM to healthy controls have shown that T2DM is an independent risk factor for endothelial dysfunction [14
]. The greater cardiovascular mortality risk observed in T2DM patients has been mainly attributed to vascular endothelial dysfunction [17
]. In T2DM patients without macrovascular or microvascular disease, we found that endothelial dysfunction, as assessed by reduced brachial artery FMD, was independently associated only with the duration of diabetes; for every 10 years of diabetes, FMD is reduced by approximately 1.0% (in absolute FMD values). Previous studies have shown significant associations of FMD with diabetes duration [29
] although not consistently [31
]. Longer T2DM duration has also been shown to increase CVD risk and total mortality significantly even after adjustment for established and novel cardiovascular risk factors [32
] suggesting that there might be a link between T2DM duration, worsening endothelial function and cardiovascular prognosis in these patients. Furthermore, we showed that impairment of endothelial function in T2DM patients was not related to the presence or levels of various established cardiovascular risk factors, vascular inflammation or glycemic control. In accordance with our findings previously reported data have not shown an association of glycemic control with endothelial dysfunction [31
]. On the other hand, endothelial dysfunction has been previously related to the presence and levels of cardiovascular risk factors in T2DM patients [23
], although not consistently [34
], while vascular inflammation has been suggested to play a central role in the development of endothelial dysfunction [35
]. It should be noted that compared to other reports [23
], our study included T2DM patients with severely impaired FMD (mean FMD 1.98%) and a high prevalence of accumulated cardiovascular risk factors; in these patients longer duration of diabetes, and not other established cardiovascular risk factors, was the only important determinant of endothelial dysfunction. Diabetes duration may appear to be a more important contributor to endothelial dysfunction compared to indices of short-term glycaemic control or other isolated risk factors as it may reflect the total exposure of the endothelium to diabetes and hyperglycaemia (metabolic memory) [36
] as well as other diabetes-related comorbidities (hypertension, dyslipidemia, obesity).
Vascular smooth muscle cell dysfunction has been previously shown in T2DM patients compared to healthy controls in addition to endothelial dysfunction [11
] indicating that T2DM may both reduce the bioavailability of endothelial nitric oxide and attenuate smooth muscle cells’ sensitivity to nitric oxide; these findings have not been consistently replicated in all studies [12
]. Vascular smooth muscle cell dysfunction has been previously reported in populations at high cardiovascular risk [38
] and a prognostic role has been suggested in such individuals [4
]. In our study, decreased NMD was independently associated with older age, the presence of hypertension and higher fasting glucose. Several previous studies have not shown any significant associations of NMD with risk factors, glycemic control, inflammation or other diabetes-related factors in T2DM patients [13
]. In agreement with our findings, hyperglycemia was recently reported to be an independent predictor of impaired NMD in T1DM patients [40
]. Hyperglycemia, by increasing advanced glycation end-products and oxidative stress in the vascular wall, may be associated with a decreased response of vascular smooth muscle cells [15
Arterial stiffness, as assessed by PWV, has been found to be increased both in prediabetes [41
] and in T2DM patients compared to healthy controls [7
]. Increased PWV has been associated with a worse cardiovascular prognosis in high risk patients [3
] including T2DM patients [7
]. In the present study, increased PWV in T2DM patients was independently associated with older age and higher systolic blood pressure values confirming well established knowledge. Both age and blood pressure are considered to be the two most important determinants of PWV in the general population [42
] as well as in T2DM patients [9
]. In contrast to previous studies we found no association of PWV with glycemic control in T2DM patients [9
]. Furthermore, although inflammation, as assessed by hs-CRP, has been suggested to related to increased PWV in healthy subjects [45
] as well as in hypertensive [46
] and T2DM [47
] patients, this has not been replicated in our study.
Our population consisted of patients with T2DM with moderate glycaemic control and less than optimal control of other cardiovascular risk factors (blood pressure, cholesterol, obesity). These results cannot be extrapolated to all patients with T2DM; it is possible that including patients with optimal control of risk factors, important associations of risk factors with vascular indices may be revealed. Finally, whether interventions to improve these risk factors may have a beneficial effect on vascular indices has not been clarified in recent studies [34
], and cannot be precluded from this study.
This was an observational study that could not reveal causal relationships. Furthermore, regression models in our study could predict a small part of the variability of vascular indices (5–25%) in our population indicating that other factors, not currently studied (e.g. insulin resistance, advanced glycation end-products, genetic factors) may play a more important role in vascular dysfunction in T2DM. Common insulin resistance/sensitivity indices were not assessed because a high proportion of the studied patients were receiving exogenous insulin.