The present study has demonstrated attenuation of postprandial FMD, both after ingestion of a test meal and after oral glucose loading, which was correlated with variables of glucose metabolism. However, the relationship between the postprandial FMD attenuation and glucose metabolic variables differed between the ingestion of a test meal and oral glucose loading.
Although PG and IRI levels in the OG group were higher than those in the TM group, the FMD60 was similar in both groups. The FMD60 was correlated only with the HOMA-IR, and no significant association was found between HOMA-IR and FMD120. In fact, the change from FMD0 to FMD60 did not differ significantly between the TM group and the OG group. These results suggest that insulin resistance is associated with short-term, but not long-term, attenuation of vascular endothelial function both after test meal ingestion and after oral glucose loading. Oral antidiabetic agents, such as pioglitazone, that decrease insulin resistance also improve endothelial function in patients with diabetes [22
] or impaired glucose tolerance [23
]. Improvement of fasting FMD is correlated with improvement of insulin resistance [24
]. The brachial artery FMD is correlated with the euglycemic hyperinsulinemic glucose clamp-derived glucose metabolic clearance rate in normotensive first-degree relatives of patients with type 2 diabetes [25
]. We speculate that the delay in glucose metabolic clearance in patients with insulin resistance induces greater attenuation of postprandial FMD in subjects with insulin resistance than in subjects with normal insulin sensitivity.
In contrast, although FMD showed a continuous decrease in the OG group, it did not decrease in the TM group during study period. The change in FMD from 0 to 120
minutes after loading was significantly correlated with the CV of PG, IRI60, and the AUC of IRI. These findings suggest that FMD120 in our subjects was associated with the magnitude of elevation and fluctuation of both postprandial PG and IRI. Endothelial dysfunction in diabetes has been attributed to elevated oxidative stress levels induced by several mechanisms, especially abnormalities in glucose metabolism [26
]. In fact, endothelial dysfunction is improved by oral antidiabetic agents in patients with type 2 diabetes [22
]. These agents ameliorate abnormalities in glucose metabolism and, as a result, reduce oxidative stress in patients with diabetes. Both FMD and PG levels are significantly correlated with plasma levels of thiobarbituric acid reactive substances during oral glucose tolerance testing in subjects with normal glucose tolerance who have first-degree relatives with type 2 diabetes [9
] and in subjects with impaired glucose tolerance [10
]. Acarbose, nateglinide, and mitiglinide have been reported to decrease postprandial hyperglycemia and to improve endothelial function in patients with type 2 diabetes [27
] and in patients with impaired glucose tolerance [32
]. Furthermore, repetitive fluctuations in PG or insulin reportedly enhance monocyte adhesion to the endothelium of the rat thoracic aorta, and stable hyperglycemia or hyperinsulinemia has been found to cause less monocyte adhesion than does repetitive PG fluctuation [33
]. These previous findings and the results of our present study suggest that the difference in oxidative stress induced by the difference in postprandial hyperglycemia between the TM and OG groups caused the difference in attenuation of FMD120 in our subjects with normal glucose tolerance.
Our study has also demonstrated that the attenuation of postprandial FMD is significantly associated with plasma insulin levels in subjects with normal glucose tolerance. Plasma insulin is generally considered to have a beneficial effect on vascular endothelial function [34
]. In contrast, insulin resistance reduces the bioavailability of endothelial nitric oxide. Insulin resistance decreases the number of endothelial progenitor cells and hinders the vascular repair induced by disturbed PI3K/AKt signaling, reactive oxygen species, inflammation, and adipokines [35
]. The continuous infusion of insulin with an euglycemic or hyperglycemic clamp causes attenuation of femoral and brachial artery endothelium-dependent vasodilation 4
hours after baseline, and attenuation of FMD induced by insulin is inhibited by the addition of an antioxidant agent (vitamin C) [36
]; however, endothelium-independent vasodilation is not attenuated by insulin. These findings suggest that a high plasma level of insulin in the postprandial state attenuates postprandial FMD and delays the recovery of FMD after absorption of PG.
Our study had several limitations. First, we could not evaluate the effect of postprandial lipid metabolism on postprandial FMD. We had concluded that the effect of 22
g of fat in the meal ingested by the TM group could be ignored. Accordingly, we measured FMD from baseline to 120
minutes after loading following the method of Lavi et al. [13
]. However, several studies have shown that postprandial attenuation of FMD induced by fat lasts for more than 120
minutes after fat loading [15
]. Therefore, a study measuring postprandial FMD for more than 120
minutes after loading is needed to clarify the effects of dietary fat intake observed in the present study. Second, Major-Pedersen et al. have reported, in contrast with our present results, that oral glucose does not induce endothelial dysfunction in healthy persons with mean insulin and PG values of 5.6
mmol/L and 27.2
mmol/L, respectively, 2
hours after a glucose load [37
]. However, the study of Major-Petersen et al. and the present study differ in the methods of FMD measurement and the characteristics of subjects. For example, the effects of reactive hyperemia on the sympathetic nerve might differ because Major-Petersen et al. used a sphygmomanometric cuff pressure that was higher (300
mm Hg) than the pressure we used (systolic blood pressure
mm Hg). Also, the subjects of Major-Petersen et al. might have been healthier than ours because they had a lower mean fasting PG level. Furthermore, the peak PG and IRI levels that induced postprandial attenuation of FMD might have appeared less than 30
minutes after loading because the mean age of subjects in our TM group was 28.5
]. Therefore, the conflicting results between the present study and the study of Major-Petersen et al. might be attributed to these differences. Third, we could not assess the relationship between oxidative stress and FMD in our subjects. It is necessary to evaluate the effects of postprandial lipid metabolism, heart rate, blood pressure, and oxidative stress on postprandial FMD. Fourth, the study population of our study was a composite group with a wide range of PG and IRI levels, whereas our study subjects had been identified with medical checkups to have normal glucose tolerance. A cross-over study should be performed to resolve these problems. Finally, because the number of subjects in the present study was small, our results should be clarified with a larger number of subjects.
In summary, our study suggests that attenuation of brachial artery FMD in the postprandial state is correlated with postprandial glucose fluctuation, insulin resistance, and the postprandial serum insulin level in non-diabetic individuals. Furthermore, differences in the attenuation of postprandial vascular endothelial function induced by different postprandial insulin levels may occur a long time postprandially but not shortly after a meal.
Further longitudinal studies are necessary in subjects with normal glucose tolerance to investigate the long-term effects of postprandial glucose metabolism on endothelial function and the possible contribution of this endothelial dysfunction to the development of atherosclerosis.