Previous studies reported that RHI correlates with vascular endothelial dysfunction and is a risk factor for the onset of cardiovascular events[12, 19, 20]. Based on this background, we used RHI as an index of vascular endothelial dysfunction. This study clarifies the relationship between vascular endothelial function and glucose metabolism, in particular, fluctuations in blood glucose levels.
While there was no relationship between L_RHI and indexes of mean hyperglycemia such as HbA1c and/or mean blood glucose level, vascular endothelial dysfunction correlated with SD, MAGE, MPPGE and the percentage of time spent with glucose ≥200 mg/dl, a measure of fluctuation of blood glucose level and known to denote acute hyperglycemia, as well as with the percentage of time at hypoglycemia. Furthermore, multivariate analysis identified MAGE as the only determinant of vascular endothelial dysfunction in this study. Vascular endothelial dysfunction occurs in the early stage of atherosclerogenesis and is involved in the progression of atherosclerosis. Buscemi et al. reported that glycemic variability influenced endothelial function even in non-diabetic subjects. Monnier et al. indicated that large fluctuations in postprandial blood glucose levels measured by CGM increased oxidative stress more than high blood glucose levels with HbA1c as an index. Using the glucose clamp method, Ceriello et al. reported that worsening of oxidative stress in association with blood glucose fluctuations resulted in endothelial deterioration and dysfunction that exceeded the harmful effects of constantly high blood glucose levels. Recently, Rizzo et al. reported that MAGE reduction is associated with reduction of oxidative stress and markers of systemic inflammation by treatment of dipeptidyl peptidase-IV inhibitor in type 2 diabetic patients. Monnier et al. reported that any strategy should target markers of glycemic variability such as MAGE to limit the risk of complications. The present study examined the relationship between blood glucose fluctuations and endothelial dysfunction using instruments commonly available in clinical practice, i.e., CGM and PAT.
In cases with normal glucose tolerance, vascular endothelial function correlates with postprandial glucose fluctuation, insulin resistance, and postprandial serum insulin level, and within the normoglycemic range, individuals whose 2-h plasma glucose levels did not return to their fasting plasma glucose levels during OGTT had elevated fasting insulin levels and increased incidence of coronary heart disease. Patients with mild abnormalities in glucose metabolism are reported to suffer from endothelial dysfunction. Transient hyperglycemia induces oxidative stress, the release of proinflammatory cytokines, increases reactive oxygen species (ROS), and reduces NO production in association with increased levels of asymmetric dimethylarginine (ADMA). These reactions are mediated through the translocation and activation of nuclear factor-κB (NF-κB) and the products are thought to be involved in vascular endothelial dysfunction. Su et al. reported that glucose excursion and hs-CRP are associated with the presence and severity of CAD and that glycemic variability measured by CGM correlates with interleukin-6 (IL-6) concentration. The present study also demonstrated that vascular endothelial dysfunction also correlated with MPPGE and the time spent at blood glucose level of ≥200 mg/dl, in addition to postprandial hyperglycemia. In agreement with Di Flaviani et al., established postprandial hyperglycemia is a detrimental factor in reduced flow-mediated vasodilation and activation of oxidative stress is associated with increased glucose variability in type 2 diabetes. In contrast, Peña et al. reported that glucose variability, as measured by CGM, is not associated with vascular function in type 1 diabetes. This highlights possible differences in the role of glucose variability in arteriosclerosis in type 1 and type 2 diabetes.
Although the sample size was very small, the results of the present study highlighted the role of hypoglycemia in vascular endothelial dysfunction. There was no significant difference in the reduction of risk for macrovascular complications between the standard treatment and consolidation treatment groups in the ACCORD study; rather, the total number of deaths was significantly higher, and the number of sudden cardiovascular deaths was also higher in patients with severe hypoglycemia. What are the underlying mechanisms of the poor outcome in patients with hypoglycemia? While the present study did not investigate this important question, others have reported the potential roles of sympathetic nerve activation, proinflammatory cytokine secretion, and activation of coagulation factors in hypoglycemic-induced cardiovascular events.
In a large community-based cohort, the factors associated with L_RHI were male sex, diabetes mellitus, use of anti-hypertension drugs and the ratio of total cholesterol to HDL cholesterol. However, in that study, L_RHI values did not correlate with male sex, hypertension drugs or markers of cholesterol metabolism. The difference in L_RHI between men and women was related to sex-specific determinants of endothelial function or, alternatively, to the presence of higher baseline pulse amplitude in men compared to women. In the present study, there was no difference in baseline pulse amplitude between males and females, which may explain why there was no difference in L_RHI values.
The present study has certain limitations. First, the subjects were patients admitted to the hospital. The mean blood glucose level measured by CGM was 176.5 mg/dl (9.8 mmol/l). However, the mean HbA1c of the patients was 9.0%; thus, the calculated mean blood glucose level corresponding to this HbA1c value is 234.6 mg/dl (13.0 mmol/l). This discrepancy was possibly related to the strict diet provided during hospitalization. Second, the results showed no correlation between L_RHI and a marker of fasting cholesterol metabolism. This finding was probably related to the small sample size and treatment of approximately half of the patients with statin. Third, this study was cross-sectional, which precluded evaluation of the cause–effect relationship between glycemic variability and vascular function. Fourth, we could not assess the relationship between oxidative stress or inflammation and PAT. Fifth, the sample size in the present study was relatively small; therefore, subgroup comparisons may lack statistical power. Finally, because the number of subjects in the present study was small, our results should be verified in another study that includes a larger number of subjects.